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TECHNICAL FIELD
The present invention relates to anti-brain-tumor drugs.
BACKGROUND ART
After a drug is administered to a living body, it reaches an affected site and exerts its pharmacological effects at that affected site, thereby exerting its therapeutic effects. On the other hand, even if the drug reaches tissue other than the affected site (that is, normal tissue), it will not be therapeutic, but also cause adverse reactions.
Therefore, how to guide the drug to the affected site is important in terms of therapeutic strategies. A technique to guide the drug to the affected site is called drug delivery, which has been actively studied and developed recently. This drug delivery has at least two advantages.
One advantage is that a sufficiently high drug concentration can be obtained at the affected site tissue. Pharmacological effects will not be seen unless the drug concentration at the affected site is a constant value or more. This is because the therapeutic effects cannot be expected if the concentration is low. The second advantage is that the drug is guided to only the affected site tissue and will not be guided to the normal tissue unnecessarily. As a result, adverse reactions can be inhibited.
Such drug delivery is most effective for a cancer treatment by anti-tumor agents. Most anti-tumor agents inhibit the cell growth of cancer cells which divide actively, so that the anti-tumor agents will also inhibit the cell growth of even the normal tissue in which cells divide actively, such as bone marrow, hair roots, or alimentary canal mucosa.
Therefore, cancer patients to whom the anti-tumor agents are administered suffer adverse reactions such as anemia, hair loss, and vomiting. Since such adverse reactions impose heavy burdens on the patients, the dosage needs to be limited, thereby causing a problem of incapability to sufficiently obtain the pharmacological effects of the anti-tumor agents.
So, it is expected to inhibit the adverse reactions and perform the cancer treatment effectively by guiding the anti-tumor agents to the cancer cells by means of the drug delivery and making the anti-tumor agents exert the pharmacological effects intensively on the cancer cells.
The applicant of the present application suggested an iron-salen complex as an example of such anti-tumor agents. Since this iron-salen complex is magnetic itself, it can be guided to the target affected site tissue by means of an external magnetic field without using a magnetic carrier. (See, for example, Patent Literature 1).
Citation List
Patent Literature
[Patent Literature 1] Japanese Patent Application Laid-Open (Kokai) Publication No. 2009-173631
SUMMARY OF INVENTION
After thorough examination, the inventors of the present invention have found that the above-described iron-salen complex cannot pass a blood-brain barrier, thereby causing a problem of insufficient applicability to a brain tumor.
Therefore, it is an object of the present invention to provide a metal-salen complex effective for the brain tumor.
After thorough examination, the inventors of the present invention have found that a metal-salen complex compound with a functional group constituting anions bonded to a trivalent metal atom is bonded has the property to be capable of passing the blood-brain barrier while maintaining its magnetism; and the metal-salen complex compound can be guided selectively from blood vessels to the brain tumor by applying the external magnetic field to the affected site where the brain tumor is located. Examples of the functional group constituting this type of anions include halogen atoms, a hydroxyl group, an amide group, and a carboxyl group and a preferred example of the functional group is halogen atoms, among which particularly a chlorine atom is desirable.
Specifically speaking, for example, an anti-brain-tumor drug is characterized in that it contains a metal-salen complex compound represented by the following Chemical Formula (I), a pharmacologically-allowable derivative, and/or a pharmacologically-allowable salt.
In the formula (I), M represents Fe (iron), Cr (chromium), Mn (manganese), Co (cobalt), Ni (nickel), Mo (molybdenum), Ru (rubidium), Rh (rhodium), Pd (palladium), W (tungsten), Re (rhenium), Os (osmium), Ir (iridium), Pt (platinum), Nd (niobium), Sm (samarium), Eu (europium), or Gd (gadolinium); at least one of a to j is a substituent that maintains the effects of the metal-salen complex, and the rest of them is hydrogen; and X represents a halogen atom. Such a substituent is described in, for example, WO2010/058280. A preferred metal-salen complex compound is structured so that M is an iron atom, X is a chlorine atom, and all of a to j are hydrogen atoms.
Advantageous Effects of Invention
A metal-salen complex compound having the therapeutic effects for the brain tumor can be provided according to the present invention as described above.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a side view (diagrammatic illustration) of a state where a magnet rod is made to be in contact with a square-type flask containing a culture medium of rat L6 cells.
FIG. 2 is a graph showing the calculation results of the number of cells by taking an image from one end to the other end of the bottom of the square-type flask after 48 hours.
FIG. 3 is a perspective view showing an example of a magnetic delivery device.
FIG. 4 is a graph showing the magnetic property of the metal-salen complex compound.
FIG. 5 is a molecular model showing a first structure of the iron-salen complex compound.
FIG. 6 is a molecular model showing a second structure of the iron-salen complex compound.
DESCRIPTION OF EMBODIMENTS
<Synthesis of Iron-Salen Complex (Chemical Formula I)>
A mixture of 4-nitrophenol (Compound 1) (25 g, 0.18 mol), hexamethylene tetramine (25g, 0.18 mol), and polyphosphoric acid (200 ml) were stirred for one hour at the temperature of 100 degrees Celsius. Then, that mixture was introduced to 500 ml of ethyl acetate and 1 L (liter) of water and stirred until it completely dissolves. Furthermore, when 400 ml of ethyl acetate was added to that solution, the solution separated into two phases. Subsequently, the aqueous phase was removed from the solution which separated into the two phases; and the remaining compound was washed twice with a basic solvent and dried over anhydrous MgSO 4 (magnesium sulfate). As a result, 17 g of Compound 2 (57% yield) was synthesized.
Compound 2 (17g, 0.10 mol), acetic anhydride (200 ml) and H 2 SO 4 (minimal) were stirred for one hour at room temperature. The resulting solution was mixed for 0.5 hour in iced water (2 L) to bring about hydrolysis. The resulting solution was filtered and dried in air, thereby obtaining white powder. The powder was recrystallized, using a solvent containing ethyl acetate. As a result, 24 g of Compound 3 (76% yield) was obtained in the form of white crystals.
A mixture of carbon (2.4 g) supporting 10% palladium with Compound 3 (24 g, 77 mol) and methanol (500 ml) was reduced over night in a 1.5 atm hydrogen reducing atmosphere. After the reduction was completed, the product was filtered, thereby allowing 21 g of Compound 4 in the form of brown oil to be synthesized.
Compound 4 (21 g, 75 mmol) and di(tert-butyl)dicarbonate (18 g, 82 mmol) were stirred over night in anhydrous dichloromethane (DCM) (200 ml) in a nitrogen atmosphere. The resulting solution (Compound 5) was allowed to evaporate in a vacuum and then dissolved in methanol (100 ml). Sodium hydroxide (15 g, 374 mmol) and water (50 ml) were then added and the solution was brought to reflux for 5 hours. The solution was then cooled, filtered, washed with water, and allowed to dry in a vacuum, thereby obtaining a brown compound. The resulting compound was processed twice by flash chromatography using silica gel, thereby obtaining 10 g of Compound 6 (58% yield).
Compound 6 (10 g, 42 mmol) was introduced into 400 ml of anhydrous ethanol, the mixture was brought to reflux while heated, and several drops of ethylene diamine (1.3 g, 21 mmol) were added into 20 ml of anhydrous ethanol while stirred for 0.5 hour. The mixture was introduced into a container of ice, where it was cooled and mixed for 15 minutes. It was then washed with 200 ml of ethanol, filtered, and dried in a vacuum, thereby obtaining 8.5 g (82% yield) of Compound 7.
Compound 7 (8.2 g, 16 mmol) and triethylamine (22 ml, 160 mmol) were introduced into N,N-dimethylformamide (abbreviated as DMF) (50 ml), and a solution of FeCI 3 .4H 2 O (iron (III) chloride solution) (2.7 g, 16 mmol) added to 10 ml of methanol was mixed in a nitrogen atmosphere. The ingredients were mixed for 30 minutes in a nitrogen atmosphere at the temperature of 40 degrees Celsius, thereby obtaining a brown compound.
Subsequently, this compound was then dried in a vacuum. The resulting compound was diluted with 400 ml of dichloromethane, washed twice with a basic solution, dried in Na 2 SO 4 (sodium sulfate), and dried in a vacuum, thereby obtaining an iron-salen complex. The resulting compound was recrystallized in a solution of diethyl ether and paraffin, and assay by high performance liquid chromatography revealed 5.7 g (62% yield) of the iron-salen complex with a purity of 95% or higher.
<Pharmacological Effects of Iron-Salen Complex (Chemical Formula (I))>
Powder of the iron-salen complex compound represented by Chemical Formula (I) was applied, in an amount (50 mg) to the degree allowing its magnetic attraction to be visibly observed, to a culture medium when the rat L6 cells were in a 30% confluent state; and the state of the culture medium was photographed after 48 hours.
FIG. 1 shows a state in which a magnet rod is in contact with a square-type flask containing the rat L6 cell culture medium. After 48 hours, an image of the bottom of the square-type flask was photographed from one end to the other end and the number of cells was calculated. This result is shown in FIG. 2 .
Referring to FIG. 2 , a proximal position from the magnet indicates within a project area of the magnet end face on the bottom of the square-type flask and a distal position from the magnet indicates an area on the opposite side of the magnet end face on the bottom of the square-type flask. FIG. 2 shows that a concentration of the iron complex increases as the iron complex is attracted at the proximal position from the magnet. So, it can be seen that the number of cells becomes extremely lower than that at the distal position due to a DNA-growth inhibition action of the iron complex.
Next, an embodiment in which a magnetic field is applied from a delivery device to an individual and the iron-salen complex is guided to the individual's brain will be explained. With this delivery device, as illustrated in FIG. 3 , a pair of magnets 230 and 232 facing each other in the direction of gravity are supported by a stand 234 and a clamp 235 , and a metal plate 236 is located between the magnets 230 and 232 . A magnetic field of uniform strength can be created locally by placing the metal plate 236 , especially an iron plate, between the pair of magnets 230 and 232 .
Incidentally, an electrical magnet can be used instead of the magnet to modify the magnetic force generated in this delivery device. The magnetism-generating means can be moved to a target position of the individual on a table to allow the pair of magnetism-generating means to move in X, Y, and Z directions.
The drug can be concentrated on specific tissue by placing the individual in the region of the magnetic field. After intravenously injecting the aforementioned metal complex (drug concentration: 5 mg/ml (15 mmol)) to veins of a tail of a mouse weighing about 30 g, the mouse's head was placed between the magnets. Another individual to which the iron-salen complex was applied under the same conditions without applying the magnetic field was prepared as a comparison target. Incidentally, the individual to which the magnetic field is applied will be referred to as the specimen and the individual to which the magnetic field is not applied will be referred to as the object.
The magnets used were Product No. N50 (neodymium permanent magnets) by Shin-Etsu Kagaku Kogyo, with a residual flux density of 1.39 to 1.44 tesla (T). The mice's brains were removed after the experiments and staining (Prussian blue; ferric hexaacyanoferrate and hydrochloric acid, Sigma) was applied to them. As a result of comparison between the specimen and the object, the brain tissue of the specimen was stained blue.
23% of the brain tumor, which is a brain cancer, is a cancer called meningioma that is produced in the meninges (area closest to the skull in the skull). The compound of Chemical Formula (I) can be guided efficiently from the veins to the meninges. Since the magnetic field is applied externally, the compound of Chemical Formula (I) is effective for particularly the meningioma produced at the meninges immediately below the skull.
<Magnetism of Iron-Salen Complex>
When a magnetic field-magnetization curve of the iron-salen complex (Chemical Formula (I)) was measured at the temperature of 37 degrees Celsius (310K) by using MPMS7 by Quantum Design, Inc., paramagnetism was observed as shown in FIG. 4 . As a result, the metal-salen complex can be guided selectively to a tumor-produced site in the head by exogenously applying 8000 Oe (0.8 T) magnetic field intensity to the tumor-produced site of the head. The magnetic field intensity within the range from 0.5 T to 0.8 T is desirable for use in guiding the drug to the head.
<Crystal Analysis>
A single crystal analysis of the iron-salen complex (Chemical Formula (I)) was performed by using Super Photon Ring -8 (Spring-8). The details of X-ray structure analysis are as follows.
Used Facility: Spring-8 Provisional Irradiation Conditions: five crystals were selected and provisional irradiation was performed under the following conditions. Detector: imaging plate Camera length: 190 mm Wavelength: 0.0710690 nm Vibrational angle: 2.0 degrees Exposure time: 30 seconds Measuring range: 0 to 20 degrees Measurement temperature: −173 degrees Celsius
As a result of the provisional irradiation, it was judged with respect to one of the five crystals that its diffraction pattern was comparatively clear and the structure analysis can be performed. So, that crystal was decided to be a target of actual irradiation.
Actual Irradiation Conditions: the actual irradiation was performed under the following conditions.
Detector: imaging plate Camera length: 190 mm Wavelength: 0.0710690 nm Vibrational angle: 1.0 degrees Exposure time: 90 seconds Measuring range: −90 to +90 degrees Measurement temperature: −173 degrees Celsius
As a result of processing of 180 pieces of image data obtained by the actual irradiation, crystal parameters were decided as follows.
Crystal system: monoclinic Lattice constants: a=14.34(6) Å b=6.907(16) Å c=14.79(4) Å β=96.73(4) degrees V=1455(8) Å 3 Space group: P21/n (#14) Z value: 4 Measurement scale: −90° to 90°
As a result of analysis by a direct method, a predicted complex structure ( FIG. 5 ) was confirmed; however, the existence of an unknown peak was observed near the Fe atom. It was thought based on the distance from the Fe atom and the peak height that it must be an atom other than C, H, Fe, N, or O. As a result of EPMA analysis performed in order to identify the unknown peak, the existence of chlorine was found. Furthermore, when the result of EI/MS measurement was checked, chlorine adducts were detected. As a result, the unknown peak was judged as the chlorine atom.
A refined final molecular structure is shown in FIG. 6 . Since each parameter did not particularly show any abnormal value in the result of a last cycle of a method of least squares, it was determined that the last structure shows an accurate composition. Incidentally, it was found that two molecules in the crystal form an aggregate (dinuclear complex) via the Fe and O atoms.
<Water Solubility of Iron Complex Compound (Chemical Formula I)>
Free energy of water solubility of the chemical formula I was calculated by using a first principle calculation. The entire first principle calculation is based on density functional formalism. An all-electron method of considering all electrons is used with respect to interactions between electrons and ions.
Regarding a wave function, a double-numeric basis function (Double Numerical basis-set including Polarization function, DNP) to which a polarization function is added for a spin-polarized, linear-combination atomic orbitals (Liner Combination of Atomic Orbitals, LCAO) was used and cutoff of the above-mentioned basis function was set to 0.4 nm in order to increase the calculation speed without impairing the calculation accuracy.
Exchange correlation term by Becke, Lee, Yang, Parr were used and software used was DMol3 by Accelrys K.K. The energy of water solubility was calculated by a method by Andreas Klamt, COSMO-RS: From Quantum Chemistry to Fluid Phase Thermodynamics and Drug Design, 2005, Elsevier. As a result, the free energy of water solubility of the iron-salen complex of the following Chemical Formula (II) was −20.13 kcal/mol. On the other hand, the free energy of water solubility of the iron chloride-salen complex of Chemical Formula (I) was −31.95 kcal/mol, so that the chlorine-added iron-salen complex of Chemical Formula (I) has higher water solubility. | A drug containing a metal-salen complex compound which is effective for a brain tumor is provided. The present invention is an anti-brain-tumor drug containing a metal-salen complex compound represented by the following Chemical Formula (I). In the formula, M represents a metal atom which is Fe, Cr, Mn, Co, Ni, Mo, Ru, Rh, Pd, W, Re, Os, Ir, Pt, Nd, Sm, Eu, or Gd, and X represents a halogen atom. | 2 |
This application is a division of application number 07/790,115, filed Nov. 12, 1991, now U.S. Pat. No. 5,260,106, which in turn is a continuation of application Ser. No. 07/562,606, filed Aug. 3, 1990 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and apparatus for vapor deposition of diamond film. More, specifically, it relates to a highly efficient method and apparatus for uniformly vapor depositing a diamond film having superior adhesiveness, superior hardness, and smoothness onto a treated object or substrate and also for depositing a diamond film onto a carburizing material.
2. Description of the Related Art
Diamond is a allotropic form of carbon (C), which exhibits a diamond structure, has a high Mohs hardness of 10, and has a superior thermal conductivity of 1000 or 2000 W/mK, compared with other materials. Therefore, various applications have been developed for using these characteristics.
For example, because of its high hardness, diamond has been considered for use in connection with drill blades or bits. Attempts have been made to cover such tools, which are made of high hardness sintered alloys such as tungsten carbide (WC), with a diamond film. Further, because of its high heat conductivity, diamond has been utilized as a heat sink for LSI, VLSI, laser diode or other semiconductor devices.
When coating a diamond film on a tool made of tungsten carbide (WC) or molybdenum carbide (MoC), even if a chemical vapor deposition apparatus (abbreviated as a "CVD" apparatus) is used similar to that shown in FIG. 1 and the film is grown directly by chemical vapor deposition (abbreviated as "CVD"), the film peels off easily due to differences in the coefficients of heat expansion.
The operation of the above-mentioned known apparatus is as follows.
An object (for example, a tool) to be treated or substrate is placed on a substrate holder 3 cooled by cooling water 2. At the top of the reaction chamber 4 is an anode 6 and a cathode 7 for forming a plasma jet 5. A starting gas 8 is supplied between the anode and the cathode. A DC power source 10 is provided connecting the anode 6 and the cathode 7. At the bottom of the reaction chamber 4 is an exhaust outlet 11. For the CVD growth of diamond, a mixed gas 8 of hydrogen (H 2 ) and a hydrocarbon, for example methane (CH 4 ), is supplied so as to flow between the anode 6 and the cathode 7 and into the interior of the reaction chamber 4. The exhaust system is operated to exhaust chamber 4 through the exhaust outlet 11 and the inside of the reaction chamber 4 is held at a low vacuum, in which state are arc discharge 12 is caused between the anode 6 and the cathode 7, the heat of which causes decomposition and plasmatization of the starting gas 8, whereupon the plasma jet 5 including carbon plasma strikes the metal plate 1 and a diamond film 13 composed of fine crystals is grown on the metal plate 1. Thus, it is possible to grow a diamond film 13 on the treated object 1, but since the coefficients of heat expansion differ (for example, the linear expansion coefficient of diamond is 0.0132×10 -4 K -1 , while that of W is 0.045×10 -4 K -1 ) and since the temperature is decreased from the high temperature of 800° C. or more at which the CVD reaction is performed to ordinary temperature, the diamond film 13 easily peels off of the treated object 1.
Therefore, in the prior art, when coating a diamond film on a tool made of WC, for example, elements (for example of Co) included in the WC as sintering reinforcements and for causing a reduction of the adhesiveness were chemically removed, and then the CVD method was used to grow the diamond film. Alternatively, mechanical scratches were made in the substrate and the growth was performed over the same. However, since adhesiveness decreases with film thickness, the thickness of the grown film was limited to several μm, and even so the adhesiveness was insufficient for practical use. The present inventors previously proposed, as a method for resolving this problem, the provision of a coating material layer 15 with a coefficient of heat expansion close to diamond on the treated object 1, as shown in FIG. 2, and the growth of a diamond film 13 on the same (Japanese Unexamined Patent Publication (Kokai) No. 1-145313 published Jun. 7, 1989). However, when actually used, the adhesiveness provided was still not satisfactory for tool use.
As mentioned above, diamond has the highest hardness among all materials, so attempts have been made to use it to form drill blades and bits. However, when diamond is coated on a tool made of WC, for example, the coating easily peels off since the heat expansion coefficients differ and therefore this has not been commercialized.
As mentioned earlier, since diamond has a high heat conductivity, it has been considered for use as a heat sink for semiconductor devices and is being commercialized for this. FIG. 2A is a perspective view of a cooling structure, wherein a heat sink 15 comprised of a diamond is brazed by gold on a subcarrier 14 comprised of cooper (Cu). On top of this heat sink 15 is bonded a semiconductor laser or other semiconductor chip 16 by, for example, gold-tin solder.
FIG. 2B shows the sectional structure of the heat sink 15, wherein a titanium (Ti) film 18, platinum (Pt) film 19, and gold (Au) film 20 are formed in successive layers at thicknesses of about 2000 Å respectively. The reason why the Ti film 18 is used is that it forms titanium carbide (TiC) with the diamond film 17 and has a good adhesiveness. Further, the reason why the Pt film 19 is interposed is so as to correct the poor wettabilities of the Ti film 18 and Au film 20. However, such a heat sink 15 suffers considerably from the effects of the heat conductivities of the metal films enclosing it and from the complicated nature of the structure. Further, the bonding of the separate layers requires high temperature, so the semiconductor chip can easily be damaged, or the bonding requires special skills, so the price becomes high.
With reference to the apparatus of FIG. 1, when plate 1 plated on a substrate holder 3 is cooled by cooling water 2, it becomes possible to form a diamond film 13 thereon.
As mentioned above, diamond has an extremely superior heat conductivity of 2000 W/mK, so it is being commercialized as a component material for heat sinks, but as shown in FIG. 2B, a Ti/Pt/Au metal film is formed in layers on the diamond film. Therefore, there are the problems that the heat conductivity of the diamond is impaired and the cost becomes higher.
Furthermore, as mentioned above, diamond is used for high performance tools utilizing its hardness, and is used as heat sinks for devices where there is a large generation of heat such as laser diodes because it has a high heat conductivity which is several times that of copper. However, the surfaces of conventional thick diamond films have been very rough and the use of these films has required polishing of the surface with a diamond disk etc. This polishing work has required considerable time and labor. The density of nucleus production of diamond is 10 7 to 10 9 cm -2 , a density which is much smaller than the density of other materials (10 13 ), therefore specific crystal particles selectively grow and the surface becomes very rough. In particular, this trend is striking in the case of thick diamond films (a roughness of about 0.2 mm with film thicknesses of 2 mm).
Furthermore, as mentioned above, attempts have been made to cover tools with diamond to utilize its high hardness. As methods for synthesizing diamonds, there are known the high pressure synthesis method and the low pressure synthesis method. The high pressure synthesis method is suitable for forming relatively large sized monocrystals, but the apparatus is cumbersome and the speed of growth is very slow, so there is the problem of a higher cost. As opposed to this, the low pressure synthesis method includes the microwave plasma chemical vapor deposition method and the electron assisted chemical vapor deposition method. The speed of growth is much higher compared with the high pressure method and it is possible to form diamond as fine crystals on the treated substrate.
Contrary to the above, the present inventors have developed a method for chemical vapor deposition (CVD) of a diamond film using the plasma jet chemical vapor growth apparatus shown in FIG. 1, as mentioned above. However, to cause the growth of the diamond film by plasma jet CVD, a carbon source such as CH 4 or other hydrocarbon must be heated rapidly to a high temperature in the arc discharge region where it is decomposed so as to be ejected as a plasma jet which strikes the metal plate 1 to lose energy whereupon the carbon crystallizes as diamond. Not all of the carbon (C) from the hydrocarbon turns into diamond at this time. Rather, a considerable amount thereof precipitates as amorphous carbon or graphite on the metal plate 1, but when hydrogen gas (H 2 ) is mixed with the hydrocarbon in the starting gas 8, the amorphous carbon or graphite nondiamond components are reduced to CH 4 , C 2 H 6 or other hydrocarbons which are removed as gases.
Actually, however, the removal action of the H 2 gas is not complete and such nondiamond components are detected in most diamonds film formed by the plasma jet CVD method. This has been a factor in reducing the hardness of diamond films.
As mentioned earlier, diamond has a high hardness of 10,000 kg/mm 2 , so it has been recognized as a potential coating material for various tools, but the diamond film obtained by the plasma jet CVD method contains amorphous carbon or graphite, resulting in insufficient hardness.
Furthermore, in the past, diamond has been used in connection with high performance tools which utilize its hardness and as heat sinks for devices which generate large amounts of heat such as semiconductor lasers since it has a high heat conductivity of as much as several times that of copper.
However, when a diamond film is formed by CVD, since the material serving as the substrate is a material (a carburizing material such as, for example, Ni, Co, and Fe) through which carbon may permeate, the carbon component has been dispersed in the substrate making synthesis of a diamond film impossible. Therefore, when using a diamond film for a tool or heat sink in the prior art, it has been limited to base materials (an arm in the case of a tool and a subcarrier in the case of a heat sink) other than carburizing materials. However, it would be very convenient if it was possible to form a hard film like diamond on a soft material like a carburizing material.
SUMMARY OF THE INVENTION
Accordingly, the objects of the present invention are to eliminate the above-mentioned disadvantages of the prior art and to provide a method and apparatus for vapor deposition of diamond film on an object to be treated and having superior adhesiveness with the treated object.
Another object of the present invention is to provide a diamond film suitable for a heat sink having superior adhesiveness with a bonding metal without impairing the heat conductivity of the diamond.
A further object of the present invention is to provide a method for forming a flat and plain diamond film on a substrate.
A still further object of the present invention is to provide a method for forming a diamond film having a high hardness on a substrate.
A still further object of the present invention is to form a diamond film on a substrate made of carburizing material.
Other objects and advantages of the present invention will be apparent from the following description.
In accordance with the present invention, there is provided a method for producing a diamond film on a surface of a substrate by chemical vapor deposition, said substrate comprising a main component. The method comprises forming a first layer over said substrate surface, said first layer comprising a mixture of said main component and a sintering reinforcement agent for diamond; forming a second layer over said first layer, said second layer comprising a mixture of said reinforcement agent and diamond; and forming a diamond film over the second layer. In accordance with the invention, the layers and the film are all formed in the same apparatus.
In accordance with the present invention, a diamond film is provided. The film comprises (i) a diamond film formed on a metal plate by chemical vapor deposition method and (ii) a mixed phase composed of components formed from a metal capable of bonding with the diamond film and which are included in the surface, bottom, or entirety of the diamond film.
In accordance with the present invention, there is further provided a method of forming a diamond coating on a substrate comprising synthesizing a diamond film on the substrate by the CVD method using a gas of a diamond forming material and a gas of a diamond nuclei formation promoter.
In accordance with the present invention, there is still further provided a method for synthesis of a diamond film comprising evacuating a reaction chamber; feeding a starting gas containing hydrogen and a hydrocarbon gas between an anode and a cathode in said evacuated reaction chamber; causing generation of a plasma jet by arc discharge between said anode and said cathode; feeding a powder of tungsten, molybdenum, silicon or titanium into said plasma jet; and causing said plasma jet to impinge on a substrate surface to thereby form a diamond film containing hard carbides on said surface.
In accordance with the present invention, there is still further provided a method for synthesizing a diamond film comprising the steps of forming a protective film of a carburizing material on a substrate by plasma injection using a component capable of forming a carbide having a high melting point; and forming a diamond film over the protective film using plasma chemical vapor deposition.
In accordance with the present invention, there is still further provided an apparatus for effecting the formation of a diamond film on an object to be treated or on a substrate. The apparatus comprises:
an electrode forming member having a first polarity comprising an enclosed body having a nozzle opening therein for jetting thermal plasma and a discharge gas feed pipe;
an electrode forming member having an opposite polarity and positioned in opposed relationship to said nozzle opening of said enclosed body;
a direct current plasma torch having a power source supply system containing a direct current source for applying a direct current voltage between said electrode of first polarity and said electrode of opposite polarity and which includes means for feeding a gas through said discharge gas feed pipe between the electrodes to which the direct current voltage is applied, forming said gas into a thermal plasma by the direct current arc discharge between the electrodes and jetting the thermal plasma formed as a plasma jet through said nozzle;
a starting gas feeding system for feeding gaseous starting compounds for vapor phase deposition to said plasma torch;
a powder supply pipe for feeding a metal powder to said arc discharge; and
a substrate supporting mechanism for supporting the substrate in a non-equilibrium plasma and permitting a thermal plasma chemical vapor deposition film to be deposited in a vapor phase on said substrate.
In accordance with the present invention, there is still further provided a method of producing a diamond film on an object to be treated on a substrate by a chemical vapor deposition method wherein a first layer is formed by feeding a powder comprising a mixture of a main component of the object and a sintering reinforcement agent into a plasma jet generated by direct current arc discharge, a second layer is formed by feeding a powder comprising said agent into a plasma jet, a diamond film is formed by feeding a starting gas containing hydrogen and a carbon source between an anode and a cathode of a thermal plasma chemical vapor deposition apparatus to generate a plasma jet including a radicalized carbon compound, and a surface of the object is inclined at an angle of 30 to 60 degrees from the flow direction of the plasma jet and rotated whereby the diamond film is deposited firmly on side faces of the surface.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be better understood from the description set forth below with reference to the accompanying drawings, in which:
FIG. 1 is a schematic view which illustrates the principles of a known apparatus for use in the formation of a diamond film on a substrate;
FIG. 2A is a perspective view of a cooling structure of the prior art;
FIG. 2B is a sectional view of a heat sink of the prior art;
FIG. 3 is a schematic view which illustrates the principles of the present invention for use in the formation of a diamond film on an object or substrate;
FIG. 4 is a sectional view for explaining the present invention;
FIG. 5 is a sectional view of a heat sink using the present invention;
FIG. 6 is a diagram illustrating an X-ray diffraction pattern of a second intermediate layer;
FIG. 7 is a diagram illustrating the Raman spectrum of Example 4;
FIG. 8 is a diagram illustrating an X-ray diffraction pattern in the case of a substrate having a protective film of the present invention;
FIG. 9 is a diagram illustrating an X-ray diffraction pattern in the case of a substrate not having a protective film;
FIG. 10 is a schematic view of an apparatus for coating a diamond film according to the present invention;
FIG. 11 is a cross-sectional view of an end portion of a substrate coated according to a prior art method; and
FIG. 12 is a cross-sectional view of the end portion of a substrate coated according to the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to a first embodiment of the present invention, a method is provided for raising the adhesiveness between a treated object and a diamond film using a CVD apparatus for forming the diamond film and two or more intermediate layers on the treated object, i.e., the resultant article comprises a first intermediate layer/second intermediate layer/diamond film or a first intermediate layer/second intermediate layer/third intermediate layer/diamond film.
The operation of the present apparatus will now be briefly explained.
An object (for example, a tool) to be treated or substrate is placed on a substrate holder 3 cooled by cooling water 2. At the top of the reaction chamber 4 is an anode 6 and a cathode 7 for forming a plasma jet 5. A starting gas 8 is supplied between the anode and the cathode. To enable formation of a metal layer, a powder feed pipe 9 opens at the tip of the anode 6. A DC power source 10 is provided connecting the anode 6 and the cathode 7. At the bottom of the reaction chamber 4 is an exhaust outlet 11. For CVD growth of diamond, a mixed gas of hydrogen (H 2 ) and a hydrocarbon, for example, methane (CH 4 ) is supplied between the anode 6 and cathode 7 and directed into the inside of the reaction chamber 4. The exhaust system is operated for exhausting chamber 4 via exhaust outlet 11 and thus the inside of the reaction chamber 4 is held at a low vacuum, in which state an arc discharge 12 is caused between the anode 6 and cathode 7, the heat of which causes decomposition and plasmatization of the starting gas 8, whereupon the plasma jet 5 including carbon plasma strikes the metal plate 1 and a diamond film 13 composed of fine crystals is grown on the metal plate 1. According to the present invention, to grow a mixed film of metal and diamond, a metal powder is supplied through the powder feed pipe 9 into the arc discharge 12, and to grow just a metal film, H 2 is used as the starting gas 8 and metal powder or inorganic material powder (e.g., silicon) is supplied through the powder feed pipe 9 into the arc discharge 12.
FIG. 4 is a sectional view for explaining the present invention. In FIG. 4, the treated object 21 is a sintered body comprising WC or Mo 2 C, in which sintered body is dispersed a sintering reinforcement 23 such as cobalt (Co). In accordance with the present invention, first intermediate layer 24 is composed of a mixture comprising, for example, 90 to 99.9 wt % of the main component material of the treated object 1, i.e., WC or MoC, and 0.1 to 10 wt % of the component elements of a diamond sintering reinforcement agent, i.e., cobalt (Co), iron (Fe), nickel (Ni), or some other transition metal. The second intermediate layer 25 is composed of a mixture comprising, for example, 0.1 to 10 wt % of the component elements of the diamond sintering reinforcement agent, i.e., cobalt (Co), iron (Fe), nickel (Ni), or other transition metal and 90 to 99.9 wt % diamond. The diamond film 22 is grown on the second intermediate layer 25.
Furthermore, according to the preferred embodiment of the present invention, three intermediate layers are included. The layers include a first intermediate layer composed, for example, of 90 to 99.9 wt % of a component element of the object and 0.1 to 10 wt % of a component element of a sintering reinforcement agent for diamond, a second intermediate layer composed of a mixture of the object component, the sintering reinforcement agent and diamond, wherein the mixture includes, for example, 0.1 to 10 wt % of the sintering reinforcement agent and 90 to 99.9 wt % of the other two ingredients, and wherein the ratio of the object component to diamond ranges from 1:9 to 9:1, and a third intermediate layer composed, for example, of 0.1 to 10 wt % of a component element of the sintering reinforcement agent and 90 to 99.9 wt % diamond.
The present invention, by providing at least two intermediate layers in this way, and gradually changing the composition of the layers, provides an article having a diamond film 22 which is free from peeling even when formed to a thickness of about 100 μm.
Although there are no critical limitations relative to the thickness of the intermediate layers and of the diamond film, the preferable thickness of each intermediate layer is 2 to 10 μm and more preferably 4 to 8 μm, and the preferable thickness of the diamond film is 10 to 100 μm and more preferably 20 to 40 μm. Furthermore, the size of the powder is preferably 0.1 to 8 μm, more preferably 0.4 to 1 μm.
According to a second embodiment of the present invention, the surface, bottom, or entirety of a diamond film formed by a plasma jet chemical vapor deposition method includes a mixed phase comprised of component metallic elements capable of bonding with said diamond film.
The present invention uses the above-mentioned CVD apparatus to form a mixed phase of diamond and a bonding metal element at the surface or bottom of the diamond film or throughout the entirety thereof.
FIG. 5 is a sectional structural view of a diamond film for use as a heat sink of a semiconductor device, wherein a mixed phase 29 of diamond and Cu is formed at the bottom surface and the top surface of the diamond film 26. The film 26 may be used in place of the film 15 of FIG. 2A, for example, with the surface 27 in contact with the subcarrier 14 made of Cu and with the surface 28 contacting the semiconductor chip 16.
Further, for mechanical applications utilizing the hardness of diamond, it is possible to form the mixed phase only at the bottom surface which bonds with the object or to form the entire film as a mixed phase.
The foregoing is made possible because, while the diamond film formed by a CVD method is generally polycrystalline and therefore shearing occurs easily at the crystalline interface and the crystal is relatively brittle, since metal is interposed in the mixed phase, the mechanical strength is superior.
That is, when the diamond film is used as a heat conductor, the mixed phase may be just the bonded portion. Alternatively, for applications where hardness is desired, the entire film may be formed of the mixed phase to eliminate shearing.
According to a third embodiment of the present invention, a flat or plain diamond film is formed on a substrate by the CVD method using a starting gas (e.g., H 2 , methane) for forming the diamond and a gas of an element for promoting formation of diamond nuclei such as a reducing metal (e.g., Pt), a carburizing metal (e.g., Ni, Co, Fe), or a metal or semiconductor capable of easily forming a carbide (e.g., W, Si, Mo, Ti).
In the present invention, a diamond coating is formed by simultaneously or alternatingly spraying the above-mentioned diamond forming starting gas and diamond nucleus promoting element gas onto the substrate by the CVD method or by constantly spraying the starting gas and intermittently spraying the nucleus promoting element gas. That is, in accordance with the present invention, in the synthesis of diamond by a vapor phase synthesis method, an element for promoting the formation of diamond nuclei is sprayed so as to generate large quantities of high density nuclei at the same time as the synthesis of the diamond film. The growth of specific crystal particles is thus suppressed to provide a smooth or plain diamond film. Thus, the present invention forms diamond coatings using the foregoing materials by CVD.
According to a fourth embodiment of the present invention, a diamond film having a desired high hardness can be formed on a substrate by evacuating a reaction chamber using an exhaust system, and at the same time supplying a mixture of a hydrocarbon gas and hydrogen gas between an anode and cathode provided in the reaction chamber. A plasma jet of carbon is thus generated by arc discharge and a diamond film is formed on the substrate. While the film is being formed, a powder of an element capable of bonding with non-diamond carbon components in said plasma jet to form hard carbides, e.g., tungsten (W), molybdenum (Mo), silicon (Si) or titanium (Ti) is added to the plasma jet.
The present invention uses a plasma jet CVD apparatus as shown in FIG. 3 to form a diamond film. As the diamond film forms, a powder of a material capable of forming hard carbides, e.g., W, Mo, Si or Ti is added through powder feed pipe 9 and reacted with amorphous carbon, graphite, and other nondiamond components to form hard carbides such as tungsten carbide (WC, hardness of 2200 kg/mm 2 ), molybdenum carbide (Mo 2 C, hardness of 1800 kg/mm 2 ), silicon carbide (SiC, hardness of 2300 kg/mm 2 ), titanium carbide (TiC, hardness of 300 kg/mm 2 ), and the like.
That is to say, amorphous carbon and graphite components are more active energy wise than diamond, and so such components selectively bond with radicals of metal elements in the plasma state to form hard carbides. Thus, the present invention provides for the growth of diamond film by a plasma jet CVD method using a gaseous mixture of a hydrocarbon such as CH 4 and H 2 as a starting material gas, and at the same time changing the small amounts of nondiamond components existing in the diamond polycrystalline layer as a result of insufficient reduction and removal by the H 2 gas into hard carbides to thus improve hardness.
According to a fifth embodiment of the present invention, a diamond film is formed on a substrate of a carburizing material. A protective film is first formed on the substrate of carburizing material by plasma injection using an element which readily forms a carbide with a high melting point. A diamond film is then formed over the protective film by plasma CVD.
That is, the present invention enables the coating of a diamond film on a carburizing base material by a vapor phase synthesis method by first providing a coating film facilitating the synthesis of diamond on the surface of the base material.
Examples of carburizing materials usable in the present invention, are Fe, Ni, Co, and other metals. Further, as elements which readily form a carbide with a high melting point, use is preferably made of WC, Si, Mo, W, or other such elements. It is possible to use these materials and to perform the method of the present invention using the same apparatus, as is clear from the examples set forth below.
When forming a protective film in accordance with the method of the present invention, hydrogen, argon, helium, or other inert gas is introduced into the apparatus and is converted to plasma by DC arc discharge. An element which readily forms a carbide with a high melting point is introduced through another pipe and is melted by the high temperature generated in the plasma to thus form a protective film over the substrate.
According to a sixth embodiment of the present invention, a diamond film is uniformly and firmly deposited even on the side surfaces of an object or substrate as shown in FIGS. 10 to 12.
That is, when the above-mentioned intermediate layers and diamond films are formed on an object (or substrate) 1, the desired layers and diamond film are not deposited on the side faces 30 of the object because the plasma jet 5 does not sufficiently impinge on such side surfaces 30. However, according to this embodiment, during the formation of the intermediate layers and the diamond film, the object 1 is inclined from the flow direction line of the plasma jet 5 by 30 to 60 degrees (See θ in FIG. 10), and the object is rotated, whereby the intermediate layers and the diamond film are uniformly and firmly deposited on the side faces 30 of the object 1.
According to the first embodiment of the present invention, for example, if the intermediate layer 39 and the diamond film 40 are to be deposited on the side surfaces 30 of the object 1, the side surfaces 30 are not well covered by the intermediate layer 39 because the plasma jet 5 does not impinge on the side surfaces 30. Accordingly, the diamond film 40 may sometimes be deposited directly on the side surfaces 39 as shown in FIG. 11. Thus, the diamond film 40 on the side surfaces 30 tends to be easily peeled off, or cracks may sometimes occur between the intermediate layer 30 and the diamond film 40, especially at the end portions of the object 1.
Contrary to the above, since the object 1 is rotated at an angle θ relative to the flow direction of the plasma jet 5 according to this embodiment, the side faces 30 of the object 1 can be uniformly and firmly covered with the intermediate layers 44 (39) and the diamond film 40, as shown in FIG. 12. In FIG. 12, a first intermediate layer 41 having a thickness of, for example, 2-5 μm is formed by introducing a powder of, for example, WC (the same material as the object), into a plasma jet 5 formed from hydrogen gas or an inert gas. A second intermediate layer 42 having a thickness of, for example, 10-20 μm is then formed by introducing a powder of WC and a powder of, for example, Fe, Co, Ni, Nb and/or Ta, into a plasma jet 5 generated from hydrogen gas and a carbon source. A third intermediate layer 43 having a thickness of, for example, 20-30 μm is formed by introducing a powder of, for example, Fe, Co, Ni, Nb and/or Ta (the same metal used in the formation of the second intermediate layer 42) into a plasma jet 5 generated from hydrogen gas and a carbon source (e.g., a hydrocarbon gas such as methane). Thereafter, a diamond film 40 having a thickness of, for example, 30-50 μm is formed in the same manner as mentioned above.
The inclination and rotation of the object (or substrate) 1 can be effected in any conventional manner. For example, as shown in FIG. 10, the supporting means 31 for the object (or substrate) 1 is composed of a cooled support 32 for the object 1, a motor 34 provided with a rotating shaft 33 for rotating the support 32, a movable base 35 for carrying the motor 34, and an arc-shaped guide member 36 for moving the movable base 35 so that the surface of object 1 to be coated is inclined at an angle θ. Although, in the above embodiment, the object 1 is moved so that it is inclined from the plasma jet flow direction, the plasma torch could also be moved in a similar manner.
EXAMPLES
The present invention will now be explained, in detail, by reference to but without limitation by the following Examples.
Example 1
As the treated object 1, a sintered body using Co as a sintering reinforcement and having a composition of WC-10% Co was used. As the component materials for the first intermediate layer 24, WC and Co were used. Further, as the component materials for the second intermediate layer 25, diamond and Co were used. As the conditions for growth of the second intermediate layer and of the diamond film, the CVD apparatus shown in FIG. 3 was used and H 2 gas at 10 to 50 liter/min and CH 4 gas at 0.05 to 1 liter/min were supplied to the apparatus. Further, an arc current of 10 to 70 A and an arc voltage variable in a range of 50 to 150 V were used. The vacuum of the reaction chamber was held in the range of 1 to 10 kPa.
When growing the first intermediate layer on the treated object, H 2 gas was supplied as the starting gas and a plasma get was generated, in which state WC and Co particles having a particle size of 1 to 5 μm were supplied from the powder feed pipe 9 at a rate of 0.01 to 0.1 cc/h and plasmatized so as to grow as a deposited mixture to a thickness of 20 μm.
The material gas was changed to a mixed gas of H 2 and CH 4 and a Co powder having a particle size of 1 to 5 μm was supplied from the powder feed pipe 9 to create a plasma jet and form a second intermediate layer comprised of a mixture of diamond and Co which was deposited to a thickness of 30 μm.
FIG. 6 is an X-ray diffraction pattern of the second intermediate layer, where the diffraction lines of diamond (abbreviated as D) and Co clearly appear, so it is understood that a mixed layer was grown. Then, a plasma jet was created using a mixed gas of H 2 and CH 4 as a material gas and a diamond film having a thickness of about 100 μm was formed on top of the second intermediate layer top. The adhesion between the treated object and the diamond film formed in this way is strong. A tensile test gave a value of more than 600 kg/mm 2 .
Example 2
The CVD apparatus shown in FIG. 3 was used and a starting gas 8 composed of hydrogen (H 2 ) gas at a variable flow rate of from 10 to 50 liter/min and methane gas (CH 4 ) at a variable flow rate of from 0.05 to 1 liter/min was supplied. Further, metallic powder comprised of Cu powder with a particle size of 1 to 5 μm was supplied through powder feed pipe 9 at a variable rate of from 0.01 to 0.1 cc/h.
When use is made of a mixture of CH 4 and H 2 as the starting gas 8, a diamond film 13 is formed, and when metal particles are mixed in, a mixed phase of diamond and metal is formed. Further, when H 2 gas and a metal powder are used, a metal film is formed. The conditions for causing CVD growth are a vacuum in the reaction chamber 4 of 1 to 10 kPa, an arc current of 10 to 70 A, and an arc voltage of 50 to 150 V. Thus, a diamond film having a thickness of 50 μm was formed so as to include a mixed phase containing Cu and having a thickness of 1 μm with a ratio of composition of the top surface and bottom surface of about 5:1. Then, using this diamond film as a heat sink and using solder with a melting point of 250° C. to bond the film to a subcarrier and to a laser diode on top of it, it was possible to obtain a sufficient bonding strength.
Example 3
In an apparatus as shown in FIG. 3, hydrogen gas, methane gas, or other starting gas 8 is introduced from the top of the plasma torch in the reaction chamber and is made into plasma by DC arc discharge. The plasma 5 reacts on the substrate 1 to form a diamond film 13. In the process of synthesis, metal particulates may be introduced along with the material gas and metal vapor sprayed on the diamond surface. In the working of the present invention, 10 to 50 liter/min of hydrogen gas, 0.05 to 1 liter/min of methane gas, and a substrate of WC having a thickness of 0.5 mm and a surface area of 10×10 mm 2 were used. As the spraying powder material, 0.001 to 0.0001 cc of 1 to 5 μm particulates of W are supplied each time the thickness of the diamond film increases 0.1 mm. The arc current is 10 to 70 A and the arc discharge is 50 to 150 V. Further, the degree of vacuum in the reaction chamber is 1 to 10 kPa. As a result, even with a diamond film having a thickness of 2 mm, the surface roughness is less than 0.05 mm.
Diamond films were synthesized under the same synthesis conditions but with different types of metal particulates and the surface roughness were measured. The results are shown in Table 1.
TABLE 1______________________________________ Pt W Mo______________________________________Particle size (μm) 1-2 0.45-1.0 0.7-1.0Arc discharge (A) 10-40 30-70 30-70Diamond film 0.3 mm 0.05 mm 0.05 mmroughness or less or less or less______________________________________
Example 4
The CVD apparatus shown in FIG. 3 was used and a super hard alloy of W including 8% Co was utilized as the metal plate 1. As the conditions for the supply of starting gas 8, the flow of hydrogen (H 2 ) gas was varied within the range of 10 to 50 liter/min and the flow of methane (CH 4 ) gas was varied within the range of 0.05 to 1 liter/min and, as a metal powder, a powder of W having a particle size of 1 to 5 μm was supplied at a rate of 0.01 to 0.1 cc/h. Then, the conditions where CVD was possible included a vacuum in the reaction chamber 4 of 1 kPa to 10 kPa, an arc current of 10 to 70 A, and an arc voltage of 50 to 150 V.
FIG. 7 compares the Raman spectrum 30 of a film obtained by supplying W as an additive with the Raman spectrum 31 of a film with no additive. As will be understood from FIG. 7, a broad peak amorphous carbon was observed near 1500 cm -1 in the spectrum 31 of the film with no additive.
On the other hand, a sharp peak of diamond was observed at 1333 cm -1 in the spectrum 30 of the film obtained by supplying W, and the peak of the amorphous carbon near 1500 cm -1 was extremely low.
It was confirmed from the Raman scattering that the diamond film synthesized in this way had an extremely small content of nondiamond components.
Further, the hardness of the diamond film formed in this way is about 10,000 kg/mm 2 , a hardness which is close to that of natural diamond.
It is to be noted that when a Mo, Si, or Ti metal powder is supplied from the powder feed pipe 9 to form a carbide, the conditions for formation of the diamond film are the same and it is possible to obtain a diamond film having a hardness that is similar to the hardness obtained in a case where WC is formed.
In an apparatus as shown in FIG. 3, use was made of a substrate 1 of Ni having a thickness of 0.5 mm and an inert gas (or hydrogen) was introduced into the plasma torch in the reaction chamber 4 at a flow rate of 10 to 50 liter/min. Then, using an arc current of 10 to 70 A and an arc voltage of 50 to 150 V, the inert gas was subjected to arc discharge and converted to plasma. The vacuum in the reaction chamber was 1 to 10 kPa.
As this plasmatization of the inert gas occurred, WC particulates of 1 to 5 μm were supplied from a powder feed apparatus at a rate of 0.01 to 0.1 cc/h. The WC particulates were melted by the high temperature plasma and together with the plasma jet 5 were deposited on the substrate 1 to form a protective film.
Then, the supply of powder from the powder feed pipe 9 was stopped and a starting gas for forming diamond (methane and hydrogen) was introduced into the reaction chamber 4. The feeding flow rates of the methane gas and hydrogen gas were respectively 0.05 to 1 liter/min and 10 liter/min to 100 liter/min. The starting gas was converted to plasma by the DC arc discharge 12 at the same time and the plasma jet 5 was directed onto the protective film to form the diamond film 13. The diamond film obtained by the method of the present invention was subjected to X-ray analysis and the resultant pattern is shown in FIG. 8. The pattern includes a pattern of a protective film and a pattern of diamond and it can be seen that a diamond film was definitely synthesized.
On the other hand, X-ray analysis was performed on a substrate where synthesis of diamond was attempted without a protective film and the resultant pattern is shown in FIG. 9. As is clear from FIG. 9, only the pattern of the Ni substrate is observed and there is no diamond pattern. Thus, it was confirmed that no diamond film was synthesized.
According to the present invention, a diamond film having superior adhesiveness can be coated on a treated object, so it is possible to provide a highly reliable diamond tool.
According to the present invention, by using a CVD apparatus which can form a mixed phase of a diamond film and metal by CVD growth and by changing the combination of the type of starting gas and metal powder, the present invention may be employed to synthesize a diamond film wherein the surface, bottom, or entirety of the diamond film includes a mixed phase and it is therefore possible to obtain a diamond film having superior adhesiveness at a low cost.
Furthermore, the method of the present invention, as explained above, uses a gas of a predetermined material to form a diamond film by the CVD method, so that is possible to considerably improve the smoothness of the surface of thickness diamond films, reduce working costs, and increase work efficiency.
According to the present invention, a diamond film having reduced contamination by amorphous carbon, graphite, or other nondiamond components may be readily synthesized, and by working the invention it is possible to provide diamond tools at low cost.
As explained above, the present invention provides for the formation of a protective film of a predetermined material on a substrate and the subsequent synthesis of a diamond film on the protective film a procedure which enables coating of a diamond film on a carburizing base material, which was previously impossible. | An apparatus for depositing a diamond film on a substrate includes a first electrode formed as an enclosed body having a nozzle for jetting thermal plasma opening therefrom and a second electrode of opposite polarity positioned in the nozzle. The apparatus additionally includes a power source for applying a direct current voltage between the electrodes. A gas is fed between the electrodes as a direct current voltage is applied thereto, whereby the gas is formed into a thermal plasma which is jetted through the nozzle. A starting gas feed system is included for feeding gaseous starting compounds for vapor phase deposition to the plasma jet and a powder supplying pipe is provided for feeding a metal powder between the electrodes. | 2 |
CLAIM OF PRIORITY
[0001] This is a continuation of copending U.S. application Ser. No. 13/016,369, filed on Jan. 28, 2011, which was a continuation of and claims the priority of copending U.S. application Ser. No. 13/055,428, filed on Jan. 21, 2011, and of PCT/EG2008/000034 and of its Egyptian priority document, including all foreign filing applications.
TECHNICAL FIELD
[0002] Drugs, Pharmaceuticals
BACKGROUND
[0003] Duchene Muscular Dystrophy (DD) is an X linked disorder primarily affecting skeletal muscles. It is caused by the lack of dystrophin, the protein product of DD gene, located on XP21chromosome. The patients are males who suffer from progressive muscle weakness extending to both cardiac and respiratory muscle failure. Patients suffering from DD, die from respiratory and/or cardiac failures at an age of 25-30 years. Female siblings are healthy carriers.
[0004] Male infertility is a multi factorial disease process with a number of potential contributing causes. Considering that the majority of male infertility cases are due to deficient sperm production of unknown origin, environmental and mutational factors must be evaluated.
[0005] The treatment of male factor infertility is a rapidly developing field. Introduction of microsurgical fertilization techniques allows assisted conception units to treat couples who previously would not have benefited from in vitro fertilization techniques.
[0006] However, these techniques are only used for the minority of sub-fertile men in andrologial practice. Many sub-fertile men are still treated pharmacologically or by sperm selection methods to enhance sperm fertilizing ability. Numerous pharmacological compounds have been described that enhance sperm motility and thus, potentially sperm fertilizing capability. Sperm motility plays an important role in the normal fertilization process. Poor sperm motility (<50% motile sperm with <2+ forward progression according to WHO protocol), is considered a major factor in diminished rates of fertilization. Medical trials for male non obstructive infertility by hormonal replacement, corticosteroids (in immune infertility). Mutational therapies were carried out but, results were not satisfactory.
[0007] Chronic fatigue is a world wide complaint affecting the productivity of a good percentage of the population. Chronic fatigue includes: unexplained fatigue, chronic fatigue syndrome, and fibromyalgia. In all types of fatigue, the complex relieved muscle pain increased the physical activity and productivity and relieved associated depression of the patients.
RELATIONSHIP OF THE INVENTION TO THE PRIOR ART
[0008] A different copper complex for pharmaceutical use was disclosed in published application PCT EGY 116/030/2006.
[0009] A Copper Nicotinate complex was an active ingredient in (Royal Top)® a food supplement preparation previously sold only in Egypt (registration No. 97/1740); but which was withdrawn from the market by the Egyptian Ministry of Health due to the following evident drawbacks, not met with the present invention:
[0010] The formulation procedure contains addition of water which is contraindicated for the stability of copper (I).
[0011] The Iron oxide included in the above named formula affords high probability of displacement of copper from the active ingredient.
[0012] Parabenzoates which were needed as preservatives are undesirably for human consumption.
[0013] Preparation of the copper (I) nicotinate complex according to the procedure by, M. A. S. Gohar and M. Dratovsky, Collection Czechoslov. Chem. Commun. 40, 26 (1975), did not give reproducible results coping with the declared analyses of the unhydrated formula of the complex (the structure referred by authors in the reference).
[0014] HPLC analyses of the complex prepared according to the procedure published by Gohar and Dratovsky, revealed a heterogeneous sample.
GENERAL STATEMENT OF THE INVENTION
[0015] The entire disclosure of U.S. application Ser. No. 13/055,428, including the specification, claim, abstract and drawings, is incorporated herein by reference, as if fully repeated herein in haec verba.
[0016] Copper (I) chloride complex of nicotinic acid was prepared, characterized by elemental analysis, IR, UV-visible spectra, and its crystal structure was determined by single crystal diffraction method. As a drug in a pharmaceutically acceptable composition, this compound exerts a very positive influence on different incurable diseases, e.g. muscular dystrophy, myopathy, myasthenia gravis, parkinsonism, Chronic Fatigue Syndrome, Male Infertility and post stroke muscle weakness are examples.
[0017] The compound of the invention is a copper chloride complex with a ligand containing nicotinate residue, different from the material of the prior art: M. A. S. Gohar and M. Dratovsky, Collection Czechoslov. Chem. Commun. 40, 26 (1975), and M. A. S. Gohar and T. C. W. Mak, Polyhedron 14(17-18),2587(1995). The complex was prepared by a procedure essentially modified with respect to that published by M. A. S. Gohar et al.
MODES OF CARRYING OUT THE INVENTION
[0018] An effective amount of a copper (I) nicotinate complex, to achieve a desired level for ameliorating fatigue, infertility, weakness of muscles, etc., is administered orally to a human. The composition for this purpose is presented as capsules, tablets, etc. The specific dose level for a particular person depends on a variety of factors including age, general health, sex, diet, body weight, and the time of administration.
[0019] According to another broad form of the invention, a method comprising the administration to a human, of an effective amount of the copper (I) nicotinate complex of this invention in a pharmaceutically acceptable formulation with other cell building factors, carriers, diluents and or excipients. The concentration of the copper (I) nicotinate complex and other adjuvant depends on different factors, e.g. type and reason of weakness of the muscles, age of the patient, etc.
[0020] According to another broad form of the invention there is provided a method for treatment of Fatigue. The method comprises administering to a human the copper (I) nicotinate complex and /or a pharmaceutically acceptable composition of the complex. The concentration of the copper (I) nicotinate complex in the pharmaceutically acceptable form is variable and depends on several factors, e.g. age of the patient, reason of fatigue, etc. According to a further broad form of the invention there is provided a method for treatment of infertility in men.
[0021] The copper (I) nicotinate complex of invention can be used as such or can be formulated in combination with other medicaments, e.g. a non-steroidal, anti-inflammatory, I. Monech, H. Prentice, Z. Rickaway, and H. Weissbach, PNAS 106(46), 19611-19616(2009)].
[0022] Such dosage forms may also comprise, as normal practice, additional substances other than inert diluents, such as food supplements:, e.g., L-carnitine, L-arginine, Nacetylcysteine, resviratrol, vitamin B 6 , vitamin B 1 , nicotinamide, folic acid, α-tocoferol, lemon grass, ginseng, omega-3, lipoic acid, wheat germ oil, ascorbic acid, other water soluble vitamins, etc. In the case of capsules the dosage forms may also comprise buffering agents.
[0023] Solid dosage forms for oral administration may include capsules, tablets, pills and granules, in such solid dosage forms, the copper (I) nicotinate complex complex may be admixed with at least one inert diluent. The dose can vary according to age, the root of administration and the state of the patient in relation to the illness.
[0024] The effective doses vary within orders of magnitude from 0.1 mg/Kg to 0.75 mg /Kg body weight of the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 : RP-HPLC analysis of the complex prepared according to previous work
[0026] Complex prepared according to previous work [M. A. S. Gohar and M. Dratovsky, Collection Czechoslov. Chem. Commun. 40, 26 (1975); M. A. S. Gohar and T. C. W. Mak, Polyhedron 14(17-18),2587(1995] gave 3 peaks with RP-HPLC analysis indicating a heterogeneous product.
[0027] The data for the first two peaks are shown in this Table 1. The full graph is shown in FIG. 1 , showing three peaks.
[0028] FIG. 2 : RP-HPLC analysis of the complex prepared according to our invention, from the procedures of Examples 1-4:
[0029] Homogenous copper (I) nicotinate complex of invention by RP-HPLC analysis. Reversed phase—High performance liquid chromatography (RP-HPLC) of the copper (I) nicotinate complex of invention revealed a single peak at Rt 3.06 min.
Column: C18 Mobile phase: Methanol/Acetonitrate UV detector: 240 nm Volume injected: 20 μL
Model of apparatus: Gilson
[0034] The datum point for the single peak is shown in this Table 2. The graph is shown in FIG. 2 .
DETAILED DESCRIPTION OF THE INVENTION
[0035] In order that the present invention can be more readily understood, reference is now made to the following examples.
Example 1
(A)—Preparation of Copper (I) Chloride
[0036] Procedure 1: Solution of purified Copper (II) chloride (40.2 g, 0.3 mol) in (100 ml) water was added gradually with efficient stirring to a solution of Lascorbic acid (26.5 g, 0.15 mol) in (130 ml) water. The mixture was left to stand; the supernatant must be free of color. Precipitated Cu(I) Cl was filtered by suction and washed with absolute ethanol. The product was then dried at 50-60° C. for 30-60 min. Yield 22 g (74.4%).
[0037] Procedure 2: Solution of L-ascorbic acid (35.2 g, 0.2 mol) in (150 ml) water was added gradually with efficient stirring to a solution of purified Copper (II) chloride (40.2 g, 0.3 mol) in (100 ml) water. Precipitated Cu(I) Cl was filtered and washed with 60-80% ethanol and then dried by suction. Yield 23 g (77.8%).
Example 2
(B)—Preparation of Nicotinic Acid Solution
[0038] Procedure 1: Pure nicotinic acid (30.75, 0.25 mol) was dissolved in 60-80% ethanol (2.5 L) by stirring and the solution was heated to boiling then Lascorbic acid (50 g) was added and stirred till dissolved.
[0039] Procedure 2: To a mixture of pure nicotinic acid (30.75, 0.25 mol) and Lascorbic acid (50 g) was added 50 ml water and 2.5 L of absolute ethanol and the mixture was stirred and heated to boiling till clear solution was obtained.
Example 3
C—Preparation of the Copper (I) Nicotinate Complex
[0040] Procedure 1: A freshly prepared suspension of Cu (I) Cl (9.85 g, 0.1 mol) Example 1 in 60-80% ethanol (150 ml) was added gradually to an efficiently stirred and heated solution B. The obtained turbid solution was filtered wile hot and the filtrate was left over night.
[0041] Procedure 2: A freshly prepared suspension of Cu (I) Cl (9.85 g, 0.1 mol) Example 1 in absolute ethanol (150 ml) was added gradually to an efficiently stirred and boiling solution B. The obtained turbid solution was boiled and filtered while boiling and the filtrate was left over night.
Example 4
D—Isolation of the Copper (I) Nicotinate Complex
[0042] Procedure 1: The reddish brown precipitate separated from the filtrate in Example 3 was filtered and washed several times with absolute ethanol and finally with acetone. The product was collected and dried at 55-60° C. for 30-60 min. Yield 9.5 g.
[0043] Procedure 2: Filter by vacuum the reddish brown precipitate separated from the filtrate Example 3, wash with aqueous ascorbic acid 5% w/v solution then with ethanol 60-90% and finally with least amount of acetone. The product was left to dry in air over night. Yield 9.2 g.
Example 5
E=Preparation of the Copper (I) Nicotinate Complex Ointment (20%)
[0044] Twenty grams of the copper (I) nicotinate complex was finely powdered in a whole glass mortar then Vaseline (80 g) was added portion wise and thoroughly triturated with the powder to obtain a homogenous mass. Stainless steel spatula was used to collect and to transfer the semisolid mass to a brown colored screw caped glass container.
[0045] The ointment was stored for more than two years at ambient conditions of temperature and humidity protected from direct sun light with no visual change of properties and clinical efficacy.
[0046] This preparation was applied in thin film once daily for treatment of female hair loss, skin lesions and surgical wounds.
Example 6
Preparation of the Copper (I) Nicotinate Complex Ointment (5%)
[0047] Five grams of the copper (I) nicotinate complex was finely powdered in a whole glass mortar then Vaseline (95 g) was added portion wise and thoroughly triturated with the powder to obtain a homogenous mass. The semisolid mass was transferred to a brown colored screw caped glass container.
[0048] The ointment was stored for more than two years at ambient conditions of temperature and humidity protected from direct sun light with no visual change of properties and clinical efficacy.
[0049] This preparation was applied in thin film once daily for treatment of burns and skin cosmetics.
Example 7
Recovery of Copper
[0050] Recovery of copper not consumed in the target complex formation was efficiently affected to afford on one hand environment friendly procedure through minimizing release of copper to the sewage. On the other hand more economic procedure was achieved by regeneration of copper in a suitable form to be recycled.
[0051] The residue on the filter (Example 3) was boiled with sodium hydroxide (5%) aqueous solution for 5-10 minutes and glucose (5%) solution was added in sufficient quantity and solution boiled till no more red precipitate was separated. Filter the red residue, wash with distilled water and dry in air. 3.5 g of Cu2O was recovered.
Example 8
[0052] Oral Dosage Form:
[0053] A typical dosage form for oral administration of copper (I) nicotinate complex was prepared according to the following prescription.
[0054] Procedure 1 (binary preparation): the copper (I) nicotinate complex (10-20 mg) was mixed with L-ascorbic acid (10-50 mg) under conditions to avoid access of unwanted moisture and delivered into colored hard gelatin capsule.
[0055] This preparation was recommended for treatment of muscular dystrophy in particular Duchene and Becker MDs.
[0056] Procedure 2 (multicomponent preparation): a) the copper (I) nicotinate complex (10-20 mg) was mixed with L-ascorbic acid (10-50 mg) under conditions to avoid access of unwanted moisture (the binary preparation) and then manipulated into a microencapsulated form; b) L-argentine (500-2000 mg) was manipulated into a microencapsulated form; c) preparations a) and b) were deliver sequentially to a colored hard gelatin capsule.
[0057] This preparation was recommended for treatment of male infertility and fatigue syndrome.
Example 9
Skin Patches Containing Copper (I) Nicotinate Complex
[0058] The copper (I) nicotinate complex molecular weight (362.5) is suitable for skin patches formulation. One hundred milligrams were mixed with the suitable adhesive matrix and kept protected from light till used as under arm or chest application.
Analytical Data of the Copper (I) Nicotinate Complex of Invention which is the Active Ingredient in all the Mentioned Pharmaceutical Preparations
[0059]
[0000]
Found %:
C: 39.76
H: 3.73
N: 7.45
Cu: 17.17
Calc. % for C 12 H 12 N 2 O5ClCu, MW 362.5:
C: 39.72
H: 3.31
N: 7.72
Cu: 17.37
Physical Properties
[0060] Color of the copper (I) nicotinate complex of invention:
Bright reddish-brown microcrystalline powder
[0061] Solubility of the copper (I) nicotinate complex of invention:
[0000] The complex is insoluble in non polar solvents, e.g. benzene, carbon tetrachloride, etc., and insoluble in polar solvents: water, methanol, ethanol, acetone, but soluble in these solvents upon heating in inert atmosphere, otherwise oxidation takes place.
[0062] Solubility in DMF and DMSO is advantageous when used in skin patches to carry the copper complex of this invention through the skin and into the system.
[0063] Infrared spectrum of the copper (I) nicotinate complex of invention: Exhibits C═O band around 1710 cm−1, and C—O around 1310 cm−1(KBr pellets) The composition of the complex formulated as [Cu Cl (nicotinic acid)2] was confirmed by the single crystal diffraction.
Reversed phase—High performance liquid chromatography (RP-HPLC) revealed a single peak at R t 3.06 min. Column: C18 Mobile phase: Methanol/Acetonitrate UV detector: 240 nm Volume injected: 20 μL Model of apparatus: Gilson
[0070] The above examples and descriptions are intended to be exemplary only. It is understood that the full scope of this invention should be determined only by the scope of the claims set forth below. | A method for preparation pharmaceutical compounds in large quantities consists of copper (I) halide, preferably the chloride complex of nicotinic acid characterized by elemental analysis, spectroscopy and crystallographic methods, used for treatment of muscular dystrophy, myopathy, myasthenia gravis, parkinsonism, Chronic Fatigue Syndrome, Male Infertility and post stroke muscle weakness.
Chlorobis (nicotinic acid) copper (I) monohydrate complex, its composition [CuCl(nicotinic acid) 2 ]. H 2 O, has been prepared and its physical and chemical properties as well as its crystal structure have been investigated for the first time. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No. 12/706,280 entitled “DEVICE FOR ACCEPTING AND STORING MESSAGES” and filed Feb. 16, 2010, which claims the benefit of U.S. Provisional Patent application Ser. No. 61/152,926 entitled “APPARATUS FOR STORING MESSAGES SECRETS AND THE LIKE” and filed Feb. 16, 2009. The entireties of the above-noted applications are incorporated by reference herein.
BACKGROUND
[0002] Educational games and toys have become prolific in today's marketplace; this is partly because parents and educators recognize the need for supplemental educational stimulation and learning outside of the classroom. However, few of the products in the marketplace provide both educational learning and fun for the child. Stimulation of a child's imagination is an important part of the childhood development cycle. Although parents, siblings, friends and teachers have a critical role in a child's development, individual imaginary play is as important to the child's development
[0003] Many believe that a child's mind is most creative around the age of eight years old. The years between birth and this age have a profound impact upon a child's future. Creativity is particularly important for a variety of reasons. First and foremost, creativity can develop and improve a child's imaginative skills. Basic skills are often honed by way of a child's creativity and imagination. Additionally, creativity and imagination enable a child to learn at their own pace in an environment that is both educational and fun.
[0004] Today, there are countless resources available for parents to help stimulate their child's creativity. As with many decisions throughout the tender years, parents sometimes struggle to make the right choice in selecting toys and activities for their child. Many toys available today offer both amusement and educational value to a child. This stimulation is invaluable in giving the child a head start in life on an educational level. Many of the toys and amusement products available today help a child to learn basic shapes, colors, numeracy, literacy, and creativity. Through the use of stimulating yet enjoyable products, children learn about everything from shapes and colors to numbers and letters.
[0005] Children often stimulate their mind through books, puzzles and imaginary friends. Encouragement of imagination both stimulates and nurtures the child's developing mind, curiosity, and creative skills. Imagination also inspires independence and creativity—there is a need for amusement devices that inspire children to learn and develop during these formative years.
SUMMARY
[0006] The following presents a simplified summary of the innovation in order to provide a basic understanding of some aspects of the innovation. This summary is not an extensive overview of the innovation. It is not intended to identify key/critical elements of the innovation or to delineate the scope of the innovation. Its sole purpose is to present some concepts of the innovation in a simplified form as a prelude to the more detailed description that is presented later.
[0007] The innovation disclosed and claimed herein, in one aspect thereof, comprises a device that can stimulate creativity and imagination of children and adolescents. Individuals of all ages can be entertained and/or educated through use of the innovation. More particularly, the innovation discloses devices that facilitate storage of messages such as secrets, memories, notes, diary entries, wishes, dreams, trivia and other educational facts, quiz and other game questions, valentines, etc.
[0008] In aspects, the device can employ multiple (e.g., two) chambers to receive and store messages. A first chamber can receive the message whereby a user can prompt storage into a second chamber, e.g., for safekeeping. In one aspect, a chamber selector is employed to transfer a message from one chamber to the other. Additional aspects can employ a single chamber or can be configured to convey the appearance of multiple chambers. Because children and adolescents generally enjoy the activity of storing secrets, memories, dreams, diary entries, etc., the innovation can promote creativity and imagination.
[0009] To the accomplishment of the foregoing and related ends, certain illustrative aspects of the innovation are described herein in connection with the following description and the annexed drawings. These aspects are indicative, however, of but a few of the various ways in which the principles of the innovation can be employed and the subject innovation is intended to include all such aspects and their equivalents. Other advantages and novel features of the innovation will become apparent from the following detailed description of the innovation when considered in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 illustrates a perspective view of an example hinged-open message storage apparatus in accordance with aspects of the innovation.
[0011] FIG. 2 illustrates a perspective view of an example closed message storage apparatus in accordance with aspects of the innovation.
[0012] FIG. 3 illustrates an example flow chart of procedures that facilitate storage of messages in accordance with an aspect of the innovation.
[0013] FIG. 4 illustrates an example exploded view of a message keeper in accordance with aspects of the innovation.
[0014] FIG. 5 illustrates an alternative example view of a message keeper in accordance with aspects of the innovation.
[0015] FIG. 6 illustrates a rear cross-sectional view of a message keeper in accordance with aspects of the innovation.
[0016] FIG. 7 illustrates a side cross-sectional view of a message keeper in accordance with aspects of the innovation.
[0017] FIG. 8 illustrates a top perspective view of an example clamshell shaped message keeper in accordance with aspects of the innovation.
[0018] FIG. 9 illustrates a side perspective view of an example clamshell shaped message keeper in accordance with aspects of the innovation.
[0019] FIG. 10 illustrates a top perspective view of an example hinged-open clamshell shaped message keeper in accordance with aspects of the innovation.
[0020] FIG. 11 illustrates a side perspective view of an example hinged-open clamshell shaped message keeper in accordance with aspects of the innovation.
[0021] FIG. 12 illustrates a perspective view of an example clamshell shaped message keeper in accordance with aspects of the innovation.
[0022] FIG. 13 illustrates an alternative perspective view of an example clamshell shaped message keeper in accordance with aspects of the innovation.
[0023] FIG. 14 illustrates a view of a locking mechanism cap in accordance with aspects of the innovation.
[0024] FIG. 15 illustrates a view of an example locking mechanism in accordance with aspects of the innovation.
[0025] FIG. 16 illustrates a perspective view of an example clamshell message keeper in a closed and locked state.
[0026] FIG. 17 illustrates a bottom perspective view of an example clamshell message keeper in a closed and locked state.
DETAILED DESCRIPTION
[0027] The following terms are used throughout the description, the definitions of which are provided herein to assist in understanding various aspects of the subject innovation. As used herein, a “message” is intended to refer to most any communication including, but not limited to, a secret, memory, note, diary entry, wish, trivia item or other educational message/fact, dream, quiz or other game entry or question, valentine, message to an imaginary friend, or the like. “Messages” may be real or virtual; in other words, tangible or intangible. For example, a “message” may be a written “message” on a slip of paper, sticker, or other suitable material but also may be spoken words or other forms of virtual (e.g., non-tangible) “messages” (e.g., thoughts or ideas).
[0028] The aspects described herein include means to store a “message” or “messages.” The devices disclosed and claimed herein are hereinafter referred to as a “message keeper” or “message keepers”. These definitions are not intended to limit the scope of the innovation or claims appended hereto. Rather, the definitions are provided to add perspective to the innovation to facilitate a complete and comprehensive understanding of the features, functions and benefits thereof.
[0029] The innovation is now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the subject innovation. It may be evident, however, that the innovation can be practiced without these specific details.
[0030] Referring initially to FIG. 1 , a perspective view of a message keeper 100 in accordance with aspects of the innovation is shown. As illustrated, the message keeper 100 can have a base housing portion 102 and a cover portion 104 . In this aspect, the cover portion 104 is hingedly connected to the base housing portion 102 by way of a hinging mechanism 106 . While the cover portion 104 is hingedly connected to the base housing portion 102 in this aspect, it is to be appreciated that other aspects can employ a snap-fit, press-fit, screw-top, etc. cover portion (not shown) without departing from the spirit and/or scope of the innovation and claims appended hereto. Additionally, aspects can be configured without a cover portion 104 . These alternatives are included within the scope of the features, functions and benefits described herein.
[0031] The message keeper 100 of FIG. 1 can stimulate a child's creativity and imagination by virtually collecting spoken (or whispered) messages. In operation, a child can speak a message (e.g., secret, wish, diary entry, idea) into message interface 108 . The message interface 108 can be configured as an aperture in communication with a message acceptance chamber within base housing portion 102 . Once a message is conveyed, the message keeper 100 can be employed to virtually store the spoken message.
[0032] Here, a chamber selector 110 can be employed to virtually transfer the message from a message acceptance chamber to a message storage chamber. As described herein, these chambers can be actual cavities within base housing portion 102 or, alternatively, can be established and conveyed merely by way of colors, textures, placement, indicia, or the like. By sliding the chamber selector 110 in a clockwise (or counter-clockwise) direction around track 112 , a child can visualize the transfer (or virtual transfer in the case of spoken messages) of the message between the acceptance and storage chambers. In particular, a chamber viewer 114 can be employed to visualize motion of the chambers simultaneously with motion of the chamber selector 110 . This motion will be better understood upon a review of the figures that follow.
[0033] Referring now to FIG. 2 , an alternative perspective view of message keeper 100 is shown in accordance with an aspect of the innovation. In particular, the message keeper 100 is depicted in a closed position in FIG. 2 . More particularly, cover portion 104 is shown in a hinged-closed position atop base housing portion 102 . In this configuration, the cover portion 104 hides the message interface, chamber selector and chamber viewer (not shown). It will be appreciated that, in an alternative aspect, cover portion 104 can be translucent thereby exposing the interior of the message keeper 100 .
[0034] FIG. 3 illustrates a methodology of inputting and storing messages in accordance with an aspect of the innovation. While, for purposes of simplicity of explanation, the one or more methodologies shown herein, e.g., in the form of a flow chart, are shown and described as a series of acts, it is to be understood and appreciated that the subject innovation is not limited by the order of acts, as some acts may, in accordance with the innovation, occur in a different order and/or concurrently with other acts from that shown and described herein. Moreover, not all illustrated acts may be required to implement a methodology in accordance with the innovation.
[0035] At 302 , the cover of a message keeper can be opened to expose a message input interface. For instance, the cover can be hinged into an open position. As described above, it will be understood that the cover is optional—aspects can exist without the cover portion. As well, in other aspects, a cover can be pivoted, slid, removed, etc. without departing from the spirit and scope herein. At 304 , a message can be input into the message interface. For instance, a secret message can be spoken, or whispered, into the interface. In other aspects, a physically documented message (e.g., written note) can be input into the interface. In either scenario, the message is transferred into a first, or message acceptance, chamber. As described above, this chamber can be a real or virtual cavity depending upon the design of the message keeper.
[0036] At 306 , a chamber selector can be activated to facilitate movement (virtual or actual) of the message from the first chamber into storage, e.g., for safekeeping. The message is either virtually, or actually, moved from the first chamber to a second, or storage, chamber at 308 . A dashed arrow is included on FIG. 3 to indicate that the process described herein is recursive and can be repeated for subsequent messages as desired.
[0037] FIG. 4 illustrates an exploded view of an example message keeper 100 . As illustrated, base housing portion 102 can include multiple subcomponents as shown. In particular, base housing portion 102 can include an upper housing portion 402 and a lower housing portion 404 that, when connected, form a cavity. Within the cavity, a chamber selector plate 406 and chamber identification plate 408 can be positioned.
[0038] The upper portion 402 of base housing portion 102 can include apertures or openings for message input, chamber selector slide as well as chamber visualization. A clear, translucent or semi-transparent window 410 can be placed onto the chamber view aperture as shown. It is to be appreciated that the components and subcomponents shown in FIG. 4 can be molded of plastic or other suitable material. As well, window 410 can be constructed of clear plastic or other translucent or semi-transparent material. In other aspects, the window portion 410 can be molded into the upper base portion 402 in a slotted or other manner that enables one to view the interworkings beneath the upper housing portion 402 . This and other modifications to design are contemplated and to be included within the scope of this disclosure and claims appended hereto without departing from the features, functions and benefits described herein.
[0039] As illustrated described above, a chamber selector 110 can be moved (e.g., slid) along a track or guide 112 to facilitate movement (actual or virtual) of a message from one chamber to another. As shown, selector plate 406 can be molded with apertures such that, when positioned in a particular location, a first chamber can appear via the chamber viewing window 410 . When the chamber selector is moved into a disparate position, an individual (e.g., a child) can view a chamber swap by way of the chamber viewer 410 as well as the message input interface. Additionally, as shown, the chamber selector 110 can be molded integral to the selector plate 406 .
[0040] As described supra, it is to be appreciated that the first and second chambers can be actual or virtual cavities without departing from the spirit and scope of this specification and claims appended hereto. In other words, if a message is actually (or physically) inserted, e.g., tangible on paper, the chambers can be real cavities whereby the paper can transfer from a first chamber to the next. In a virtual aspect, the chambers can be imaginary and need not be physical chambers or cavities. In this aspect, colors, patterns, etc. viewed through the chamber viewer 410 can be employed to translate an appearance of the message moving from a first to a second chamber. Still further, it is to be understood that aspects exist that employ actual chambers which are able to be used with both tangible (e.g., paper) and intangible (e.g., spoken) messages.
[0041] Chamber plate 408 can be configured in a manner so as to convey an appearance of actual chamber swap, in both physical and virtual aspects. In aspects, the chamber plate 408 can be configured (or molded) with patterns, indicia, colors, etc. that convey a switch from one chamber to the next. For example, a first chamber can be shown to have a yellow background whereas, after the chamber selector is moved, the background can change to purple. This visual change can convey an appearance of moving the message from one chamber to the next, regardless of whether the movement is actual or virtual.
[0042] Referring now to FIG. 5 , an alternative exploded view of example message keeper 100 is shown. In the alternative view, the lid portion 104 is illustrated in an open or “hinged-open” position. Hinging means 106 , in this example, is configured using a molded portion of the lid portion 104 and upper base portion 402 . These portions are illustrated at 502 and 504 respectively in FIG. 5 . While a specific hinging means 106 is shown, those skilled in the art will appreciate that other aspects exist that employ different or no hinging means. These aspects are included within the scope herein.
[0043] FIGS. 6 and 7 are respectively rear and side cut-away views of example message keeper 100 . Essentially, each of these figures illustrates interconnection and placement of the subcomponents to the base housing portion 102 . The chamber viewing aperture is illustrated at 602 within selector plate 406 . As described, the aperture 602 enables visualization of the chamber plate 408 . The chamber plate 408 can include effects such as colors, textures, indicia, etc. that facilitate visualization of chamber changes.
[0044] Additionally, the upper 402 and lower 404 portions of base housing portion ( 102 of FIG. 1 ) can be connected using tabs 604 . In this example, tabs 604 are molded into the lower portion 404 . Upon assembly, the tabs 604 lock into raised portions of the inner side of upper portion 402 causing the two portions 402 , 404 to fixedly connect.
[0045] FIG. 7 illustrates a side cross-sectional view of the example message keeper 100 . As shown, the cross-sectional view illustrates interconnection and placement of each of the subcomponents. Further, it will be appreciated that this example resembles a locket such that a string, carry strap, necklace or the like can be inserted into aperture 702 . This and other design aspects are contemplated and to be included within the scope of this innovation.
[0046] Additionally, message keeper 100 can include a key locking means (not shown) that prohibits the lid portion 104 from opening. Other aspects of locking means are contemplated, including, but not limited to, key locks, combination locks, digital locks that recognize handwriting, digital locks that recognize a code, digital locks that recognize voices, and others.
[0047] Referring to FIGS. 8 through 11 , an example message keeper 800 in the shape of a makeup or cosmetic compact is shown. In this example, the components are fabricated (or molded) from plastic. FIG. 8 illustrates a top perspective view of message keeper 800 . As with the aforementioned aspects, the components of this aspect may be transparent (or semi-transparent) such that the messages may be seen transferring between chambers, e.g., if they are physical messages.
[0048] With continued reference to FIG. 8 , the message keeper 800 is configured in a clam shell-like arrangement similar to a makeup compact or a locket and represents potentially a pocked-sized version. The message keeper utilizes a hinge 802 which allows the device 800 to be opened. The hinge 802 pivots the cover 804 thereby exposing the interior of the device 800 . A latching mechanism 806 can be employed to trigger opening of lid portion 804 . In this aspect, latching mechanism 806 employs a push button. However, it is to be understood that most any mechanism (e.g., detent/snap) can be employed without departing from the spirit and/or scope of the innovation and claims appended hereto.
[0049] A side perspective view of device 800 is illustrated in FIG. 9 . As described with reference to the previous aspect, device 800 can be equipped with a locking means that prohibits opening of the lid portion 804 . In yet other aspects, a locking mechanism (not shown) can secure access to the interior components housed below the lid 804 . These locking mechanisms will be better understood upon a review of the figures that follow.
[0050] In the open state depicted in FIGS. 10 and 11 , there is a first side 1002 (e.g., lid 804 ) and a second side 1004 pivotably connected by way of hinging means 802 . The first side 1002 may be used for makeup and include a reflective surface (e.g., mirror as in a makeup compact), to store a picture (e.g., as in a locket) or for other purposes. The second side 1004 is the message storing portion where the message storage chamber(s) is enclosed with a lid 1006 . The lid 1006 pivots on hinging means 1010 and can be locked with a locking mechanism 1008 . Though the locking mechanism 1008 is shown as a means that most likely uses a key, other locking means are contemplated such as combination locks or the like. In this aspect, messages may be retrieved from a single chamber message keeper by opening the lid 1006 to provide access to the message storage chamber. Similarly, in a multiple chamber aspect, a similar mechanism can be employed to access stored messages.
[0051] FIG. 11 illustrates a side view of device 800 in an open position. As will be understood, the device 800 is most often used in connection with tangible or physical messages that can be placed within cavity 1102 for safekeeping. The locking means 1008 can provide security to a child (or other user) by knowing that their messages are safe from public view.
[0052] This message keeper 800 may utilize most any message input system, for example, though a simple sliding mechanism that exposes an aperture for message entry. The user may deposit physical or spoken messages through an opening created by a sliding mechanism in an open state. Unlike the earlier aspect that employed two chambers, in this aspect, messages can reside in a single storage chamber 1102 . The chamber can be locked by a locking means 1008 and pivoted open by way of hinging means 1010 .
[0053] In addition to the examples shown and described, other pocket type configurations similar to the embodiments are also possible such as a sliding arrangement instead of a pivoting arrangement. Aspects may include a detent or snap-to-close feature and retention devices such as key chains, necklaces, clips, lanyards, and the like. It is to be understood that most any of the message keeper embodiments may be configured as single- or multi- (e.g., double) chamber devices.
[0054] FIGS. 12 to 16 illustrate another example of a clamshell shaped embodiment of a message keeper 1200 in accordance with the innovation. As shown in FIG. 12 , the apparatus 1200 includes a cover portion 1202 and a base portion 1204 . The cover portion 1202 can be hingedly connected to the base portion 1204 by way of a hinging means 1206 . In other aspects, the cover portion 1202 can be press-fit, snap-on, screwed on, or the like. As shown, the cover portion can include a latching means 1208 (e.g., detent/snap).
[0055] In one particular aspect, once closed, a locking means 1210 can be employed to secure the apparatus in a closed position. The aspect of FIG. 12 can optionally employ a locking means 1210 and a key 1212 to secure the apparatus in a closed position. Other aspects can employ combination-type locks or the like.
[0056] With continued reference to FIG. 12 , a cavity cover 1214 can include impression 1216 that is configured or adapted for storing a pad of paper (e.g., 3M-brand Post-It™ products or the like). The cavity cover 1214 can be hingedly connected to the base portion 1204 by way of a hinging means 1218 (or other suitable connection).
[0057] Referring now to FIG. 13 , here, the cavity cover 1214 is illustrated in an open position thereby exposing the cavity 1302 . In operation, a message can be written onto a piece of paper and subsequently stored within cavity 1302 . It will be appreciated that, the locking mechanism 1210 can be used to securely store the message within cavity 1302 by locking the cavity cover 1214 in a closed position atop the base portion 1204 .
[0058] FIGS. 14 and 15 illustrate an example locking means or mechanism 1210 in accordance with aspects of the innovation. As shown in FIG. 14 , the locking mechanism can include a cap portion 1402 that encloses the locking mechanism 1210 . An example locking mechanism is illustrated in FIG. 15 to add perspective to the innovation. As will be understood, rotation of a key will open the locking means thereby enabling the message keeper to open. It will be understood that most any locking mechanism can be employed in alternative aspects without departing from the spirit and/or scope of the innovation and claims appended hereto.
[0059] FIGS. 16 and 17 are illustrative of the example clamshell message keeper in a closed and locked state. As described herein, it will be appreciated that the message keeper can be configured in most any shape without departing from the features, functions and benefits set forth herein.
[0060] The message keeper is a device that can be used to stimulate the creativity and imagination of young children. Accordingly, the innovation will most likely be used in a manner for amusement and entertainment purposes. However, due to its nature as a verbal device, it may be used as an educational tool to promote literacy as an edutainment device to a wide age range.
[0061] In place of, or in addition to, storage chamber(s), it is to be appreciated that message keepers described herein can be equipped with electronics means capable of capturing audible messages. The following paragraphs describe how these aspects of a message keeper can be used as an educational device and how it can integrate to a software tool, for example, an Internet (Web) software tool, software-based educational tool or the like. Unlike other educational devices and toys that have a significant learning element to them, the message keeper is a device that can integrate directly with the daily lives of children. This means that it is a device that is likely to be with the user throughout the day and is not a game that either one is forced to use for learning or one that the user easily tires of. To make the message keeper a device that is prolifically used, the learning element can be partially separated from amusement elements.
[0062] Thus, children are able to use the innovation, have fun with the device, and then re-live the enjoyable moments while they transfer their day's activity to a software tool, e.g., standalone software or Web-based (or other computer-based environment) learning tool. It is contemplated that this learning tool can complement the product and provide targeted marketing opportunities.
[0063] In these examples, an online or computer-based tool can be provided that allows users to upload messages for secured storage. The tool can also facilitate generation of diary or journal entries and to be able to link these entries to the dreams, secrets, etc. Still further, the tool can allow for social networking with other users (e.g., Web users), for example, via an invited friend network. Other uses of the tool can include providing story starter aides that are both general and targeted to key words from the user's inputs, delivery of vocabulary words and grammar tips each day, correction of grammar and spelling of the inputs in an enjoyable manner, providing parental controls and parental monitoring of learning trends and needs for further educational supplement; and providing a mechanism for targeted advertising through a wide range of ages.
[0064] As will be understood, the message keeper can be packaged into a product that is fun to use and can stand alone on this merit. The features, functions and benefits of the innovation can also be integrated with significant educational elements that promote literacy through enjoyable and contributory learning.
[0065] As described herein, the message keeper device can be designed in a multitude of different versions, types, and aesthetic configurations. However, they all are similar in that they are designed to be message storage devices. As described, aspects differ in the way that messages are input and stored within the device, whether physical or spoken messages. Messages may be whispered into the device, written on a note card, or recorded with an audio recording device.
[0066] In electronic aspects, with regard to whispered messages (typical for younger users), the person using the device will benefit by remembering the message for later interface to a Web or software tool. For written messages, they may be extracted from the message keeper and, if desired, transcribed into a Web tool. Recorded and other electronically captured messages may be uploaded automatically by using a computer docking tool which may interface (e.g., via Universal Serial Bus (USB) or wirelessly) to a computer.
[0067] As stated above, the drawings and this detailed description are provided not to limit the scope of the innovation and device but rather to depict several embodiments that illustrate features, functions and benefits of the innovation. Many of the aspects of each embodiment are applicable to many of the other embodiments but are, for simplicity, described only for some of the embodiments.
[0068] Some of these flexible and interchangeable attributes are: sizes and shapes, materials, colors, opacity, types and placement of openings, types and placement of closures, types and placement of locking mechanisms, types and placement of hinging means, position of storage chamber(s) relative to the receiving chamber(s), types of messages that the device can store, means to remove the messages, ancillary devices, electronics, etc.
[0069] Accordingly, embodiments may have different sizes and shapes including, but not limited to, the following shapes: conical, frusto-conical, cylindrical, spherical, those with a polygonal cross-section, clamshell, shapes with amorphous cross-sections, free form three dimensional shapes, round, square, rectangular, and others. Additionally, embodiments are contemplated to be vertical devices. That is that the message is deposited in a top down manner and is in turn routed to another vertically oriented opening to be received by a storage chamber that is generally vertically underneath the first chamber and delivery mechanism. Other configurations are possible such as side-by-side, diagonally oriented chambers, and routings that also take on free form shapes as well as multiple storage chambers into which messages can be stored.
[0070] In accordance with aspects of the innovation, the message keepers can be constructed in a manner that includes two primary components/sub-assemblies: the storage chamber, and the delivery mechanism. Essentially, the delivery mechanism can be used to describe the input together with the chamber selector.
[0071] The embodiments of the innovation can be fitted with additional openings with closures of various types to the storage chamber. This will allow the easy removal of a message. Preferably, these closures would be threaded but all types of closures are possible (e.g., press-fit, snap-fit). As well, the closures can be equipped with locking means as desired.
[0072] Each of the described embodiments may be fabricated from materials of different colors, transparency, and, opacity. These materials include, but are not limited to, plastic fiberboard, composite materials, various ferrous and non-ferrous metals, wood, aluminum, alloys, and others. In other words, most any suitable material can be employed. Additionally, it is to be appreciated that aspects can include non-rigid configurations without departing from the scope of this specification. For example, where appropriate, non-rigid materials can be employed together with rigid materials in some aspects.
[0073] Each of the described embodiments may have different types and sizes of openings and closures. The openings through which a message is deposited may be of a variety of sizes and shapes including, but not limited to, round, oval, elliptical, polygonal, free form, and others. Typically, there is both a first and second opening per message keeper; one for depositing the message and one through which the message passes (or virtually passes) from the first chamber to the second or storage chamber. The relative position of the first and second opening to one another is not fixed and may be coincident or non-coincident and may even be non-parallel. The innovation contemplates many types of closures, most of which are interchangeable from embodiment to embodiment, and some of which ensure that one opening is closed at all times.
[0074] Some of the embodiments are described to be used in conjunction with tools and other devices. Other devices and toys that message keepers integrate with include, but are not limited to, voice/sound recorders, USB and other computer interface devices, wireless communication protocols, text entry devices, digital cameras, diaries and scrapbooks, dolls and other toys and figurines, and music players such as MP3 devices, and others.
[0075] What has been described above includes examples of the innovation. It is, of course, not possible to describe every conceivable combination of components or methodologies for purposes of describing the subject innovation, but one of ordinary skill in the art may recognize that many further combinations and permutations of the innovation are possible. Accordingly, the innovation is intended to embrace all such alterations, modifications and variations that fall within the spirit and scope of the appended claims. Furthermore, to the extent that the term “includes” is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim. | A message storage apparatus that can stimulate creativity and imagination of children and adolescents is disclosed. The apparatus facilitates storage of messages such as secrets, memories, notes, diary entries, wishes, dreams, trivia and other educational facts, quiz and other game questions, valentines, etc. More particularly, the apparatus can virtually (or physically) store intangible (and tangible) messages, thereby enhancing creativity and imagination. The message storage apparatus has a message delivery system that receives a message and delivers it securely to a storage chamber where the message can be accessed at a later time. | 0 |
[0001] This is a Division of application Ser. No. 08/944,945 wherein applicant elects Species No. 8, Fig. No. 21, of the Parent Issued U.S. Pat. No. 6,435,611, for prosecution.
CROSS REFERENCE TO RELATED APPLICATIONS
[0002] Provisional application No. 60/027,767, filed on Oct. 4, 1996.
STATEMENT REGARDING FEDERALLY SUPPORTED RESEARCH OR DEV
[0003] Not applicable.
REFERENCE TO A SEQUENCE LISTING, A TABLE, ETC
[0004] Not applicable.
BACKGROUND OF THE INVENTION
[0005] This invention relates generally to devices used in physical therapy and, more particularly, to a spine tensioning, traction and muscle exercise apparatus.
[0006] Back pain is a national health problem. It is the second most likely reason people go to the doctor. It is estimated Americans spent $20 billion alone in 1990 on back-related medical bills. More and more people sit for hour upon hour and perform computer work. Studies show that sitting creates two times the pressure on the low back as compared to standing.
[0007] Numerous devices have been devised to help with this problem, including the following:
[0008] U.S. Pat. No. 4,793,665 to Kvalheim discloses a chair with a seat rest and separate backrest. However, it cannot provide spine tensioning because it supports the user's posterior.
[0009] U.S. Pat. No. 4,432,108 to Chapman, U.S. Pat. No. 2,248,369 to Laudersen and U.S. Pat. No. 2,112,678 to Rausch all teach leg supports, but do not teach spine tensioning.
[0010] U.S. Pat. No. 5,042,800 to Walter teaches a spine tensioning body support whereby the user's back and legs are supported but not the posterior. The four vertical risers and two elongated members are fixed and require dismounting and disassembly to change leg and back support location. Additionally, the users must support themselves with their arms on the elongated members and lift one leg at a time over the leg rest to place them in the device. This feat is difficult for some users and may prohibit older users and those with back pain from obtaining the benefits of the device.
SUMMARY OF THE INVENTION
[0011] It is thus an object of this invention to provide the user a simplified access for practicing spine tensioning, traction and development.
[0012] Another object of this Invention is to provide an economical means to practice spine tensioning, traction at a minimal cost without the aide of a therapist.
[0013] Still another object of this invention is to provide a device, which may readily be utilized as a chair and, with no structure adjustments, nor dismounting also function as a dual support spine-tensioning device.
[0014] Another object of the invention is to provide the user with an opportunity to vary and increase the mild limited tension to the spine by allowing the user to lay face down in the apparatus.
[0015] Another object of this invention is to provide a chair that, in the reclined position, decompresses the low back as opposed to doubling the pressure when sitting upright.
[0016] Still another object of this invention is to provide a computer input chair that may also function as a spine tensioning computer input chair from which one may still be able to perform computer related tasks.
BRIEF SUMMARY OF THE INVENTION
[0017] These and other objects of the invention are accomplished by a spine tensioning dual body support chair that includes two substantially planar body supports that rotate in similar direction and opposite elevation to one another. A rotating means will move body supports in similar rotation and opposite elevation to one another. Preferably, body support rotating means will have two end limits which will hold the body supports in a chair position, one support higher than the other, or in a spine tensioning position, both body supports in near equal elevation. Rotating means may also be fixable so that body supports may be fixed in any rotation or elevation to one another so desired to perform various spine tensioning, traction or developing exercises. These body supports will support the human body with different reactive forces depending on their relative elevations, rotational position and distance from one another.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0018] FIG. 1 is a perspective view of the dual body support spine-tensioning chair, an enhanced chair apparatus for sitting and spine developing.
[0019] FIG. 2 is a side view of the apparatus with the user in a sitting position, one body support higher than the other.
[0020] FIG. 3 is a side view of the apparatus with a user in a reclined seated position with body supports near equal in elevation.
[0021] FIG. 4 is a side view of the apparatus with body supports near equal in elevation user in horizontal position.
[0022] FIG. 5 is a side view of the apparatus with the body supports near equal in elevation user stretching VIA hips elevated face up.
[0023] FIG. 6 is a side view of the apparatus with the body supports near equal in elevation user stretching VIA hips elevated face down.
[0024] FIG. 7 is an enlarged side view of the body support pivot and elevation limit device.
[0025] FIG. 8 is a side view of the upper body support-connecting block
[0026] FIG. 9 is an enlarged side view of an alternate body support elevation limit device.
[0027] FIG. 10 is a side view of the lower body support-connecting block
[0028] FIG. 11 is a side view of alternate means to achieve and maintain chair and spine tensioning dual body support elevations.
[0029] FIG. 12 is a side view of an alternate support-connecting block.
[0030] FIG. 13 is a side view of alternate means to achieve and maintain chair and spine tensioning dual body support elevations.
[0031] FIG. 14 is section A A of FIG. 12 .
[0032] FIG. 15 is a side view of alternate means to achieve and maintain chair and spine tensioning dual body support elevations.
[0033] FIG. 16 is section B B of FIG. 10 , showing alternate lower body support movements in relation to support rod.
[0034] FIG. 17 is a side view of alternate means to achieve and maintain chair and spine tensioning dual body support elevations.
[0035] FIG. 18 is front view of office chair spine tensioning dual body support base.
[0036] FIG. 19 side view of alternate spine tensioning dual body support chair
[0037] FIG. 20 is a perspective view of the apparatus with alternate base for mounting positioning means.
[0038] FIG. 21 is water application of dual body support VIA floats.
[0039] FIG. 22 is a side view of alternate user positioning.
[0040] FIG. 23 is a perspective view of alternate attachment of rod to elongated member with sliceable adjustment.
[0041] FIG. 24 is a side view of each dual body supports reactive force on a 100-LB. user as body supports rotate and elevation changes occur.
[0042] FIG. 25 load, shear and moment diagrams, of a simple beam with two supports.
[0043] FIG. 26 side view with rollers at upper and lower body support
[0044] FIG. 27 is a side view of alternate rounded pad body supports.
[0045] FIG. 28 perspective view with rope between upper and lower body support
[0046] FIG. 29 perspective view of cloth upper and lower body support
[0047] FIG. 30 perspective view of cloth upper and lower body support suspended via rope.
[0048] FIG. 31 perspective view of upper and lower body support suspend via metal straps
[0049] FIG. 32 side view of computer application
[0050] FIG. 33 side view of computer application in reclined position
[0051] FIG. 34 side view mattress application
[0052] FIG. 35 perspective view of alternate base
[0053] FIG. 36 front view of alternate base
[0054] FIG. 37 side view of alternate base
[0055] FIG. 38 side view of alternate base in reclined position
[0056] FIG. 39 side view of alternate base
[0057] FIG. 40 side view of alternate base
[0058] FIG. 41 side view of alternate base in reclined
[0059] FIG. 42 side view of alternate upper body support
[0060] FIG. 43 side view of alternate upper body support in hyper extension mode
[0061] FIG. 44 side view alternate upper body support
[0062] FIG. 45 front view alternate back support
[0063] FIG. 46 side view alternate upper back support practiced VIA lower body support
[0064] FIG. 47 side view alternate upper body support
[0065] FIG. 48 side view alternate upper body support
[0066] FIG. 49 side view auto application
[0067] FIG. 50 respective alternate with rope reversibly connected
[0068] FIG. 51 side view with upper body support positioned to target L1
[0069] FIG. 52 side view with upper body support positioned to target L2
[0070] FIG. 53 side view with upper body support positioned to target L3
[0071] FIG. 54 perspective with rotating upper body support to target thoracic spine
[0072] FIG. 55 front view upper body support demonstrating independent or concurrent movement
[0073] FIG. 56 front view neck support
[0074] FIG. 57 side view neck support
[0075] FIG. 58 side view neck support that extends with clockwise movement of upper body support
[0076] FIG. 59 side view alternate upper or lower body support connection
[0077] FIG. 60 side view alternate positioning means
[0078] FIG. 61 section AA of FIG. 60
[0079] FIG. 62 side view alternate arm support
[0080] FIG. 63 side view alternate upper and lower body support hangers
[0081] FIG. 64 side view alternate upper and lower body support for compression
[0082] FIG. 65 side view alternate upper and lower body support tension
[0083] FIG. 66 side view alternate upper and lower body support rope/rubbers hangers
[0084] FIG. 67 side view alternate lower body support with alternate heal attachment
[0085] FIG. 68 end view of alternate lower body lower body support heal attachment
[0086] FIG. 69 top view alternate upper and lower body support
[0087] FIG. 70 side view alternate upper and lower body support
[0088] FIG. 71 side view with upper body support lower
[0089] FIG. 72 side view lower body support lower
[0090] FIG. 73 side view person face down in apparatus
[0091] FIG. 74 side view upper body support/skeletal force diagram
[0092] FIG. 75 side view upper body support and lower body support with sliceable/adjustable knee to chest movement in compressed position
[0093] FIG. 76 side view upper body support and lower body support in compressed position
[0094] FIG. 77 side view showing upper body support extension/movement
[0095] FIG. 78 side view force diagram and resulting hip elevation force
[0096] FIG. 79 perspective view alternate neck support with hand grips
[0097] FIG. 80 side view bicycle application
[0098] FIG. 81 side view dimensioning of upper and lower body supports separation distance when compared to different size people
[0099] FIG. 82 side view of alternate neck support
[0100] FIG. 83 top view of alternate neck support
[0101] FIG. 84 side view of extremity spine exercising
[0102] FIG. 85 side view of alternate lower body support
[0103] FIG. 86 is A A view of FIG. 85
[0104] FIG. 87 is a contoured upper body support
[0105] FIG. 88 end view of various alternate arm positions
[0106] FIG. 89 perspective view spine exercising with round support holding means
[0107] FIG. 90 detail of pivot locking means
[0108] FIG. 91 side view of supports equipped with retaining straps
[0109] FIG. 92 side view of paddle boat spine exercising application
[0110] FIG. 93 side view of upper body support
[0111] FIG. 94 is a perspective view of another alternative embodiment in which the back support and the leg support are suspended by rope running through pulleys attached to portions of a frame, and in which hand grips are provided above the back support.
[0112] FIG. 95 is the same embodiment as FIG. 94 , except with the back support omitted.
[0113] FIG. 96 is a perspective view of the embodiment of FIG. 94 , except with a flexible non-stretchable strap (instead of ropes) connecting the back support to the hand grips.
[0114] FIG. 97 is a perspective view of the embodiment of FIG. 95 , with a flexible non-stretchable strap mounted between the hand grips.
[0115] FIG. 98 is a perspective view of the embodiment of FIG. 97 showing a user using the flexible strap to support his neck and also using the hand grips.
[0116] FIG. 99 is a perspective view of the embodiment of FIG. 95 except with an alternate leg support for the user's feet of the underside of the user's knees.
[0117] FIG. 100 is a perspective view showing a user employing the embodiment of FIG. 99 for rotational tension along the spine.
[0118] FIG. 101 shows an alternate rigid contoured back support for all of the previous embodiments.
[0119] FIG. 102 is an end view of the user of FIG. 100 using the apparatus of FIG. 99 .
[0120] FIG. 103 is a perspective view of neck support with retaining strap
[0121] FIG. 104 side view of upper body support
[0122] FIG. 105 side view of three support mode
[0123] FIG. 106 side view of upper body support positioned to place force on the sacrum for those suffering from spondylolisthesis
[0124] FIG. 107 side view of force above or under for rear end support
[0125] FIG. 108 perspective view of alternate upper body support
[0126] FIG. 109 is a side view of alternate roller to select and set rod to arm location
[0127] FIG. 110 front view of alternate upper body support equipped with hand grips
[0128] FIG. 111 side view FIG. 110
[0129] FIG. 112 shows the natural opposite movements of upper and lower body members when rotating
[0130] FIG. 113 side view of single body support
[0131] FIG. 114 side view of hinged supports
[0132] FIG. 115 side view of FIG. 114 in reclined position
[0133] FIG. 116 side view of turning block applicable to FIG. 109 part 1134
[0134] FIG. 117 is an elderly application that allows for near standing mounting in to instant invention
[0135] FIG. 118 side view of lower body support
DETAILED DESCRIPTION OF THE INVENTION
[0136] Referring to FIG. 1 , the apparatus comprises a base member 2 , consisting of two parallel elongated horizontal base members, two vertical risers, and a horizontal base member perpendicular to and connecting the two elongated horizontal base members. Body support elevation arms 14 , 14 a are elongated members pivotally mounted to base member 2 via pivot connection 26 . Dual body supports, 18 and 22 , are pivotally mounted to body support elevation arms 14 and 14 a via support rods 32 and 34 . Hand grips 10 and body support elevation limit blocks 24 and 24 a are attached to base member 2 .
[0137] FIG. 2 shows a user in the sitting position. The elevation of body support 18 is higher than body supports 22 creating a chair or seated position. A fixed, stable seat is created when body support elevation arm 14 rests on body support elevation limit block 24 .
[0138] FIG. 3 shows the user in the reclined seated position dual body supports at near equal elevation. A fixed, stable, reclined position is the result of body support elevation arm 14 resting on body support elevation arm limit block 24 . Hand grip 10 enables the user to change from seated to reclined position via a light force. Pivot 26 is placed near center of body support elevation arm 14 , between rods 32 , 34 such that body support elevation arm 14 will rest in either the seated or reclined position.
[0139] FIG. 4 shows the user in a horizontal position body supports near equal in elevation. Body supports 18 and 22 , pivotally mounted to rod 32 and 34 , enable this positioning.
[0140] FIG. 5 shows the user enabled to perform gravity assisted inverted stretch with body supports near equal in elevation. The body mass distributed on the A side of body supports creates this gravity assisted stretch by placing an upward force to the mid section of the body via resulting B pivot force.
[0141] FIG. 6 demonstrates dual body supports, near equal in elevation, user lying face down. The lever arm of users legs L about pivot 32 creates a greater traction force T than is achievable in FIG. 3 , user face up. This is because FIG. 3 traction force is not increased via lever arm L of FIG. 6 . Additionally, the resulting force T of FIG. 6 is directed to the lumbar portion of the spine where a majority of back discomfort occurs. FIG. 3 on the other hand is gravity induced only.
[0142] FIG. 7 shows body support elevation limit block 24 with its two limits: for sitting, 246 , and for reclining, 244 , that produces a fixed seat position S or fixed reclined position R.
[0143] FIG. 8 shows the upper body connecting block 180 . with travel range created by void 182 that allows support rod 32 to move freely within void 182 . Arm support 184 provides an arm rest that doubles as a means to provide the user a means to counteract the gravity forces that create spine tensioning. Neck rest 186 is pivotal mounted to upper body support VIA pivot 188 . Pivot 188 allows 360 degree movement of neck rest support 186 . Neck rest 186 has the ability to work in combination with armrest support 184 to match the gravity forces generated when the back support is positioned such that traction/gravity is acting on the upper body. All or half or combinations thereof of the gravity forces acting on the upper body may be countered with these supports.
[0144] FIG. 9 teaches another means for establishing fixed elevation relationships between the two body supports via limit block 264 . This body support elevation relationship block is adjustable through adjustment holes 260 to fix and hold body support elevation arm at any desired body support relationship.
[0145] FIG. 10 shows the connecting block 220 with void 222 that allows rod 34 to move freely within the void.
[0146] FIGS. 11, 13 , 15 and 17 show alternate body support elevation relationship varying means. FIG. 11 is a typical stack able chair consisting of a base 2 with four support risers 202 . FIG. 13 is a rocking chair with rounded bottom end 209 . FIG. 15 is a wheelchair. FIG. 17 utilizes ropes supported by rollers above. All above FIGS. 11, 13 , 15 , 17 utilize dual body supports 18 , 22 and a form of the body support elevation relationship varying means 26 and limit blocks, 246 for sitting, and 244 for reclining.
[0147] FIG. 12 shows an alternate mounting block that has void 182 that allows leg support 22 to rotate in any direction.
[0148] FIG. 14 shows the ranges of motion A and B for either upper body support 18 or lower body support 22 .
[0149] FIG. 16 shows the A and B movements of either upper body support or lower body support in relation to rod 34 .
[0150] FIG. 18 shows an office chair base 2 for mounting dual body support elevation arms 14 via pivots 26 . FIG. 19 shows alternate dual body supports 18 and 22 that are substantially planar with convex cross section.
[0151] FIG. 20 shows an alternate enhanced chair for spine developing, tensioning and development. It comprises a base member 2 that consist of two upside down u shaped members that are interconnected and made stable by members 244 and 246 that also serve as limit blocks 246 and 244 . Positioning means 14 assumes a 90 degree fixed position as opposed to the elongated members 14 of FIG. 1 . Upper body support 18 is fixedly mounted to positioning means 14 canceling the need for rods shown in FIG. 1 as does the fixed lower body support 22 cancel the need for rod 34 shown in FIG. 1 . Pivot 26 performs the same function as 26 of FIG. 1 allowing the positioning means 14 to assume either a sitting position or a reclined position in FIG. 11 . Alternately upper body support and lower body support could be pivotally mounted in the alternate base mode FIG. 20 to provide the same benefits to the user as taught in FIGS. 4 and 5 . Benefits to the user in the alternate base mode FIG. 20 are equal to those taught by FIGS. 3 and 4 with fixed upper and lower body supports as shown in FIG. 22 . To gain the benefits of this enhanced chair for aiding the spine one sits in the chair and reclines. By reclining the body weight is distributed over two supports. This places the human spine under the same member forces as a simple beam supported by two vertical forces, it produces tension and compression. The human spine is undoubtedly the most important muscle bone structure in the human body. Chiropractic teaches this and anyone realizes the many functions of the spine. Simply supporting the human body in two different places with the only human link between the supports places the spine subject to any number of forces in any number of directions. It is this placing the human spine as the only human link between the two vertical supporting forces that enables one to practice exercise of the spine.
[0152] Referring to FIG. 21 , body supports 22 and 18 are shown as floats to be utilized in a pool or body of water to practice another mode of dual body support spine tensioning. The water 14 acts as the dual body support elevation relationship arms 14 of FIG. 2 .
[0153] Referring to FIG. 22 , dual body support elevation relationship arm 14 is set with body support 22 higher than body support 18 to facilitate sit ups and alternate directional forces on the spine.
[0154] FIG. 23 teaches slide able mounting of rod 32 to arm 14 of FIG. 1 as a preferred alternate. Position is fixed via pin 160 into holes 162 into arm 14 . This allows for easy adjustment to accommodate the varying user's height as required. A clamp means would also be applicable here. This connection could also be slide able with user in device to create another exercise range for the device.
[0155] FIG. 24 represents the dual body supports weight transfer from one support to the other as rotation and elevation changes occur. The support locations shown in FIG. 24 a depicts the full 100 pound user load on the lower support. In FIG. 24 b , the user's load is distributed 70/30 and in FIG. 24 c it is 50/50. In FIGS. 24 d and e , the user's weight continues to transfer until the full user weight is carried by the body support of FIG. 24 a that had no load on it. This, in combination with the moment and shear drawings, is what distinguishes this device from a traditional chair. The dual body supports in this invention can take a user from a seated position and place their body subjected to two forces that are spaced apart and create beneficial forces to the skeletal system.
[0156] Referring to FIG. 25 , shear and moment diagrams are shown for simple beams with two supports. What is important about these diagrams is the way shear and moment forces change, as a result of supports location change. Body support location changes have similar effect on the user's body and spine. The two supports are created in the Dual Body Support spine-enhancing chair. Varying support locations under a simple beam/user, supported by two supports, creates different shear, moment, compression and tension forces, induced in the supported beam/user. The ability to adjust the dual body supports' horizontal distance from each other, as well as their relative elevation and rotation positioning enables any number of force combinations; compression, tension, shear and moment, to be applied to the spine and skeletal system. This enables the dual body support spine-enhancing chair to increase spinal mobility, flexibility and health through a rotatable dual body support means.
[0157] FIG. 26 demonstrates an alternate leg and back support that consists of rollers 180 which enables a person to roll and receive greater stimulation from the rollers when sitting in this apparatus.
[0158] FIG. 27 is a side view of alternate padded rounded supports.
[0159] FIG. 28 shows another version of the apparatus where part 190 may serve as a limiting device, which may limit the distance between the back support and leg support. Knots or something similar (like rosary beads) will enable the flexible 190 to fix position on the lower body support 22 .
[0160] FIG. 29 shows another alternate means of the chair to where the leg support 22 and the back support 18 consists of a canvas type of material stretched around the frame 24 and form leg support 204 and back support 208 .
[0161] FIG. 30 shows an alternate means of supporting the leg support and the back support via flexible member 214 that will enable the leg support or the back support move in the various ways shown.
[0162] FIG. 31 is another alternate means of supporting the body supports 22 and 18 via straps 224 that will enable legs support to move in the A B motion or the back support to move in the A B motion.
[0163] FIG. 32 shows another alternate version of the apparatus in the sitting position, back support 18 equipped with a mouse support 238 also shown is a video screen to 234 .
[0164] FIG. 33 the computer version of the apparatus is shown in the reclined position.
[0165] FIG. 34 shows an alternate means for the lower and upper support in which they consist of mattress or cushion 250 .
[0166] FIG. 35 is a perspective view of the apparatus with the leg support 22 and back support 18 are supported by a substantially rectangular members 260 .
[0167] FIG. 36 the front view of the alternate apparatus shown of FIG. 35 is shown with the substantially rectangular base member 260 and back support 18 and leg support 22 . The rectangular members 260 are connected via a horizontal member 260 .
[0168] FIG. 37 is a side view of FIG. 35 in which the pivot for the leg 284 is shown and the pivot for the back 288 is shown connected to the substantial rectangular member 260 .
[0169] FIG. 38 members 284 and 288 the FIG. 37 are shown able to move within slide 294 for the leg and 298 for the back which will enable the apparatus the sitting and reclined position.
[0170] FIG. 39 shows another alternate version of the apparatus which the leg support 22 and back support 18 maybe mounted on the floor.
[0171] FIG. 40 is a an exercise apparatus of the device where leg support 22 and back support 18 are connected via semi circular member 314 . This member 314 is a pivot connected to the base member 318 via pivot 322 .
[0172] FIG. 41 shows reclined position.
[0173] Referring to FIG. 42 , it has round ridged member 334 under upper body support 18 and lower arm grips 338 .
[0174] Referring to FIG. 43 the reclined position is shown rocking backwards on number 334 .
[0175] FIG. 44 is a alternate means where user is supported only on the upper body support. Pivot 358 may be set and locked for varying pivot positions or alternate pivot ranges.
[0176] FIG. 45 is a front view of back support 18 showing arm supports 184 and notches 364 to enable user's arms to pass by back support 18 .
[0177] FIG. 46 alternate means where back support 18 provides upper body support only. 184 can hold user in position pivot 358 may be rotated or fixed in location. Positioning arm 14 is connected to said base member 2 via pivot 26 which is fixable or rotated.
[0178] FIG. 47 alternative use is shown, where the user kneels and obtains body support on 2 .
[0179] FIG. 48 alternate means of upper body support 18 where 184 arm supports have hand grips attached whereby user may obtain a varying means of skeletal forces.
[0180] FIG. 49 defines the upper and lower back support in motor vehicle operated mode. Supports 22 and 18 are shown, steering wheel 424 and gas pedal 428 are also shown.
[0181] FIG. 50 another alternate method where rope 434 of FIG. 43 is shown across 442 and 438 so that reverse horizontal variances are created between 18 upper body support and lower body support 22 .
[0182] FIG. 51 shows alternate positioning of upper body support so its force is discontinued at L1 vertebrae creating force directed specifically on L1 vertebrae.
[0183] FIG. 52 upper body support is positioned to create a force change (support vs. no support) directed at the L2 vertebra.
[0184] FIG. 53 upper body support is positioned to create differing forces on the L3 lumbar.
[0185] FIG. 54 rotational movement of upper body support allows user to exercise the thoracic portion of the spine.
[0186] FIG. 55 shows the upper body support 18 able to rotate side to side what is beneficial to the users spine is that neck support 186 may rotate in the same and opposite direction of upper body support 18 , additionally neck support 186 may operate independently of a fixed upper body support 18 .
[0187] Referring to FIG. 56 neck support 186 is shown with pivot 188 that enables neck support 186 to rotate side to side
[0188] Alternate version of neck support 186 is shown in FIG. 57 . It is connected to upper body support 18 via 514 spring or similar means to allow forward backward movement of neck support 186 with resistance.
[0189] FIG. 58 alternate view upper body support 18 is shown where upper body support clockwise rotation creates extension of neck support 186 .
[0190] Referring to FIG. 59 alternate connection of lower support 22 is achieved via ball joint 534 equipped with tensioning screw 538 that locks ball joint 534 or allows its user lower back support position to be subjected to resistance to movement.
[0191] FIG. 60 shows alternate version of positing arms slide 544 enables rod 34 to move within its opening. Pin 552 may limit movement of rod 34 and be adjusted via pin sleeves 548 .
[0192] FIG. 61 is section A-A of FIG. 60 . Rod 34 narrowed at 554 and enlarged at 558 provides slide able attachments of rod 34 to positing arms 14 .
[0193] FIG. 62 displays an alternate version of positioning means 14 with springs 564 incorporated to create a spring like resistance to movement of rod 34 .
[0194] FIGS. 63, 64 , 65 all displays the same positioning means 14 with flat bar 224 . What is significant is the gravitational effect when the user is supported in these three different figures.
[0195] In FIG. 63 the pivots 228 are directly above leg support 22 and back support 18 .
[0196] In FIG. 64 pivots 228 are extended and create an increased volatile tension on the body due to gravity acting on flat bar 224 , attempting to cause it to hang vertical. The opposite body effect, compression is created when flat bars 224 are moved inwards of FIG. 63 .
[0197] Flat bar 224 's rotatable connection to positioning means 14 in FIGS. 63, 64 and 65 allows dynamic movement of lower back support 22 and upper back support 18 .
[0198] In FIG. 66 positioning means 14 has a rope or rubber element 604 connecting to and supporting upper body support 18 and lower back support 22 enabling these body supports any horizontal movement and also with resistance if 604 where rubber or elastic.
[0199] Referring to FIG. 67 foot support 614 is pivotally mounted via pivot 618 to arm 616 that is slide able mounted to lower body support 18 via slide 612 . This enables the user to extend foot support 614 and lock slide 612 so the users heels will rest beyond foot support 614 . Once in 450 this position the user may obtain tension and muscle exercise from neck support 186 continuously down through the body to the ankles. Contracting one ankle cause the other ankle to be extended via pivot 618 .
[0200] Referring to FIG. 68 an alternate version of leg support 614 or FIG. 67 consists of ankle supports 624 that may be tubular in shape and U shaped to receive users heels and fixedly attached to heel rest 614 . Additionally pivots 628 may be utilized to allow foot rotation as shown in the A or B direction.
[0201] Referring to FIG. 69 a plan view is shown of an alternate lower body support 22 and upper body support 18 . Pivots 632 enable substantially planar support members to rotate in clockwise or counterclockwise direction.
[0202] Referring to FIGS. 70, 71 and 72 the planar upper body support 18 and lower body support 22 are shown at varying elevations to each other by alternating height of pivot 632 .
[0203] Referring to FIG. 73 an alternate use of the instant invention shows the user able to mount the apparatus face down, to reverse the spine stimulation/forces obtained when using the apparatus.
[0204] Referring to FIG. 74 a force diagram displays the counteracting forces to keep the user in a static position. Notable is the neck force N (at one end of the spine) and the lower arm force that is transferred into the upper body support 18 .
[0205] FIG. 75 demonstrates the users ability to perform sit ups via slides 544 of FIG. 60 .
[0206] FIG. 76 demonstrates the users ability to flatten their body into a horizontal plane, hips higher then FIG. 75 .
[0207] FIG. 77 displays the user with hips in a higher position than FIG. 76 ; and the ability to further extend upper body support 18 via slide opening 710 . It is the users hip movement from FIG. 75 to 76 to 77 and back to FIG. 75 that is very therapeutic to the spine.
[0208] Referring to FIG. 78 , the user is shown in the apparatus moving in direction A with resulting hip in the C motion. Additionally what is significant in FIG. 78 is back support 18 's pivotal motion around pivot 32 , such that as the weight increases to the right of pivot 32 an opposite uplifting force occurs to the left of 32 via back support 18 .
[0209] Referring to FIG. 79 an alternate neck support 186 is shown with hand grips 730 attached thereto. This enables skeletal forces to be transferring from hand grips 730 through users arms 480 to users spine and thoracic vertebrae.
[0210] Referring to FIG. 80 another alternate means of the invention is shown where the lower body supports 22 are independently mounted to gear driver rods 740 , which in turn rotate axle 742 to power wheel 744 .
[0211] Referring to FIG. 81 , two different height individuals are shown on the upper body support 18 and the lower body support 22 . What is significant about the two individuals of daring heights is that no modification is required to upper body support 18 nor lower body support 22 . The only difference required to accommodate the individuals height difference is only a greater A dimension for the taller individual.
[0212] Referring to FIG. 82 an alternate version of neck support 186 is shown connected to pivot 188 which allows neck support 186 up and down rotation.
[0213] Referring to FIG. 83 a plan view of neck support 186 is shown whereby pivot 188 allows the user to turn their head side to side. Note that FIG. 82 and FIG. 83 may be combined to produce each affect simultaneously.
[0214] Referring to FIG. 84 the user is shown in a reclined position. What is important is the dimension L over which spine tensioning compression and twisting may occur. It extends from neck support 186 down through heel support 614 .
[0215] Referring to FIG. 85 an alternate means of the apparatus is shown. The lower body support 22 and upper body support 18 are positioned to provide an unsupported distance D of FIG. 86 . Thus creating an upper body support and lower body support which are connected only by the spine so that independent movements of either body support will be transferred via the spine.
[0216] Referring to FIG. 87 a contoured version of back support is shown. This may be a felt or plastic molded member.
[0217] FIG. 88 displays front view of FIG. 1 . Base 2 , positioning means 14 , pivot 26 , lower body rod 34 are shown. What is significant of these three different views is different horizontal plain variances of the upper and lower body supports which enables the user to twist the spine longitudinally along its length promoting spine health through, compression, traction, muscle development and increased blood flow.
[0218] Referring to FIG. 89 an alternate version of the instant invention is shown with tubular round guides slidabley connected to lower body rod 34 and upper body rod 32 to enable 360 degree rotation of upper body support 18 and lower body support 22 .
[0219] Referring to FIG. 90 alternate pivot 8800 with nut 8840 enables the tensioning of positioning means 14 to be set so that, with a balanced lower body rod 34 and upper body rod 32 , the positioning arm 14 will hold user in any position from sitting to reclining and allow changes in rotational position with minimal effort/force on hand grip 10
[0220] Straps 8900 shown in FIG. 91 would be of nylon or similar material to retain user in position while partially or fully inverted.
[0221] Referring to FIG. 94 shown is another alternative embodiment 800 of the present invention. In this embodiment 800 , the collapsible frame 810 comprises a leg support frame 820 and a back support frame 850 joined together by a positioning means for positioning the leg support frame 820 and the back support frame 850 appropriately so that a user's posterior will not be supported, preferably a longitudinal member 890 . The leg support frame 820 comprises an elevated leg support member 822 joined to vertical leg support legs 824 and 826 by elbow joints 828 and 830 . The longitudinal member 890 is joined to the elevated leg support member 822 by a T-joint 832 Two pulleys 834 and 836 are preferably mounted on the elevated leg support member 822 , preferably on opposite sides of the T-joint 832 , and preferably adjustably spaced apart from each other. A leg support rope 838 preferably is run between the pulleys and preferably V-shaped leg supports 840 and 842 are suspended from the ends of the leg support rope 838 by a triangular trapeze arrangement so that the underside of a user's knees can contact the leg supports 840 and 842 . Thus, downward movement of the left leg support will cause equal upward movement of the right leg support and vice versa. The back support frame 850 preferably comprises an elevated back support member 852 joined to two vertical back support legs 854 and 856 by elbow joints 858 and 860 . The longitudinal member 890 is preferably joined to the elevated back support member 852 by a T-joint 862 . Two pulleys 864 and 866 are preferably mounted on the elevated back support member 852 on opposite sides of the T-joint 862 and adjustably spaced apart from each other. A hand grip rope 868 is preferably run through both pulleys 864 and 866 and hand grips 870 and 872 are preferably suspended from the ends of the hand grip rope 868 by a triangular trapeze arrangement. Thus, downward movement of the left hand grip will cause equal upward movement of the right hand grip and vice versa. Preferably a back support 874 is suspended from the hand grip 870 and 872 by back support ropes 876 . Preferably, the elevated leg support member 822 , the two vertical leg support legs 824 and 826 , the elevated back support member 852 , the two vertical back support legs 854 and 856 and the longitudinal member 890 are adjustable in length either through being telescoped or through the use of joints that would allow attachment of the various members and legs to each other at points other than their ends. Preferably also, these members and legs are rigid piping of a material such as metal or plastic and have a circular or square cross-section. Preferably, the leg support ropes 838 , hand grip rope 868 and back support ropes 876 all comprises a strong, light, durable rope, such as nylon rope. The pulleys 834 , 836 , 864 and 866 can be a conventional construction as can the elbow joints 828 , 830 , 858 and 860 and the T-joints 832 and 862 . The hand grips 870 and 872 preferably comprise a cylindrical cushioned material for comfort. With the construction, it can be seen that the device is easy and economical to manufacture, ship and store, and easily assembled and collapsed by the user. The device also allows the user to turn his body sideways and to create tension along different lines of the body.
[0222] Referring to FIG. 95 shown is still another embodiment 900 identical to the embodiment of FIG. 94 but without the back support ropes or back support.
[0223] Referring to FIG. 96 shown is still another embodiment 920 non-stretching strap 922 is mounted between the hand grips 870 and 872 and the back support 874 , instead of the back support ropes 876 .
[0224] Referring to FIG. 97 shown is an embodiment 930 identical to the embodiment of FIG. 95 , except that a flexible non-stretching strap 932 has been suspended between the hand grips 870 and 872 .
[0225] Referring to FIG. 98 shown is the manner in which a user would use the embodiment 930 of FIG. 97 by resting his or her neck on the strap 932 while the user's legs are retained by the leg supports.
[0226] Referring to FIG. 99 shown is an alternative embodiment 940 in which the leg supports are replaced by a leg support bars 942 and 944 , preferably of cylindrical cushioned material similar to the hand grips 870 and 872 .
[0227] Referring to FIG. 100 shown is a side view of a user using the embodiment 940 and FIG. 99 for rotational spinal tension, with only the hand grips 870 and 872 , leg support bars 942 and 944 and ropes 838 and 868 shown for clarity and the user's feet engaged with the leg support bars. Alternatively, the user can engage the leg support bars with his or her knees or other parts of his or her legs.
[0228] Referring to FIG. 101 shown is an alternate rigid contoured back support for use with all the preceding embodiments. Referring to FIG. 102 shown is an end view of the user using the embodiment 940 of FIG. 99 . Optionally, for greater strength and stability, additional longitudinal members can be added between the leg support frame 820 and the back support frame 850 of any of the preceding embodiments in order to provide additional bracing. Other additional bracing can be provided, such as anchored wires or additional reinforcing members, attached to various portions of the leg support frame 820 , the back support frame 850 , or the longitudinal member 890 .
[0229] Referring to FIG. 103 neck support 186 is equipped with nylon or similar straps that may be utilized for securing and retaining the users head in the neck support. This increases the amount of tension that may be created from the neck down.
[0230] FIG. 104 shows a upper body support that is connected to pivot 36 to base member 2 . This alternate version enables facilitation of spine movement due to the A movement of the user's weight over pivot 36 .
[0231] Referring to FIG. 105 an alternate version of the teaching of the instant invention is shown with three independent supports, lower 22 , middle 201 , and upper 18 . These three forces may be applied under the body to create any one of a variety of force, moment and shear forces as 590 indicated in FIG. 25 by adding the third force or support.
[0232] Referring to FIG. 106 the upper body support is positioned to create shear forces on the hips to facilitate spinal movement and correction of individuals who suffer from spondylolisthesis.
[0233] FIG. 107 indicates how the forces of FIG. 106 may be applied, from the bottom Au, from below or above, Afa via ropes or hangers. Dv, shows the distance of the miss aligned spine, that AFu attempts to help correct or assist.
[0234] Referring to FIG. 108 an alternate upper body support is shown. Planar members 1112 are rounded and oblong and connected via clips 1114 . These supports 1112 are designed to permit as near complete movement similar to the spine itself, vertebrae by vertebrae. These spine like supports may be supported in any number of ways either from ropes 1110 or from below.
[0235] FIG. 109 shows an alternate of FIG. 112 whereby casing 1120 is adjusted by grip 1130 that rolls in track 1138 along 14 in opening 1142 .
[0236] FIGS. 110 and 111 show how the user may practice upper body support only and facilitate the forces on ones body by adding the vertical hand grips 1150 to body support 20 that enable lever arm forces to be generated and transferred to the spine. Additionally important is the pivot forces that may be created about pivot 26 . User weight to the left of 26 will cause a raising force to the right of 26 . Preferably pivot 26 will be equipped with any number of means available today to create locking and holding of 20 as it rotates degree by degree in the counter clockwise direction. Preferably the pivot 26 would lock after every increasing degree movement in the counterclockwise direction and remain locked until a button or similar switch were activated on the hand grips 1150 . This apparatus will allow a user to walk up to it and grab hand grips 1150 and rotate forwards and be retained in the counterclockwise rotation and continue to rock in that direction until their feet or heels became elevated, 26 would lock and the user could practice spine exercise with heels just off the ground so as to create tension along the spine. At which tinie user is ready hand grips 1150 would have a switch that could be activated which would release 20 to rotate clockwise which would return the user's feet to the ground.
[0237] Referring to FIG. 112 the natural movement of the body is shown when they rotate when sitting. The user's upper rotates right and their lower body moves to the left. The instant invention immolates these natural motion as shown in application of FIG. 88 .
[0238] FIG. 113 shows an expanded body support 4 similar to 20 of FIGS. 110 and 111 . Pivot 26 preferably has the same rotate and lock increments, as well as releasing ability of FIGS. 110 and 111 .
[0239] FIGS. 114 and 115 teach a hinge mounting of body supports. The hinge mounting will not allow the upper body support to rotate any further counterclockwise in FIG. 114 that would allow the user to fall through, yet it allows rotation of upper body support in the clockwise direction, FIG. 115 , which benefits the user. Additionally and for the same reasons hinge 1180 is utilized at the lower body support. While it may have hinge pivot in the wrong place in FIG. 114 , if it were switched with hinge pivot on other side it could be easily seen how it would provide the similar function of the upper body hinge in FIG. 114 , stopping the user from falling through the supports and allowing for rotation in horizontal position.
[0240] Referring to FIG. 117 the arm 14 is positioned near vertical that will allow an older individual easy access as both upper and lower body supports are in the near vertical plane, like leaning up against the wall. This makes it easier for them to mount the device by eliminating the drop to the sitting position, rather they are taken from a standing position to a sitting or horizontal position by supports 18 and 22 connected to arms 14 to pivot 26 to base member 2 .
[0241] FIG. 118 teaches a seat similar to the lower body support of previous figures. What is important about this lower body support is its ability to function as a resting plane VIA pivot 1240 and pivot limit device 1244 . Yet when user wants to get out of chair they simply rotate forward and pivot 1240 allows lower body support 22 to rotate counterclockwise yet limit device 1244 will stop clockwise rotation. | A chair has two independent body supports which move in similar rotation and inverse elevation to one another to change from a chair configuration, one support higher than the other, to a spine tensioning apparatus, supports near equal in elevation. Preferably body supports are spaced apart from one another such that the only interconnecting human link between the two supports, when in a near equal elevation configuration, is the human spine. The spine, in this configuration is then subjected to similar forces as a simple beam supported by two separate forces, tension, compression, shear and moment. The spine is aided by and through tension and compression and increased blood flow and afforded the ability for spinal muscle, nerve and soft tissue development and maintenance. The supports, independent of each other, comprise an upper body support and a lower body support and allow an individual's body to practice spine enhancement, development, & or traction, laying in any combination of, or alternately, face up, face down, or on either left or right side. The apparatus is also applicable to retrofitting existing chairs. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates to clones for the FnuDI restriction endonuclease and modification methylase, and to the production of these enzymes from the clones.
Restriction endonucleases are a class of enzymes that occur naturally in bacteria. When they are purified away from other contaminating bacterial components, restriction endonucleases can be used in the laboratory to break DNA molecules into precise fragments. This property enables DNA molecules to be uniquely identified and to be fractionated into their constituent genes. Restriction endonucleases have proved to be indispensable tools in modern genetic research. They are the biochemical 'scissors' by means of which genetic engineering and analysis is performed.
Restriction endonucleases act by recognizing and binding to particular sequences of nucleotides (the 'recognition sequence') along the DNA molecule. Once bound, they cleave the molecule within, or to one side of, the sequence. Different restriction endonucleases have affinity for different recognition sequences. Over one hundred different restriction endonucleases have been identified among many hundreds of bacterial species that have been examined to date.
Bacteria usually possess only a small number restriction endonucleases per species. The endonucleases are named according to the bacteria from which they are derived. Thus, the species Haemophilus aegyptius, for example synthesizes 3 different restriction endonucleases, named HaeI, HaeII and HaeIII. These enzymes recognize and cleave the sequences (AT)GGCC(AT), PuGCGCPy and GGCC respectively. Escherichia coli RY13, on the other hand, synthesizes only one enzyme, EcoRI, which recognizes the sequence GAATTC.
While not wishing to be bound by theory, it is thought that in nature, restriction endonucleases play a protective role in the welfare of the bacterial cell. They enable bacteria to resist infection by foreign DNA molecules like viruses and plasmids that would otherwise destroy or parasitize them. They impart resistance by binding to infecting DNA molecule and cleaving them each time that the recognition sequence occurs. The disintegration that results inactivates many of the infecting genes and renders the DNA susceptible to further degradation by exonucleases.
A second component of bacterial protective systems are the modification methylases. These enzymes are complementary to restriction endonucleases and they provide the means by which bacteria are able to protect their own DNA and distinguish it from foreign, infecting DNA. Modification methylases recognize and bind to the same nucleotide recognition sequence as the corresponding restriction endonuclease, but instead of breaking the DNA, they chemically modify one or other of the nucleotides within the sequence by the addition of a methyl group. Following methylation, the recognition sequence is no longer bound or cleaved by the restriction endonuclease. The DNA of a bacterial cell is always fully modified, by virtue of the activity of its modification methylase and it is therefore completely insensitive to the presence of the endogenous restriction endonuclease. It is only unmodified, and therefore identifiably foreign, DNA that is sensitive to restriction endonuclease recognition and attack.
With the advent of genetic engineering technology, it is now possible to clone genes and to produce the proteins and enzymes that they encode in greater quantities than are obtainable by conventional purification techniques. The key to isolating clones of restriction endonuclease genes is to develop a simple and reliable method to identify such clones within complex 'libraries', i.e. populations of clones derived by 'shotgun' procedures, when they occur at frequencies as low as 10 -3 to 10 -4 . Preferably, the method should be selective, such that the unwanted, majority, of clones are destroyed while the desirable, rare, clones survive.
Type II restriction-modification systems are being cloned with increasing frequency. The first cloned systems used bacteriophage infection as a means of identifying or selecting restriction endonuclease clones (HhaII: Mann et al , Gene 3: 97-112, (1978); EcoRII: Kosykh et al., Molec. gen. Genet 178: 717-719, (1980); PstI: Walder et al., Proc. Nat. Acad. Sci. USA 78 1503-1507, (1981)). Since the presence of restriction-modification systems in bacteria enables them to resist infection by bacteriophages, cells that carry cloned restriction-modification genes can, in principle, be selectively isolated as survivors from libraries that have been exposed to phage. This method has been found, however, to have only limited value. Specifically, it has been found that cloned restriction-modification genes do not always manifest sufficient phage resistance to confer selective survival.
Another cloning approach involves transferring systems initially characterized as plasmid-borne into E. coli cloning plasmids (EcoRV: Bougueleret et al., Nucleic Acids Res. 12:3659-3676, (1984); PaeR7: Gingeras and Brooks, Proc. Natl. Acad. Sci. USA 80:402-406, (1983); Theriault and Roy, Gene 19:355-359, (1982); PvuII: Blumenthal et al., J.BacterioI. 164:501-509, (1985)).
A third approach, and one that is being used to clone a growing number of systems, involves selecting for an active methylase gene referring to our patent application No. 707079 and (BsuRI: Kiss et al., Nucleic Acids Res. 13:6403-6421, (1985)). Since restriction and modification genes tend to be closely linked, clones containing both genes can often be isolated by selecting for just the one gene. Selection for methylation activity does not always yield a complete restriction-modification system however, but instead sometimes yields only the methylase gene (BspRI: Szomolanyi et al., Gene 10:219-225, (1980); BcnI: Janulaitis et al, Gene 20: 197-204 (1982); BsuRI: Kiss and Baldauf, Gene 21: 111-119, (1983); and MspI: Walder et al., J Biol. Chem. 258:1235-1241, (1983)).
A potential obstacle to cloning restriction-modification genes lies in trying to introduce the endonuclease gene into a host not already protected by modification. If the methylase gene and endonuclease gene are introduced together as a single clone, the methylase must protectively modify the host DNA before the endonuclease has the opportunity to cleave it. On occasion, therefore, it might only be possible to clone the genes sequentially, methylase first then endonuclease. Another obstacle to cloning restriction-modification systems lies in the discovery that some strains of E.coli react adversely to cytosine modification; they possess systems that destroy DNA containing methylated cytosine (Raleigh and Wilson, Proc. Natl. Acad. Sci., USA 83:9070-9074, (1986)). Cytosine-specific methylase genes cannot be cloned easily into these strains, either on their own, or together with their corresponding endonuclease genes. To avoid this problem it is necessary to use mutant strains of E.coli (McrA - and McrB - ) in which these systems are defective.
Because purified restriction endonucleases, and to a lesser extent, modification methylases, are useful tools for characterizing and rearranging DNA in the laboratory, there is a commercial incentive to obtain strains of bacteria through recombinant DNA techniques that synthesize these enzymes in abundance. Such strains would be useful because they would simplify the task of purification as well as providing the means for production in commercially useful amounts.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a clone containing the genes for the FnuDI restriction endonuclease and modification methylase derived from Fusobacterium nucleatum D, as well as related methods for the production of the enzymes. More specifically, this invention relates to clones which express the restriction endonuclease FnuDI, an enzyme which recognizes the DNA sequence GGCC and cleaves between the G and C. See Lui, A. C. P., McBride, B. C., Vovis, G. F. and Smith, M., Nucleic Acids Res. 6:1-15, (1979), the disclosure of which is hereby incorporated by reference herein. FnuDI restriction endonuclease produced in accordance with the present invention is free of the contaminanting FnuDII and FnuDIII endonucleases present in F.nucleatum D.
The preferred method for cloning this enzyme comprises forming a library containing the DNA from F.nucleatum D, isolating those clones which contain DNA coding for the FnuDI modification methylase and screening among these to identify those that also contain the FnuDI restriction endonuclease gene.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates the scheme for cloning and producing the FnuDI restriction endonuclease.
FIG. 2 is a restriction map of a 5.5 Kb HindIII fragment of F.nucleatum D DNA that encodes the FnuDI restriction endonuclease and modification methylase. The fragment was cloned into the HindIII site of pBR322 (ATCC 37017) to create pFnuDIRM 2-33, then it was transferred into the HindIII site of pUC19 (ATCC 37254) to create pFnuDIRM 102-1.
FIG. 3 is a photograph of an agarose gel demonstrating FnuDI restriction endonuclease activity in a cell extract of E.coli RR1 (ATCC 31343) carrying pFnuDIRM 2-33.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to clones of the FnuDI restriction and modification genes, as well to the restriction endonuclease FnuDI produced from such clones. The FnuDI genes are cloned by a method which takes advantage of the fact that certain clones which are selected on the basis of containing and expressing the FnuDI modification methylase gene also contain the FnuDI restriction gene. The DNA of such clones is resistant to digestion by the FnuDI restriction endonuclease and the HaeIII restriction endonuclease. The resistance to digestion affords a means for selectively isolating clones encoding the FnuDI methylase and restriction endonuclease.
The method described herein by which the FnuDI restriction gene and methylase gene are preferably cloned and expressed are illustrated in FIG. 1, and they include the following steps:
1. The DNA of Fusobacterium nucleatum D is purified. F.nucleatum D has been described by Lui et al, supra, and was provided to us by Dr. Michael Smith, Dept. of Biochemistry, Faculty of Medicine, The University of British Columbia, Vancouver, Canada.
2. The DNA is digested with a restriction endonuclease such as HindIII.
3. The digested DNA is ligated to a cloning vector such as pBR322 (ATCC 37017), that contains one or more FnuDI sites. The ligated DNA is transformed into an appropriate host such as Escherichia coli strain RR1 (ATCC 31343).
4. The transformed mixture is plated onto media selective for transformed cells, such as the antibiotic ampicillin. After incubation, the transformed colonies are collected together into a single culture, the cell library.
5. The recombinant plasmids are purified in toto from the cell library to make the plasmid library.
6. The plasmid library is digested to completion with the FnuDI restriction endonuclease, or with an equivalent endonuclease, such as HaeIII, from Haemophilus haemolyticus. FnuDI (or HaeIII) digestion differentially destroys unmodified, non-methylase-containing, clones, increasing the relative frequency of FnuDI methylase clones.
7. The digested plasmid library is transformed back into an appropriate host such as E.coli RR1 and transformants are recovered by plating onto selective media. The colonies are picked and their DNA is analyzed for the presence of the FnuDI modification gene: the plasmids that they carry are purified and incubated with the FnuDI (or HaeIII) restriction endonuclease to determine whether they are resistant to digestion. Total cellular DNA (chromosomal and plasmid) is also purified and incubated with the FnuDI (or HaeIII) restriction endonuclease. The DNA of clones that carry the FnuDI modification gene should be fully modified, and both plasmid DNA and total DNA should be substantially resistant to digestion.
8. Clones carrying the FnuDI restriction endonuclease are identified by preparing cell extracts of the FnuDI methylase clones, identified in step 8, and assaying the extracts for FnuDI restriction endonuclease activity.
9. The quantity of FnuDI restriction endonuclease produced by the clones may be increased by elevating the gene dosage, through the use of high copy number vectors, and by elevating the transcription rate, through the use of highly active, exogenous promotors.
10. The FnuDI restriction endonuclease may be produced from clones carrying the FnuDI restriction and modification genes by propagation in a fermenter in a rich medium containing ampicillin. The cells are collected by centrifugation and disrupted by sonication to produce a crude cell extract containing the FnuDI restriction endonuclease activity.
11. The crude cell extract containing the FnuDI restriction endonuclease activity is purified by standard protein purification techniques such as affinitychromatography an ion-exchange chromatography.
Although the above-outlined steps represent the preferred mode for practicing the present invention, it will be apparent to those skilled in the art that the above described approach can vary in accordance with techniques known in the art. The following example is given to illustrate embodiments of the present invention as it is presently preferred to practice. It will be understood that this example is illustrative, and that the invention is not to be considered as restricted thereto except as indicated in the appended claims.
EXAMPLE
Cloning of FnuDI Restriction Endonuclease Gene
1. DNA purification: 10 g of frozen Fusobacterium nucleatum D cells were thawed on ice for 1 hour then resuspended in 20 ml of 25% sucrose, 50mM Tris pH 8.0. 10 ml of 0.25M EDTA pH 8.0, and 6 ml of 10 mg/ml lysozyme in 0.25M Tris pH 8.0 were added. The suspension was kept on ice for 2 hours, then lysed by the addition of 24 ml of 1% Triton X-100, 50 mM Tris pH 8.0, 67 mM EDTA and 5 ml of 10% SDS. The solution was extracted with 70 ml of phenol, (previously equilibrated with 0.5M Tris pH 8.0), and 60 ml of Chloroform. The emulsion was centrifuged at 10K rpm for 30 minutes to separate the phases. The viscous upper phase was transferred to a new bottle and extracted with phenol and chloroform once more. The emulsion was again centrifuged then the upper phase was dialyzed against four changes of DNA buffer (10 mM Tris pH 8.0, 1 mM EDTA). The dialyzed solution was then digested with RNase at a final concentration of 200 ug/ml for 1 hour at 37° C. The DNA was then precipitated by the addition of 5M NaCl to a final concentration of 0.4M, and 0.55 volumes of isopropyl alcohol. The precipitated DNA was spooled onto a glass rod, air-dried, then dissolved in DNA buffer to a concentration of approximately 300 ug/ml and stored at 4° C.
2. Digestion of DNA: 30 ug of F.nucleatum D DNA was diluted into 300 ul of restriction endonuclease digestion buffer (10mM Tris pH 7.5, 10 mM MgCl 2 , 10 mM mercaptoethanol, 50 mM NaCl). 60 units of HindIII restriction endonuclease were added and the solution was incubated at 37° C. for 2 hr. Digestion was terminated by heating to 72° C. for 12 minutes.
3. Ligation and transformation: 6 ug (60 ul) of HindIII-digested F.nucleatum D DNA was mixed with 3 ug (30 ul) of HindIII-cleaved and dephosphorylated pBR322 (ATCC 37017). 20 ul of 10 X ligation buffer (500 mM Tris pH 7.5, 100 mM MgCl 2 , 100 mM DTT, 5 mM ATP), and 90 ul of sterile distilled water were added to bring the volume to 200 ul. 7.5 ul of T4 DNA ligase was added and the solution was incubated at 17° C. for 4 hours. The solution was sterilized by extraction with 20 ul of chloroform, then clarified by microcentifugation for 15 sec. 100 ul of the ligation solution was mixed with 800 ul of SSC/CaCl 2 (50 mM NaCl, 5 mM Na 3 Citrate, 67 mM CaCl 2 ) and 1.7 ml of ice-cold, competent E.coli RR1 (ATCC 31343) cells were added. The solution was incubated at 44° C. for 4 mins, then 10 ml of Luria-broth (L-broth) was added and incubation was continued at 37° C. for 3 hr.
4. Cell Library: The transformed culture was gently centrifuged, the supernatant was discarded and the cells were resuspended in approximately 1.2 ml of L-broth. The resuspended cells were plated in approximately 200 ul portions onto 8 Luria-agar (L-agar) plates containing 100 ug/ml ampicillin. The plates were incubated overnight at 37° C. The transformed cells that grew up on the surfaces of the plates were collected together by flooding each of the plates with 2 5 ml of 10 mM Tris pH 7.5, 10 mM MgCl 2 , scraping the colonies together, and pooling the suspensions into a single tube.
5. Plasmid Library: 2.0 ml of the cell library was inoculated into 500 ml of L-broth containing 100 ug/ml ampicillin. The culture was shaken overnight at 37° C. then centrifuged at 4K rpm for 5 minutes. The supernatant was discarded and the cell pellet was resuspended in 10 ml of 25% sucrose, 50 mM Tris pH 8.0, at room temperature. 5 ml of 0.25M EDTA, pH 8.0, and 3 ml of 10 mg/ml lysozyme in 0.25M Tris pH 8.0 were added. The solution was kept on ice for 1 hour, then 12 ml of 1% Triton X-100, 50 mM Tris pH 8.0, 67 mM EDTA was added and the suspension was gently swirled to induce cell lysis.
The lysed mixture was transferred to a 50 ml tube and centrifuged for 45 min. at 17K rpm, 4° C. The supernatant was removed with a pipette. 20.0 gm of solid CsCl was weighed into a 50 ml plastic screw-cap tube and 22.0 gm of supernatant was pipetted into the tube and mixed. 1.0 ml of 5 mg/ml ethidium bromide in 10 mM Tris pH 8.0, 100 mM NaCl, 1 mM EDTA was added. The solution was transferred to two 5/8 in.×3 in. centrifuge tubes and spun in a Beckman Ti70 rotor for 42 hours at 44K rpm, 17° C. To collect the plasmids, the tubes were opened, illuminated with ultraviolet light, and the lower of the two fluorescent bands was collected by syringe. The lower band from each tube was combined and the ethidium bromide was removed by extracting four times with an equal volume of water-saturated, ice-cold N-Butanol.
The extracted solution was dialyzed against 4 changes of DNA buffer, then the nucleic acid was precipitated by the addition of 2 vols. of isopropanol and sufficient 5M NaCl to reach a final concentration of 0.4M. The solution was stored overnight at -20° C. then centrifuged for 15 min. at 15K rpm, 0° C. The supernatant was discarded, the pellet was air-dried for 15 min. then dissolved in 500 ul of 10 mM Tris pH 7.5, 1 mM EDTA and stored at -20° C. The plasmid DNA concentration was found to be approximately 100 ug/ml.
6. Digestion of the Plasmid Library: 6 ug (60 ul) of the plasmid library was diluted into 450 ul of restriction endonuclease digestion buffer (section 2). 60 units (7.5 ul) of HaeIII restriction endonuclease were added and the tube was incubated at 37° C. for 1 hr. The reaction was terminated by heating to 72° C. for 12 minutes.
7. Transformation: 12.5 ul (0.18 ug) aliquots of the digested library were mixed with 100 ul of SSC/CaCl 2 (section 3) and 200 ul of ice-cold, competent, E.coli RR1. The mixtures were warmed to 42° C. for 3 min. then plated onto L-agar plates containing 100 ug/ml ampicillin. The plates was incubated overnight at 37° C. HaeIII digestion was found to reduce the number of transformants by a factor of approximately 10 3 . Fourteen colonies were picked from the survivors of the HaeIII digestion; each was inoculated into 10 ml of L-broth containing ampicillin, to prepare a miniculture, and streaked onto an L-agar plate containing ampicillin, to prepare a master stock.
8. Analysis of surviving individuals: Fourteen of the surviving colonies described in section 7 were grown into 10 ml cultures and the plasmids that they carried were prepared by the following miniprep purification procedure, adapted from the method of Birnboin and Doly, Nucleic Acids Res. 7: 1513 (1979).
Miniprep Procedure: Each culture was centrifuged at 8K rpm for 5 minutes; the supernatant was discarded and the cell pellet was resuspended in 1.0 ml of 25 mM Tris, 10 mM EDTA, 50 mM glucose, pH 8.0, containing 1 mg/ml lysozyme. After 10 minutes at room temperature, 2.0 ml of 0.2M NaOH, 1% SDS was added to each tube and the tubes were shaken to lyse the cells, then placed on ice. Once the solutions had cleared, 1.5 ml of 3M sodium acetate, pH 4.8, was added to each and shaken. The precipitates that formed were spun down at 15K rpm, 4° C. for 10 minutes. Each supernatant was poured into a centrifuge tube containing 3 ml of isopropanol and mixed. After 10 minutes at room temperature, the tubes were spun at 15K rpm for 10 minutes to pellet the precipitated nucleic acids. The supernatants were discarded and the pellets were air-dried at room temperature for 30 minutes. Once dry, the pellets were resuspended in 850 ul of 10 mM Tris, 1 mM EDTA, pH 8.0. 75 ul of 5M NaCl was added to each and the solutions were transferred to Eppendorf tubes containing 575 ul of isopropanol, and again precipitated for 10 minutes at room temperature. The tubes were then spun for 45 seconds in a microfuge, the supernatants were discarded and the pellets were air-dried. The pellets were then dissolved in 500 ul of 10 mM Tris, 1 mM EDTA, pH 8.0, containing 100 ug/ml RNase and incubated for 1 hour at 37° C. to digest the RNA. The DNA was precipitated once more by the addition of 50 ul of 5M NaCl followed by 350 ul of isopropanol. After 10 minutes at room temperature, the DNA was spun down by centrifugation for 45 seconds, the supernatants were discarded and the pellets were redissolved in 150 ul of 10 mM Tris 1 mM EDTA, pH 8.0. The plasmid minipreps were subsequently analyzed by digestion with FnuDI and HindIII.
9. FnuDI Methylase Gene Clones: Eight of the 14 plasmids analyzed were found to be sensitive to HaeIII digestion and to carry diverse fragments of F.nucleatum D DNA. These plasmids were discarded. The remaining 6 plasmids were found to be resistant to HaeIII digestion and to carry a 5.5 Kb HindIII fragment in common. These plasmids, typical of which is pFnuDIRM 2-33 , appeared to be identical. Several of them were chosen and were shown to encode not only the FnuDI modification methylase but also the FnuDI restriction endonuclease.
10. FnuDI Restriction Gene Clone: pFnuDIRM 2-33, and similar plasmids, were found to encode and express the FnuDI restriction endonuclease by assaying extracts of E.coli RR1 that carried the plasmids. 50 ml cultures of the clones were grown overnight at 37° C. in L-broth containing 100 ug/ml ampicillin. The cultures were centrifuged at 5K rpm for 5 min and the cell pellets were each resuspended in 3 ml of cell lysis buffer (l0 mM Tris pH 7.5, 10 mM mercaptoethanol, 0.1 1 MM EDTA). 0.5 ml of 10 mg/ml lysozyme in the same buffer was added to each and the suspensions were left on ice for 2 hr. The suspensions were frozen overnight at -20° C., then thawed on ice and 3.5 ml of cell lysis buffer containing 0.005% Triton X-100 was vigorously mixed in to each to induce cell lysis. The lysed solutions were microcentrifuged for 5 min to compress the nucleic acids and the supernatants were assayed for endonuclease activity in the following way:
35 ug of phage lambda DNA was diluted into 700 ul of restriction endonuclease digestion buffer (section 2). The solution was dispensed into 6 tubes, 150 ul into the first tube and 100 ul into each of the remaining 5 tubes. 7.5 ul of the extract was added to the first tube to achieve 1 ul extract/ug DNA. 50 ul was then removed from the first tube and transferred to the second tube to achieve 0.3 ul/ug. 50ul serial transfers were continued into tubes number 3 (0.1 ul/ug), 4 (0.03 ul/ug) and 5 (0.001 ul/ug). the sixth tube received no extract and served as a negative control. The tubes were incubated at 37° C. for one hour, then 20 ul from each was analyzed by gel electrophoresis. The extracts were found to contain approximately 3×10 4 units of FnuDI restriction endonuclease per ml, which corresponds to about 1×10 6 units per gram of cells (FIG. 3).
11. Transfer of the 5.5Kb fragment to pUC19: 5 ug (50 ul) of purified pFnuDIRM 2-33 DNA was prepared in 100 ul of restriction endonuclease digestion buffer (section 2) containing 20 units of HindIII restriction endonuclease. The solution was incubated at 37° C. for 1 hr. then digestion was halted by heating at 72° C. for 12 min. 3 ug (60 ul) of the digested pFnuDIRM 2-33 DNA was mixed with 1.5 ug (7.5 ul) of HindIII-cleaved and dephosphorylated pUC19 (ATCC 37254). 10 ul of 10 X ligation buffer (section 3) and 22.5 ul of sterile distilled water were added to bring the volume to 100 ul. 4 ul of T4 DNA ligase was added and the solution was incubated at 17° C. for 4 hr. The ligation was sterilized by extraction with 15 ul of chloroform, then clarified by brief microcentrifugation.
12.5 ul of the sterile ligation was mixed with 100 ul CaCl 2 /SSC (section 3) and 200 ul of competent, ice-cold, E.coli RR1. The mixture was incubated at 42° C. for 3 min, then plated onto an L-agar plate containing ampicillin. The plate was incubated overnight at 37° C. The transformants were collected by flooding the plate with 2.5 ml of 10 mM Tris ph 7.5, 10 mM MgCl 2 and scraping the colonies together to form a pool. The pool was inoculated into 500 ml of L-broth containing ampicillin, and a plasmid preparation was purified (section 5). 5 ug of the purified plasmid was digested with 40 units of HaeIII restriction endonuclease in 100 ul of restriction endonuclease buffer (section 6). 12.5 ul of the digested DNA was transformed into E.coli RR1 (section 7) and survivors were recovered by plating onto L-agar plates containing ampicillin and incubating the plates overnight at 37° C.
Fourteen transformants were picked and screened by the miniprep procedure (section 8) to identify plasmids composed of pUC19 with the 5.5 Kb fragment inserted at the HindIII site. Thirteen of the plasmids were found to possess this structure; they carried the 5.5 Kb fragment and they exhibited complete resistance to HaeIII digestion. Cell extracts of E.coli RR1 carrying two of these plasmids, pFnuDIRM 102-1 and pFnuDIRM 102-4, were assayed for FnuDI restriction endonuclease activity. A sample of pFnuDIRM 102-1 has been deposited at the American Type Culture Collection under ATCC Accession No. 40521. The extracts were found to contain approximately 1×10 5 units of FnuDI restriction endonuclease per ml of extract, which corresponds to 3×10 6 units/gm cells.
E.coli RR1 carrying pFnuDIRM 2-33 or pFnuDIRM 102-1 are the preferred hosts from which the FnuDI restriction endonuclease can be purified. The strains should be grown to stationary phase at 37° C. in a fermenter, in L-broth containing ampicillin. The cells should then be collected by centrifugation and either broken immediately for extract preparation, or stored frozen at -70° C. until it is convenient to do so. | The present invention is directed to a method for cloning and producing the FnuDI restriction endonuclease by (1) introducing the restriction endonuclease gene from F. nucleatum D into a host whereby the restriction gene is expressed; (2) fermenting the host which contains the vector encoding and expressing the FnuDI restriction endonuclease, and (3) purifying the FnuDI restriction endonuclease from the fermented host which contains the vector encoding and expressing the FnuDI restriction endonuclease activity. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application incorporates by reference, and claims priority to and the benefit of, U.S. Provisional Patent Application Ser. No. 60/472,922, which was filed on May 23, 2003.
FIELD OF THE INVENTION
[0002] The present invention relates to apparatus and methods for creating three-dimensional objects by printing.
BACKGROUND
[0003] Generally, 3D printing involves the use of an inkjet type printhead to deliver a liquid or colloidal binder material to layers of a powdered build material. The printing technique involves applying a layer of a powdered build material to a surface typically using a roller. After the build material is applied to the surface, the printhead delivers the liquid binder to predetermined areas of the layer of material. The binder infiltrates the material and reacts with the powder, causing the layer to solidify in the printed areas by, for example, activating an adhesive in the powder. The binder also penetrates into the underlying layers, producing interlayer bonding. After the first cross-sectional portion is formed, the previous steps are repeated, building successive cross-sectional portions until the final object is formed. See, for example, U.S. Pat. Nos. 6,375,874 and 6,416,850, the disclosures of which are incorporated herein by reference in their entireties.
[0004] Apparatus for carrying out 3D printing typically move the printheads over the print surface in raster fashion along orthogonal X and Y axes. In addition to the time spent printing, each printhead move requires time for acceleration, deceleration, and returning the printhead to the starting position of the next move. The inefficiencies inherent in these reciprocating motions reduce the productivity of the 3D printing process.
[0005] It is, therefore, an object of the present invention to provide apparatus and methods for continuously and efficiently performing 3D printing.
SUMMARY
[0006] Generally, the invention relates to apparatus and methods for producing three-dimensional objects, such as casting cores, toys, bottles, cans, architectural models, automotive parts, molecular models, models of body parts, cell phone housings, and footwear, more rapidly and efficiently than heretofore achievable. Additionally, the invention relates to systems and methods for maintaining and operating the aforementioned apparatus. In particular, if a user wants to produce large volumes of three-dimensional objects rapidly, a 3D printing apparatus in accordance with the invention can achieve a high throughput by continuously printing, using multiple printheads.
[0007] In one aspect, the invention relates to an apparatus for fabricating a three-dimensional object from a representation of the object stored in memory. The apparatus includes a rotary build table for receiving successive layers of a build material and an array having at least one printhead disposed above the build table. In one embodiment, the rotary table rotates continuously.
[0008] In another aspect, the invention relates to an apparatus for fabricating a three-dimensional object from a representation of the object stored in memory. The apparatus includes a generally circular build table for receiving successive layers of a build material and an array having at least one printhead disposed above the build table and movable relative to the build table. In one embodiment, the generally circular build table is movable in a vertical direction. In various embodiments, the printhead is movable over at least a portion of a build surface defined by the generally circular build table and the printhead can move continuously about the build table. In one embodiment, the array is configured to dispense fluid at substantially any radial location of the build table by moving the array radially to the desired location.
[0009] In yet another aspect, the invention relates to a method of fabricating a three-dimensional object. The method includes the steps of depositing successive layers of a build material on a rotary build table and depositing a liquid in a predetermined pattern on each successive layer of the build material to form the three-dimensional object. In various embodiments, the method includes the steps of: rotating the build table continuously, distributing the build material over at least a portion of the build table with a spreader, measuring an amount of excess build material deposited on the build table, and adjusting the amount of build material deposited on the build table based on the amount of excess build material measured. Additionally, the liquid can be deposited by an array of one or more printheads.
[0010] In still another aspect, the invention relates to a method of fabricating a three-dimensional object. The method includes the steps of depositing successive layers of a build material on a generally circular build table and depositing a liquid in a predetermined pattern on each successive layer of the build material to form the three-dimensional object. In various embodiments, the liquid is deposited by an array of at least one printhead and the printhead is movable over at least a portion of a build surface defined by the generally circular build table. In addition, the printhead can move continuously about the build table and the build table can move in a vertical direction.
[0011] In various embodiments of the foregoing aspects, the apparatus includes a build material delivery system. The system includes a storage means for holding the build material and a conveying means for delivering the build material to the build table. In one embodiment, the storage means includes at least two storage chambers for holding at least two build material components separate from each other and the system further includes a blender for mixing the build material components in a predetermined ratio for delivery to the build table. In addition, the apparatus can include a spreader for distributing the build material over at least a portion of the build table. The spreader can be a counter-rotating roller, and the counter-rotating roller can be skewed with respect to a radius of the rotary build table to induce excess build material to migrate over an edge of the build table.
[0012] In additional embodiments, the apparatus can include a sensor disposed below an edge of the build table to detect an amount of the excess build material. An amount of build material delivered to the build table can be adjusted in response to the amount of excess build material detected. In one embodiment, the sensor can automatically monitor printhead condition, and the apparatus can automatically modify its operation in response to a signal from the sensor. In one example, printhead cleaning is initiated if print quality is inadequate. In another example, the apparatus can utilize the redundant printheads in areas where the printing coverage is inadequate.
[0013] In other embodiments, the array can include a plurality of printheads disposed above the build table. In one embodiment, the array is configured to dispense fluid at substantially any radial location of the rotary build table without adjustment. In another embodiment, the array prints an entire surface of the build table by continuous consecutive radial scanning motions. In addition, the array can be adjusted incrementally radially and/or can be displaced from a normal printing position for servicing. Further, the array can be displaced radially with respect to the rotary build table. The array can include redundant printheads.
[0014] In further embodiments, the apparatus defines an opening for removing the three-dimensional object. In one embodiment, the three-dimensional object is removed through a top opening of the build table. Additionally, the apparatus can include a sensor to monitor at least one performance characteristic of the apparatus, such as print quality, printing errors, print speed, printhead condition, build material quantity, and table position. In one embodiment, the array is movable in response to a signal from the sensor. The apparatus can also include a plurality of rotary build tables.
[0015] In still other embodiments, the invention can include methods and apparatus for cleaning the printheads of the apparatus. Methods of cleaning the printhead can include wiping the printhead with a roller including a cleaning fluid, drawing a vibrating member across the printhead, drawing a cleaning fluid across the printhead by capillary action through a wick, and/or combinations thereof. In addition, the methods can include optionally the step of applying a vacuum to the printhead to remove debris. The apparatus for cleaning a printhead used in a 3D printer can include a wick disposed adjacent the printhead for drawing a cleaning fluid across the printhead.
[0016] In another aspect, the invention relates to an apparatus for cleaning a printhead used in a 3D printer. The pressure in the interior of a printhead is typically lower than atmospheric pressure. This negative pressure is balanced by the surface tension of the meniscuses that form over the outlets of the printhead nozzles. It is desirable to flush the accumulated powder off the face of the printhead with a clean wash solution without allowing the solution to be drawn into the printhead when the meniscuses are destroyed. This goal is achieved in this apparatus by maintaining an environment outside the printhead in which the pressure is lower than the pressure inside the head. In addition, this induced pressure differential causes binder to flow out of the heads through the nozzles, flushing out any powder that may have lodged in the nozzle passageways. The apparatus includes a base, a cam track disposed within the base, a cap carrier slidably engaged with the cam track, and a sealing cap defining a cavity and disposed on the carrier. The cap being transportable into engagement with the face of the printhead by the carrier. In various embodiments the apparatus includes a cleaning fluid source in communication with the cap for cleaning the printhead face and a vacuum source in communication with the cap for removing used wash fluid and debris.
[0017] In further embodiments, the apparatus can also include a spring coupled to the carrier and the base to bias the carrier into a receiving position for receiving the printhead. In one embodiment, the carrier includes a stop disposed on a distal end of the carrier for engaging the printhead as the printhead enters the apparatus. The printhead slides the carrier rearward along the cam track after engaging the stop and until the printhead face and cap sealably engage. In a further embodiment, the apparatus includes a latch pawl coupled to the base for engaging with the carrier to prevent forward movement of the carrier and a squeegee disposed on a proximal end of the carrier. The squeegee is positioned to engage the printhead face as the printhead exits the apparatus.
[0018] In still another aspect, the invention relates to a method of cleaning a printhead used in a 3D printer. The method includes the step of receiving the printhead within an apparatus that includes a base, a cam track disposed within the base, a cap carrier slidably engaged with the cam track, and a sealing cap defining a cavity and disposed on the carrier. Additional steps include engaging the face of the printhead with the cap, drawing a vacuum on the cavity, and introducing a cleaning fluid into the cavity and into contact with the printhead face. In one embodiment, the method includes the step of removing the cleaning fluid from the cavity. The method can further include disengaging the cap from the printing surface and wiping the printing surface with a squeegee as the printhead is withdrawn from the apparatus.
[0019] In another aspect, the invention relates to an apparatus for cleaning or reconditioning a printhead. The apparatus includes a nozzle array for spraying a washing solution towards a face of a printhead and a wicking member disposed in proximity to the printhead face for removing excess washing solution from the printhead face.
[0020] In various embodiments, the nozzle array includes one or more individual nozzles. The wicking member and the printhead are capable of relative movement. A fluid source can also be included in the apparatus for providing washing solution to the nozzle array under pressure. In another embodiment, the wicking member includes at least one of a permeable material and an impermeable material.
[0021] The nozzle array can be positioned to spray the washing solution at an angle with respect to the printhead face. In another embodiment, the wicking member is disposed in close proximity to the printhead face, without contacting print nozzles located on the printhead face. The spacing between the wicking member and the print nozzles can be automatically maintained. In one embodiment, the spacing is maintained by causing a portion of the wicking member to bear on the printhead face in a location removed from the print nozzles. The apparatus can also include a basin for collecting washing solution and debris.
[0022] In another aspect, the invention relates to a method of cleaning or reconditioning a printhead. The method includes the steps of positioning a face of the printhead relative to at least one nozzle and operating the at least one nozzle to spray washing solution towards the printhead face. Excess washing solution is then removed from the printhead face by passing a wicking member in close proximity to the printhead face, without contacting the printhead face.
[0023] In one embodiment, the step of operating the at least one nozzle includes spraying the washing solution at an angle to the printhead face. In another embodiment, the method can include the step of operating the printhead to expel washing solution ingested by the printhead during cleaning. The method can include automatically maintaining a space between the wicking member and print nozzles located on the printhead face by, for example, causing a portion of the wicking member to bear on the printhead face in a location removed from the print nozzles.
[0024] These and other objects, along with advantages and features of the present invention herein disclosed, will become apparent through reference to the following description, the accompanying drawings, and the claims. Furthermore, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] In the drawings, like reference characters generally refer to the same parts throughout the different views. In addition, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:
[0026] FIG. 1 is a schematic top perspective view of one embodiment of an apparatus for 3D printing in accordance with the invention;
[0027] FIG. 2 is an enlarged schematic side perspective view of the apparatus of FIG. 1 ;
[0028] FIG. 3 is an enlarged schematic perspective view of a portion of the apparatus of FIG. 1 ;
[0029] FIG. 4 is a schematic top view of the apparatus of FIG. 1 illustrating the spreader apparatus;
[0030] FIG. 5A is a schematic partial cross-sectional view of the apparatus of FIG. 1 taken at line 5 A- 5 A in FIG. 4 ;
[0031] FIG. 5B is an enlarged schematic perspective view of an overflow sensor in accordance with the invention;
[0032] FIG. 6A is a schematic perspective view of one embodiment of a system for 3D printing including a 3D printing apparatus and a build material delivery system in accordance with the invention;
[0033] FIG. 6B is a schematic perspective view of an alternative embodiment of a system for 3D printing including a 3D printing apparatus and a build material delivery system in accordance with the invention;
[0034] FIG. 7A is a schematic perspective view of one embodiment of an apparatus for 3D printing in accordance with the invention with a build drum partially cut-away;
[0035] FIG. 7B is a schematic perspective view of the apparatus of FIG. 7A with a portion of the build material removed from the build drum;
[0036] FIG. 8A is an enlarged schematic perspective of one embodiment of a printbar assembly including a print diagnostic station in accordance with the invention;
[0037] FIG. 8B is a schematic representation of the diagnostic station of FIG. 8A ;
[0038] FIGS. 9A-9J are schematic representations of one embodiment of an apparatus and method for cleaning a printhead in accordance with the invention;
[0039] FIG. 10 is a schematic representation of one step of the method of cleaning a printhead depicted in FIGS. 9A-9J ;
[0040] FIG. 11 is a schematic perspective view of an alternative embodiment of a printhead cleaning station in accordance with the invention;
[0041] FIGS. 12A-12C are schematic side and perspective views of a printhead being cleaned at the cleaning station of FIG. 11 ;
[0042] FIGS. 13A-13D are schematic perspective views of another alternative embodiment of a printhead cleaning station in accordance with the invention;
[0043] FIGS. 14A-14D are schematic representations of one embodiment of a radial printing process in accordance with the invention; and
[0044] FIGS. 15A and 15B are schematic top views of an alternative embodiment of an apparatus for 3D printing in accordance with the invention.
DETAILED DESCRIPTION
[0045] Embodiments of the present invention are described below. It is, however, expressly noted that the present invention is not limited to these embodiments, but rather the intention is that variations, modifications, and equivalents that are apparent to the person skilled in the art are also included.
[0046] FIGS. 1-3 depict an apparatus 10 for 3D printing. The apparatus 10 produces three-dimensional objects by depositing alternating layers of build material and binder on a build surface or in a container to print multiple layers that ultimately form the three-dimensional object. The apparatus 10 includes a rotary build table, in this case a build drum 12 , a structural frame 14 , a base 16 , at least one printbar assembly 18 , a powdered build material dispenser assembly 20 , and a spreader assembly 22 . In the embodiment shown, the apparatus 10 includes two printbar assemblies 18 A, 18 B. The apparatus 10 further includes a component-mounting surface 26 attached to the frame 14 . In one embodiment, the component mounting surface 26 may be movable to provide access to the build drum 12 . The various assemblies 18 , 20 , 22 are typically mounted to the component mounting surface 26 and/or the frame 14 . It is generally advantageous, for maintenance purposes, for the assemblies 18 , 20 , 22 to be stationary and the build drum 12 to rotate. For example, with redundant stationary printbar assemblies 18 , a user can change out one printbar assembly 18 while the other printbar assembly 18 continues to operate. In addition, the apparatus 10 can include essentially any number of printbar assemblies 18 mounted in a variety of configurations for accomplishing printhead redundancy, increasing print speeds, and/or printing multiple colors.
[0047] The build drum 12 shown is generally cylindrical in shape and is mounted about a center shaft 28 attached to the base 16 and the frame 14 . A bottom surface 17 of the build drum 12 may be substantially perpendicular to a sidewall 19 of the build drum 12 , or the bottom surface 17 can be angled. For example, the bottom surface 17 may be conical, such that the surface tilts toward a center point of the build drum 12 . The tilt may be from about 1 degree to about 15 degrees or more. In such an arrangement, the dispenser, the spreader, and the printbars should be slanted to correspond to the angle of tilt.
[0048] In a particular embodiment, the build drum 12 is mounted on a rotary actuator 29 that rotates the build drum 12 about the center shaft 28 . The rotary actuator 29 could be hydraulically, pneumatically, or electrically driven. The rotary actuator 29 can include gears and belts for driving the build drum 12 . In addition, the rotary actuator 29 may include one or more encoders 46 , or similar devices, that cooperate with a controller to monitor and adjust the speed and/or position of the build drum 12 . The encoders 46 can also be used to control the firing of the printheads 48 , such that the printheads 48 print accurately and repeatedly, regardless of variations in the rotational speed of the build drum 12 .
[0049] The build drum 12 receives build material from the build material dispenser assembly 20 that is located adjacent to the build drum 12 . In particular, the build material dispenser assembly 20 is mounted above the build drum 12 and dispenses build material onto the build drum 12 as it rotates. Typically, the build material dispenser assembly 20 deposits a predetermined amount of material onto the build drum 12 in the form of a line substantially along a radius of the build drum 12 . Alternatively, the build material dispenser assembly 20 could include nozzles for spraying the material onto the build drum 12 . In addition, the build material dispenser assembly 20 could include a volumetric adjuster, for manually or automatically adjusting the amount of material being deposited. The build material dispenser assembly 20 is supported on the component-mounting surface 26 . In one embodiment, the build material dispenser assembly 20 may be supplied by a larger dispenser assembly located remotely from the apparatus 10 (see FIGS. 6A and 6B ). Further, the build material dispenser assembly 20 may include an agitator to maintain the build material in a loose powder form.
[0050] Located adjacent the build material dispenser assembly 20 is the spreader assembly 22 . The spreader assembly 22 spreads the build material uniformly across the build drum 12 as it rotates. The spreader assembly 22 is shown in greater detail in FIG. 3 . The spreader assembly 22 includes a counter-rotating spreader roll 52 that spreads the build material radially across the build drum 12 , thereby forming a build surface 24 . The spreader assembly 22 also includes a roll scraper 54 that removes build material that may become stuck to the roll 52 . The spreader assembly 22 is also mounted on the component-mounting surface 26 .
[0051] The operation of the build drum 12 varies in different embodiments to accommodate the multiple layers of build material. For example, in one embodiment, the build drum 12 moves downwardly relative to the assemblies 18 , 20 , 22 mounted on the component mounting surface 26 . In a particular embodiment, at least a portion of the center shaft 28 and the build drum 12 are threaded and the build drum 12 threadedly engages the center shaft 28 . As the build drum 12 rotates, it moves down the center shaft 28 . In another embodiment, as shown in FIGS. 2 and 5 A, the build drum 12 includes a bottom surface 17 that moves downwardly relative to the build drum 12 to continuously receive layers of build material. The bottom surface 17 is moved vertically by one or more linear actuators 191 . The linear actuators could be hydraulically, pneumatically, or electrically driven. In yet another embodiment, the assemblies 18 , 20 , 22 move upwardly relative to the build drum 12 and the build surface 24 .
[0052] It is advantageous for a user to be able to remove finished parts without stopping the printing process, therefore, the build drum 12 may include structure for facilitating removal of completed parts. In one example, the build drum 12 includes an opening in its bottom or side surface that allows for removal of the parts from the bottom and/or side, while the apparatus 10 continues to print above. In this example, the apparatus 10 may print a bottom plate covering essentially the entire build surface 24 before printing any parts. The bottom plate(s) would separate the layers of printed parts to prevent the inadvertent removal of build material or unfinished parts. Alternatively, the user could stop the printing process and remove the parts manually from the top, bottom, or side (see FIGS. 7A and 7B ).
[0053] As shown in FIG. 4 , the spreader assembly 22 is disposed slightly non-radially, with respect to the build drum 12 . The build material dispenser assembly 20 deposits a substantially radial line of material in front of the spreader assembly 22 as the build drum 12 rotates (arrow 44 ). The apparatus 10 can be configured to operate with the drum 12 rotating in a counter-clockwise direction when viewed from the top as illustrated or clockwise in a mirror image of the configuration shown. The non-radial spreader assembly 22 spreads the material, forcing the excess material to migrate towards a center opening 56 in the build drum 12 . The excess material falls into an overflow tray 68 (see FIGS. 1-2 ) located beneath the build drum 12 . In one embodiment, the apparatus 10 is configured to reclaim the excess material for later use. In the embodiment shown, the apparatus 10 includes an overflow sensor 58 . The sensor 58 monitors the amount of excess material falling through the center opening 56 . The sensor 58 sends a signal to the apparatus controller indicative of the amount of excess material measured. The apparatus 10 can, in response to the signal, adjust the amount of material dispensed by the build material dispenser assembly 20 .
[0054] The sensor 58 is shown in greater detail in FIGS. 5A and 5B . FIG. 5A depicts the general location of the sensor 58 on the apparatus 10 . The sensor 58 is disposed within the center opening 56 and is mounted to the non-rotating center shaft 28 . FIG. 5B is an enlarged view of the sensor 58 . The sensor 58 includes a shaft 66 for mounting the sensor 58 to the center shaft 28 . At a distal end of the shaft 66 is a paddlewheel assembly including a magnetic sensor 60 and a series of magnets 62 located on individual legs 64 of the paddlewheel 65 . As excess material falls, it impinges on the legs 64 , causing the paddle wheel 65 to rotate. The speed and/or period of rotation can be used to ascertain the amount of excess material being deposited, which can be adjusted accordingly. Alternatively, other types of sensors or more than one sensor can be used.
[0055] Referring back to FIGS. 1-3 , two printbar assemblies 18 A, 18 B are shown disposed about the apparatus 10 . Each printbar assembly 18 includes a printhead carrier 42 , for carrying at least one printhead 48 , a service station 34 , a printhead diagnostics station 38 , a printbar motor 36 , a printbar cable guide 32 , and a printbar slide 30 . One of the two assemblies 18 A, 18 B can be redundant to the other. Alternatively, many more printbar assemblies 18 could be included on the apparatus 10 . The printbar cable guide 32 guides and secures the electrical connections to the printheads 48 . The printbar slide 30 is attached to the component-mounting surface 26 and supports the printhead carrier 42 , the service station 34 , the printhead diagnostics station 38 , and the printbar motor 36 . The print bar motor 36 can be a servo type motor, used to radially move the printbar assembly 18 relative to the build drum 12 along the slide 30 . It is generally advantageous to use a positioning system capable of accurate and repeatable control, because this directly influences the accuracy of the objects being produced. The printhead carrier 42 is radially movable to position the printheads 48 for printing and for performing service on the printheads 48 .
[0056] The printhead carrier 42 can be moved along a radius of the build drum 12 to correct for deficiencies in print quality. For example, the printhead carrier 42 supports a printhead array 40 , which may include any number of printheads 48 , for example a single printhead 48 or eight rows of six printheads 48 . The printhead array 40 may include redundant printheads 48 , which compensate for the deficiencies in print quality. The printheads 48 can be commercially available inkjet type printheads or custom manufactured printheads to suit a particular application. The printheads 48 include multiple jets, for example 512 jets, each jet for depositing a drop of binder onto the build surface 24 .
[0057] The printheads 48 can be moved incrementally back and forth along the radius in a “shingling” fashion to compensate for irregularities in printing, for example, if some jets are not working, misfire, or are out of alignment. Shingling allows the apparatus 10 to produce stronger parts, because printing errors are averaged out. For example, shingling reduces the affect of jets that are not printing properly by offsetting the jets by a small amount such that any line of unprinted build material caused by a missing jet is in a different location on each print layer. Shingling can be carried out in various ways, for example, in response to an error message or the apparatus 10 can be programmed to continuously shingle by moving the printheads 48 in and out along the radius a random distance between the printing of each layer. Alternatively, the apparatus 10 can be programmed to run a printing routine, where the printheads 48 are moved a set distance for a specific number of print layers and then reset to a starting position. For example, the printheads 48 can be moved out along the radius 1/16″ for each print layer until the printheads 48 have been moved a total of ¼″. Then, the printheads 48 can be moved back in along the radius to their starting position or be moved back incrementally. Therefore, the apparatus 10 is printing over the same areas with different printheads 48 to average out any errors.
[0058] FIGS. 14A-14D depict generally a radial scanning print process, where a printhead array moves continuously in and out along a radius of a build drum, as the build drum rotates continuously. In such a process, the printhead array scans an entire build surface of the 3D printer. FIG. 14A is a schematic isometric view of a 3D printer 200 in accordance with the invention. The 3D printer 200 is similar to the 3D printer 10 previously described with respect to FIGS. 1-3 . The 3D printer 200 includes a build drum 212 and two printbar assemblies 201 A, 201 B. Each printbar assembly 201 A, 201 B includes a printhead array 202 . FIG. 14B is a schematic top view of the 3D printer 200 of FIG. 14A . The printbar assemblies 201 A, 201 B include printhead carriers 203 that move in and out, generally along a radius of the build drum 212 , as shown by arrow 204 . As shown in FIG. 14B , the build drum 212 includes a build surface 224 and rotates counter-clockwise, as shown by arrow 244 . Generally, the build drum 212 moves relatively slowly, while the printhead carriers 203 move more rapidly.
[0059] FIGS. 14C and 14D are enlarged schematic top views of the 3D printer 200 of FIG. 14A . As shown in FIG. 14C , the printhead array 202 includes six printheads 248 staggered along a length of the printhead carrier 203 ; however, the array 202 could be made up of essentially any number or arrangement of printheads 248 . The six staggered printheads 248 define the printing swath width 206 . In one embodiment, each printhead 248 prints a ½″ swath, resulting in a swath width 206 of about 3″. The width 206 is obtained with all of the jets printing; however, different swath widths and shapes can be achieved by controlling the number and arrangement of jets that actually fire. As the printhead carrier 203 moves the printhead array 202 radially in and out, the printheads 248 print on the in stroke, as shown by arrow 205 .
[0060] FIG. 14D depicts the specific details of the print swaths. Generally, the swaths print canted to a radius of the build drum 212 , because the build drum 212 is rotating as the printheads 248 are printing along the radius. The printhead travel path 207 includes a print stroke 208 and a return stroke 209 (the lines shown represent the centerline of the printhead array 202 ). The return stroke 209 occurs as the printhead carrier 203 moves radially outward, and the print stroke 208 occurs as the printhead carrier 203 moves radially inward. When printing, not all of the jets are firing along the entire print stroke 208 , resulting in a used printable area 213 and an unused printable area 211 . This is done to compensate for the fact that the printed swaths would otherwise overlap as the build drum 212 rotates. As shown, the printed segments 210 abut one another, thereby forming a fully printed area, as shown. The used printable area 213 of the swath is widest at a point furthest from the center of the build drum 212 .
[0061] It should be noted that the various 3D printers disclosed herein print based on polar coordinates (i.e., r, θ), as opposed to linear printers, which print based on rectangular coordinates (i.e., x, y). The disclosed 3D printers include logic for converting rectangular coordinates to polar coordinates for printing on a radial build surface. The converting logic typically resides in the controller that controls the operation of the 3D printer.
[0062] In addition, because the printheads are printing along a radius, not all of the jets of the printhead print every time. In particular, the jets located closest to the center of the print arrays tend to print less, thereby resulting in a longer duty life. Correspondingly, the printheads located on the outsides of the print arrays tend to fail first.
[0063] In one embodiment, the apparatus 10 can include one or more sensors to measure the print quality or other characteristics of the apparatus 10 , such as print speed, printhead condition (e.g., an empty or dirty printhead), misfiring jets, build material quantity, and/or build drum position. In a particular embodiment, a sensor can monitor the print quality by determining if the printheads 48 are printing properly and, if not, can send a signal to the apparatus controller to shift the printheads 48 to compensate for printheads 48 that are not printing properly. For example, the controller could move the printheads 48 radially a very small amount for shingling purposes. In one embodiment, a sensor can be used to determine whether all, or at least a minimum number, of jets are firing and, if not, signal the user to replace a printhead 48 . Additionally, sensors can be used to monitor and control other functions, such as running diagnostic tests, performing cleaning of the printheads 48 , refilling the build material dispenser assembly 20 , cleaning the spreader assembly 22 , and performing any other desired function of the apparatus 10 .
[0064] The printbar assembly 18 can also be moved for diagnostic or service purposes. Moving the printhead array 40 radially from the build drum 12 provides the user with access to the printheads 48 for maintenance purposes, such as cleaning or replacement. Printhead cleaning is described in detail with respect to FIGS. 9A-9J , 10 , 11 , 12 A- 12 C, and 13 A- 13 D. The printhead array 40 can also be moved radially outwardly to run a diagnostic routine of the printhead array 40 (see FIGS. 8A and 8B ). In an alternative embodiment, the printbar assembly 18 can be raised from the build drum 12 for service purposes.
[0065] The size and exact configuration of the apparatus 10 can vary to suit a particular application. For example, the apparatus 10 could be sized to fit on a tabletop to produce relatively small three-dimensional objects, or the apparatus 10 could have a substantial footprint for producing relatively large three-dimensional objects. In a particular embodiment, the build drum 12 has an outside diameter of about six feet, an inside diameter of about two feet, and a depth of about two feet. The size of the build drum 12 can vary to suit a particular application. In addition, the apparatus 10 can be situated within an enclosure and can include air handling equipment for cleaning the work environment. The enclosure can include windows for monitoring operation of the apparatus 10 .
[0066] Additionally, the apparatus 10 may include multiple build drums 12 and printbar assemblies 18 . In one possible configuration, the apparatus 10 includes multiple build drums 12 spaced about a centrally located gantry that carries the printing components, i.e., material dispenser, spreader, and the printheads. The gantry can be rotated into position above one of the build drums 12 . In this configuration, the user can be printing on one build drum 12 while removing parts from another build drum 12 , thereby allowing for continuous operation. In another embodiment, the build drum 12 can be radially stationary, but vertically movable. In this embodiment, the printing components are configured to move radially about the build drum 12 . In a particular embodiment, the gantry supporting the printing components rotates radially about the build drum 12 while the printheads move back and forth along a radius of the build drum 12 . This configuration allows for printing over substantially the entire surface area of the build drum 12 .
[0067] FIGS. 15A and 15B depict an alternative embodiment of a 3D printing apparatus 300 in accordance with the invention. As shown in FIG. 15A , the apparatus 300 includes three build drums 312 disposed on a carousel 313 . The printing hardware is stationary as the carousel 313 rotates the build drums 312 around a carousel pivot shaft 314 into alignment with the printing hardware. The build drums 312 and printing hardware are essentially the same as previously described.
[0068] FIG. 15B depicts the carousel 313 rotating counter-clockwise (arrow 315 ) to move one build drum 312 A out of alignment with the printing hardware and a second build drum 312 B into alignment with the printing hardware. The carousel can rotate in either the clockwise or counter-clockwise direction. One advantage to this arrangement is that the apparatus 300 can be printing on one build drum 312 C, while one set of printed objects can be curing in the second build drum 312 B and another set of printed objects are being removed from the third build drum 312 A.
[0069] FIGS. 6A and 6B depict systems 70 , 92 for 3D printing utilizing two different build material feed systems 74 , 96 . Referring to FIG. 6A , the system 70 includes a 3D printing apparatus 72 , similar to that previously described with respect to FIGS. 1-3 , and the build material feed system 74 remotely connected to the 3D printing apparatus 72 . The build material feed system 74 includes a storage bin, or hopper 80 , for holding the build material and structure for conveying the build material to the 3D printing apparatus 72 . The hopper 80 may include multiple internal compartments for holding multiple build material components that are mixed before being conveyed to the three-dimensional printing apparatus 72 . Additionally, the multiple compartments might hold different types of build materials, with the build material feed system 74 including structure for delivering one or more different materials to the apparatus 72 .
[0070] The build material feed system 74 shown in FIG. 6A includes a supply duct 82 , a supply pump 84 , a return (or overflow) duct 88 , and a return (or overflow) pump 90 . These components 82 , 84 , 88 , 90 connect the hopper 80 with the 3D printing apparatus 72 and are capable of conveying a continuous or intermittent flow of material to the 3D printing apparatus 72 , as needed. The ducts 82 , 88 can be rigid or flexible or combinations thereof. For example, a flexible hose can be used at the connection points between the ducts 82 , 88 and the 3D printing apparatus 72 , while the portion of the ducts 82 , 88 running between the build material feed system 74 and the 3D printing apparatus 72 can be rigid pipe. In alternative embodiments, the build material feed system 74 could include a conveyer belt system, a carousel, a feed screw, a gravity feed system, or other known components for transporting loose powder materials. The systems could be operated manually or driven pneumatically, hydraulically, or electrically. Additionally, the build material feed system 74 may include a main fill port or duct 86 on the hopper 80 . Further, the build material feed system 74 may include one or more sensors connected to the controller 73 to monitor and control material levels in the hopper 80 and/or the amount and the rate of the materials being delivered to the 3D printing apparatus 72 .
[0071] The hopper 80 is filled with build material, typically in powder form, via the duct 86 . Alternatively, the hopper 80 may include a removable cover for filling. The material is directly fed to the 3D printing apparatus 72 via the supply duct 82 exiting the bottom of the hopper 80 . The supply pump 84 is located in the supply duct 82 to facilitate transportation of the material to a build material dispenser assembly 76 on the 3D printing apparatus 72 . In the embodiment shown, the excess material is collected in a material overflow tray 78 located on the 3D printing apparatus 72 and returned directly to the hopper 80 via the return duct 88 and the return pump 90 located in the return duct 88 . The material is returned to the top of the hopper 80 . In an alternative embodiment, the return material is processed before being returned to the hopper 80 . In a particular embodiment, the build material feed system 74 may include an agitation component to maintain the build material in a powder form. Alternatively or additionally, the build material feed system 74 may include components for handling build materials supplied in other than powder form.
[0072] As shown in FIG. 6B , the system 92 includes a 3D printing apparatus 94 , similar to that previously described with respect to FIGS. 1-3 , and the build material feed system 96 remotely connected to the 3D printing apparatus 94 . The build material feed system 96 is similar to the system 74 described with respect to FIG. 6A and includes a hopper 102 , a supply duct 106 , a supply pump 108 , a return (or overflow) duct 114 , and a return (or overflow) pump 116 . The build material feed system 96 further includes a blending assembly 110 . In the embodiment shown, the blending assembly 110 is disposed in the supply duct feeding the 3D printing apparatus 94 ; however, the blending assembly 110 could be located in the hopper 102 to blend the materials before they leave the hopper 102 .
[0073] The blending assembly 110 includes multiple component hoppers 112 . In this configuration, the main hopper 102 holds one or more of the major constituents of the build material that are supplied to the blending assembly 110 , such as sand. One or more additional constituents are introduced to the blending assembly 110 via the component hoppers 112 . The blending assembly 110 controls the feed rate and blending of the various constituents to create the final build material. Additionally, the blending assembly 110 can blend the excess material received from the return duct 114 into the build material supplied to the 3D printing apparatus 94 . In a particular embodiment, the blending assembly 110 meters the excess material into the blended build material in such a manner as to not effect the quality of the material being delivered to the 3D printing apparatus 94 .
[0074] FIGS. 7A and 7B depict the removal of three-dimensional objects or printed parts 126 from one embodiment of a 3D printing apparatus 120 in accordance with the invention. In FIG. 7A , the build drum 124 is shown in partial section to illustrate the positioning of the printed parts 126 . Layers of the build material accumulate in the build drum 124 and the printed parts 126 are surrounded by non-printed (unbound) build material 128 . There are various ways of removing the parts 126 ; however, in the embodiment shown, the parts 126 are removed though a top opening 122 of the build drum 124 . Specifically, the unbound build material 128 is evacuated from the build drum 124 by, for example, vacuuming. Alternatively, the unbound material 128 could be drained through bottom or side openings in the build drum 124 . Once the unbound material 128 is removed, the parts 126 can be manually or automatically removed from the build drum 124 . In one embodiment, the top opening 122 is partially covered. The parts 126 may be further processed, as needed.
[0075] FIGS. 8A and 8B illustrate the diagnostic station 38 of FIG. 1 . Other diagnostic systems are possible; for example detecting drops of binder or printing a test pattern on the build material. The diagnostic station 38 , as shown in detail in FIG. 8B , includes chart paper 130 mounted between a paper supply roll 132 and a paper take-up roll 134 , an optical scanner 138 , a fixed reference printhead 140 , and a paper drive capstan 136 . The capstan 136 is used to accurately feed and position the chart paper 130 . To run a diagnostic test, a portion of the printhead array 40 is moved in position over the diagnostic station 38 (arrow 142 in FIG. 8A ). A clean section of chart paper 130 is positioned below the printhead array 40 (arrow 144 in FIG. 8 A). The printheads 48 , including the reference printhead 140 , print on the chart paper 130 . The printed test pattern is passed under the optical scanner 138 for analysis. In one embodiment, the optical scanner 138 is a CCD camera that reads the test image. The apparatus controller 73 , via the diagnostic station 38 , is able to determine if the printheads 48 are printing correctly or are in need of cleaning or replacement. In an alternative embodiment, the chart paper 130 may move continuously while the printhead array 40 moves continuously over it, printing a test pattern on the paper.
[0076] FIGS. 9A-9J illustrate a system 146 for cleaning a printhead 150 . The system 146 is located in the service station 34 ( FIG. 1 ). In one embodiment, the system 146 includes a cleaning station 148 made up generally of a latch pawl 152 , a spring 154 , a squeegee 156 , a printhead cap 158 , a cap carrier 192 , a second spring 162 , and a cam track 164 . Only a single cleaning station 148 is shown for descriptive purposes; however, multiple stations 148 may be disposed in the service station 34 . Alternatively, a single cleaning station 148 may service multiple printheads 150 by, for example, successively positioning the printheads 150 relative to the cleaning station 148 .
[0077] FIG. 9A represents a starting position of the cleaning system 146 . As shown in FIG. 9B , the printhead 150 approaches the cleaning station 148 and engages the latch pawl 152 . The latch pawl 152 is actuated as the printhead 150 passes over the latch pawl 152 . The printhead 150 continues to move past the latch pawl 152 and engages the squeegee 156 ( FIG. 9C ). The printhead 150 passes over squeegee 156 . As shown in FIG. 9D , the printhead 150 contacts the cap carrier 192 , which is driven along the cam track 164 and compresses the spring 162 . The printhead cap 158 is positioned against a printhead face 160 ( FIGS. 9E and 9F ). As shown in FIG. 9F , the printhead cap 158 seals against the printhead face 160 while the face 160 is rinsed with wash fluid (see FIG. 10 ).
[0078] After the printhead face 160 is cleaned, the printhead 150 begins to move out of the cleaning station 148 ( FIG. 9G ). The latch pawl 152 engages the cap carrier 192 , halting its movement. As shown in FIG. 9H , the printhead 150 engages the squeegee 156 , which wipes the printhead face 160 . In an alternative embodiment, the squeegee 156 vibrates to further clean the printhead face 160 . The printhead 150 continues its forward movement, actuating the latch pawl 152 ( FIG. 9I ), which, in turn, releases the cap carrier 192 ( FIG. 9J ). The cap carrier 192 snaps back to the start position. The system 146 is now ready to clean another printhead 150 .
[0079] FIG. 10 depicts the action of FIG. 9F in greater detail. The printhead 150 is positioned with the printhead face 160 against the printhead cap 158 , which in this embodiment is made of rubber. The cap includes a seal lip 172 for sealing about the printhead face 160 . The cleaning station 148 is coupled to a wash fluid supply container 182 via a supply duct 184 and a wash fluid return container 186 via a return duct 188 . The wash fluid return container 186 is in communication with a vacuum source 180 , in this case a vacuum pump, via a vacuum duct 190 . Additionally, a valve 178 is located in the return duct 188 . The valve 178 may be manually or automatically actuated.
[0080] In operation, the vacuum source 180 creates a vacuum within a cavity 174 in the printhead cap 160 . The vacuum pulls wash fluid from the supply container 182 through the supply duct 184 . The wash fluid enters the cavity 174 as a spray 176 against the printhead face 160 . The spray 176 washes debris, such as excess build material and dried binder, off the printhead face 160 . The used wash fluid and debris are drawn out of the cavity 174 by the vacuum source 180 and into the return container 186 via the return duct 188 . Additionally, the negative pressure created in the cavity 174 by the vacuum source 180 prevents the wash fluid from entering the jet nozzles and, in fact, may cause a small amount of binder to flow out of the nozzles to flush any powdered build material out of the nozzle. Blockages or obstructions in the jet nozzles can cause the jets to fire in the wrong direction. Once the operation is complete, the system 148 moves onto the step depicted in FIG. 9G .
[0081] FIG. 11 depicts an alternative embodiment of a cleaning station, also referred to as a reconditioning station 406 . The reconditioning station 406 is shown removed from the printing apparatus 10 ; however, the reconditioning station 406 can be included on the printbar assembly 18 or in the service station 34 . The reconditioning station 406 includes a plurality of wiping elements 408 and a plurality of lubricators 410 . The wiping elements 408 and the lubricators 410 are mounted on a plate 412 that can be actuated to travel, as indicated by arrow 401 . The engaging surfaces 414 of the wiping elements 408 and the lubricators 410 are disposed upwards so that when the printhead 476 is in the reconditioning station 406 , the wiping elements 408 and the lubricators 410 clean the printheads 476 from below ( FIGS. 12A-12C ). Also, in the illustrated embodiment, one wiper 408 and one lubricator 410 acting as a pair 416 are used to clean each printhead 476 . Further, in the illustrated embodiment, each wiper and lubricator pair 416 are offset from each other to correspond with the offset spacing of the printheads 476 (see, for example, printheads 48 in FIG. 8A ). In other embodiments, however, any number of wiping elements 408 and lubricators 410 can be used to clean the printheads 476 , and the wiping elements 408 and lubricators 410 can be spaced using any desirable geometry.
[0082] FIGS. 12A-12C depict one method of using the reconditioning station 106 . The printhead(s) 476 is disposed above the reconditioning station 406 ( FIG. 12A ). The plate 412 on which the wiping elements 408 and lubricators 410 are mounted is then actuated into alignment with the printheads 476 , and the printheads 476 are wiped and lubricated from beneath to remove any accumulated grit and to improve the flow of binding material out of the printheads 476 . Specifically, the lubricator 410 applies a lubricant to the printhead face 477 to moisten any debris on the printhead face 477 . Then, the printhead 476 is moved to pass the printhead face 477 over the wiping element 408 (e.g., a squeegee), which wipes the printhead face 477 clean. Alternatively, the printhead face 477 could be exposed to a vacuum source to remove any debris present thereon.
[0083] FIGS. 13A-13D depict an alternative embodiment of a reconditioning station 506 in accordance with the invention. The reconditioning station 506 may also be mounted in the service station 34 . The reconditioning station 506 includes a reservoir 542 that holds a washing solution 543 and a pump 545 that delivers the washing solution 543 under pressure to at least one nozzle 540 and preferably an array of nozzles 540 . The nozzles 540 are capable of producing a high velocity stream of washing solution 543 . In operation, the nozzles 540 are directed to the printhead face 577 of the printhead 576 . When directed onto the printhead face 577 , the washing solution 543 loosens and removes contaminants, such as build material and binding material, from the printhead face 577 . The orientation of the nozzles 540 may be angled with respect to the printhead face 577 , such that a fluid flow is induced across a plane of the printhead face 577 . For example, the washing solution can contact the printhead 576 at the side nearest the nozzles 540 and drain from the side of the printhead 576 furthest from the nozzles 540 . This approach improves the efficacy of the stream of washing solution 543 by reducing the accumulation of washing solution on the printhead face 577 , as well as the amount of washing solution 543 and debris that would otherwise drain near and interfere with the nozzles 540 . A splash guard may also be included in the reconditioning station 506 to contain splashing resulting from the streams of liquid washing solution 543 .
[0084] It is desirable to remove a large portion of the washing solution 543 that remains on the printhead face 577 after the operation of the nozzles 540 is complete. This is conventionally accomplished by drawing a wiping element 408 across the printhead face 477 , as shown in FIG. 12C . A disadvantage of this approach is that contact between the wiping element 408 and the printhead face 477 may degrade the performance of the printhead 476 by, for example, damaging the edges of the inkjet nozzle orifices. Accordingly, it is an object of this invention to provide a means of removing accumulated washing solution from the printhead face 577 , without contacting the delicate region around the inkjet nozzles. In one embodiment, a wicking member 544 may be disposed such that the printhead face 577 may pass one or more times over its upper surface 546 in close proximity, without contact, allowing capillary forces to draw accumulated washing solution 543 away from the printhead face 577 . The wicking member 544 may be made from rigid, semi-rigid, or compliant materials, and can be of an absorbent or impermeable nature, or any combination thereof.
[0085] For the wicking member 544 to effectively remove accumulated washing solution 543 from the printhead face 577 , the gap between the upper surface 546 of the wicking member 544 and the printhead face 577 must be small, a desirable range being between about 0 inches to about 0.03 inches. A further object of this invention is to provide a means for maintaining the gap in this range without resort to precise, rigid, and costly components.
[0086] In another embodiment, the wicking member 544 may consist of a compliant rubber sheet oriented approximately orthogonal to the direction of relative motion 547 between the wicking member 544 , and the printhead 576 and with a portion of its upper edge 546 disposed so that it lightly contacts or interferes with the printhead face 577 only in non-critical areas away from the printhead nozzle orifices. The upper edge 546 of the wicking member 544 may include one or more notches 548 at locations where the wicking member 544 might otherwise contact delicate components of the printhead face 577 . System dimensions are selected so that the wicking member 544 always contacts the printhead face 577 , and is deflected as the printhead 576 passes over it, independent of expected variations in the relative positions of the printhead 576 and the reconditioning station 506 . The upper edge 546 accordingly follows the position of the printhead face 577 , maintaining by extension a substantially constant space between the printhead face 577 and the relieved surface notch 548 . To further prolong the life of the printhead 576 , a bending zone of the wicking object 544 can be of reduced cross-section to provide reliable bending behavior with little deformation of the upper edge 546 of the wicking member 544 .
[0087] FIGS. 13B-13D illustrate a reconditioning cycle in accordance with the invention. FIG. 13B shows the printhead 576 approaching the reconditioning station 506 along the path 547 . When the printhead 576 lightly contacts the wiping member 544 , as shown in FIG. 13C , motion stops along the path 547 and the washing solution 534 is directed at the printhead face 577 by the nozzle array 540 . When the spraying operation is complete, the printhead 576 continues to travel along the path 547 , as shown in FIG. 13D . The wiping member 544 is further deflected to allow passage of the printhead 576 , and the accumulated washing solution 543 is wicked away from the printhead face 577 . After being sprayed and wiped, the printhead 576 may print a plurality of droplets to eject any washing solution that may have been ingested during the reconditioning process.
[0088] Additional cleaning methods are contemplated, such as wiping the printhead face with a cylindrical “paint roller” that cleans and moistens itself by rolling in a reservoir of wash fluid. In another embodiment, a cleaning system could include a continuous filament that carries wash fluid up to a printhead face and carries debris away to a sump. The system may include a small scraper that can be run over the filament to remove built up debris.
[0089] Having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. The described embodiments are to be considered in all respects as only illustrative and not restrictive. | The invention relates to apparatus and methods for producing three-dimensional objects and auxiliary systems used in conjunction with the aforementioned apparatus and methods. The apparatus and methods involve continuously printing radially about a circular and/or rotating build table using multiple printheads. The apparatus and methods also include optionally using multiple build tables. The auxiliary systems relate to build material supply, printhead cleaning, diagnostics, and monitoring operation of the apparatus. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of Ser. No. 480,660 filed June 19, 1974, now U.S. Pat. No. 3,900,511 issued Aug. 19, 1975, which in turn is a divisional application of Ser. No. 338,018 filed Mar. 5, 1973, now U.S. Pat. No. 3,853,946 issued Dec. 10, 1974 which in turn is a divisional application of Ser. No. 197,968, filed Nov. 11, 1971, now U.S. Pat. No. 3,742,015 issued June 26, 1973, which in turn is a divisional application of our U.S. Pat. application Ser. No. 42,528, filed June 1, 1970, now U.S. Pat. No. 3,655,716, issued Apr. 11, 1972, which in turn is a divisional application of our U.S. Pat. application Ser. No. 719,834, filed Apr. 9, 1968, now U.S. Pat. No. 3,542,848, issued Nov, 24, 1970.
BACKGROUND OF THE INVENTION
The synthesis of thiamine has been described by a number of investigators such as Todd and Bergell in Journ. Chem. Soc., pg. 364 (1937). In these syntheses a pyrimidine ring compound, i.e., 2-methyl-2-amino-5-bromomethylpyrimidine dihydro-bromide and a thiazole ring compound, i.e., 4-methyl-5-β-hydroxyethyl thiazide are condensed to form the thiamine ring structure. This pyrimidine compound is prepared from 2-methyl-4-amino-5-cyanopyrimidine which is formed by the condensation of aminomethylene malononitrile with acetimino ethyl ether, as described in Chapter 16 of the Vitamins, Chemistry, Physiology, Pathology, Vol. III, Sebrell and Harris, Academic Press. Inc., New York (1954).
This procedure therefore depends on the use of the aminomethylene malononitrile which has been a difficult material to synthesize economically. In view of this fact, it has long been desired to provide an economical means of synthesizing aminomethylene malononitrile utilizing inexpensive and readily available starting materials.
SUMMARY OF THE INVENTION
In accordance with this invention, it has been found that aminomethylene malononitrile, which has the formula: ##EQU1## can be synthesized economically from a dialkyl aminoacrylonitrile of the formula: ##EQU2## wherein R 1 and R 2 are lower alkyl.
In accordance with another embodiment of this invention, we have found that the starting material of formula II can be easily synthesized from readily available and commercially economical materials by two methods. In the first method of producing the compound of formula II above, an acetal compound of the formula: ##EQU3## wherein R 1 and R 2 are as above, and R 3 is lower alkyl, is condensed at a temperature of at least 80°C. with acetonitrile. In accordance with the second method of producing the compound of formula II above, a compound of the formula: ##EQU4## wherein R 1 and R 2 are as above,
is treated with a hydrogen acceptor at a temperature of at least 50°C. in the presence of a dehydrogenation catalyst.
DETAILED DESCRIPTION
As used throughout the specification, the term "lower alkyl" includes both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, and the like. As used throughout the specification, the term "lower alkanoyl" includes alkanoyl groups containing from 2 to 6 carbon atoms such as acetyl, propionyl, and butyryl.
The reaction of acetonitrile with the acetal of formula III to form the compound of formula II is carried out at a temperature of at least 80°C. Generally, it is preferred to utilize a temperature of from 100°C. to 250°C. in carrying out this reaction. While this reaction can be carried out at atmospheric pressure, superatmospheric pressures are utilized when higher temperatures are utilized. This reaction can be carried out without the need for utilizing any solvent. However, if desired, an inert organic solvent can be utilized. Any conventional inert organic solvent such as benzene, toluene, methylene chloride, can, if desired be utilized in carrying out this reaction.
The second method of preparing the compound of formula II above is by treating a compound of formula IV above with a hydrogen acceptor at a temperature of at least 50°C. in the presence of a dehydrogenation catalyst. Any conventional dehydrogenation catalyst can be utilized in carrying out this reaction. Among the preferred dehydrogenation catalysts which can be utilized in this reaction are palladium, Raney nickel and cupric chromite. In carrying out this reaction, any conventional hydrogen acceptor can be utilized. Among the preferred hydrogen acceptors is oxygen which can be supplied by carrying out the reaction in the presence of air. Alternatively, the oxygen can be supplied in the form of bottled oxygen. Other hydrogen acceptors which can be advantageously utilized in this process are aliphatic ethers containing at least one ethylenic moiety bound to the oxygen atom and having from 3 to 15 carbon atoms such as methyl vinyl ether and cyclic ethers such as dihydropyran.
In converting the compound of formula IV above to the compound of formula II above, no solvent need be present. Generally, in carrying out this reaction, a temperature of at least 50°C. should be utilized with temperatures of between 80°C. to 200°C., being preferred. If high temperatures are utilized, the reaction may be carried out under superatmospheric pressure.
In accordance with this invention, the compound of formula I above is synthesized from the compound of formula II above by means of the following reaction scheme: ##SPC1##
wherein R 1 and R 2 are as above, R 3 , R 4 , R 6 , R 7 and R 8 are lower alkyl, Y - is a halide ion, and R 5 is lower alkanoyl, and Z - is the CH 3 OSO 3 ion.
The conversion of compounds of the formula II above to compounds of the formula V above is carried out, as in reaction step (a), by treating the compound of the formula II above with a diloweralkyl formamide in the presence of an inorganic acid halide condensing agent. These three reactants may be used in any molar ratio in carrying out the reaction of step (a). In carrying out the reaction of step (a), temperatures of from about -10°C. to +10°C. should be utilized. Generally, it is preferred to carry out the reaction of step (a) in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. However, the preferred solvents are the halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc. In carrying out this reaction, any of the lower alkyl formamides, preferably dimethyl formamide can be utilized. Among the preferred inorganic acid halide condensing agents which can be utilized in accordance with this invention are included phosphorous oxychloride, phosgene, thionyl chloride, phosphorous pentachloride, etc.
The compound of formula V above is converted into the compound of formula VI above, as in reaction step (b), by raising the pH of an aqueous solution containing the compound of formula V above to a value of from 7 to 9. This is accomplished by treating the compound of formula V above with an aqueous alkaline medium sufficient to raise the pH to a range of from 7 to 9. Any conventional inorganic base such as sodium hydroxide, potassium hydroxide, etc. can be utilized as the alkaline medium to provide a pH within the range of from about 7 to 9. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, elevated or reduced temperatures can be utilized.
The compound of formula VI above is converted to the compound of formula VII-A above, via reaction step (c 1 ), by means of reacting the compound of the formula VI above with a compound of the formula:
NH.sub.2 OR.sub.5 XI
wherein R 5 is as above.
In the reaction of step (c 1 ), the two reactants may be used in any molar ratio. The reaction of step (c 1 ) is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the inert organic solvents that can be utilized are included halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc. Generally, in carrying out this reaction, room temperature is utilized. During the reaction of step (c 1 ), the temperature utilized should not be above 30°C. It is preferred to carry out this reaction at a temperature of from about 0°C. to 25°C.
The compound of formula VII-A can be converted to the compound of formula VIII via reaction step (d 1 ) by heating the compound of formula VII-A to a temperature of from 70°C. to 90°C. The reaction of step (d 1 ) is carried out in the presence of an inert organic solvent. Any of the solvents hereinbefore mentioned in connection with reaction step (c 1 ) can be utilized in carrying out the reaction of step (d 1 ).
The compound of formula VI above can be converted to the compound of formula VII, via reaction step (c) by means of reacting the compound of the formula VI with a compound of the formula:
NH.sub.2 OSO.sub.3 H XI-A
this reaction is preferably carried out by suspending the two reactants in water and allowing the reaction to proceed at room temperature. During the reaction of step (c), the temperature utilized should not exceed about 30°C. Generally, it is preferred to utilize a temperature of from 0°C. to 25°C. in this reaction.
The compound of formula VII above can be converted to the compound of formula VIII, as in reaction step (d) by adjusting the pH of the aqueous reaction mixture containing the compound of formula VII to about 5.5 to 8.5 warming the reaction mixture to a temperature of from about 60°C. to 90°C. The pH of the reaction mixture is adjusted to a range of 5.5 to 8.5 by treating the aqueous mixture with an alkali such as an alkali metal hydroxide. Among the preferred alkali are included sodium hydroxide, potassium hydroxide, etc.
The conversion of compounds of the formula VI above to the compound of the formula IX above is carried out, as in reaction step (f), by treating the compound of the formula VI above with a hydrazine of the formula: ##EQU5## wherein R 6 and R 7 are as above.
In carrying out the reaction of step (f) any mole ratio of the reactants can be utilized. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the preferred solvents are included the lower alkanols, such as methanol, ethanol, etc. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. However, it is preferred to carry out this reaction at the reflux temperature of the solvent. Therefore, temperatures of from 50°C. to 100°C. are generally utilized, depending upon the reflux temperature of the solvent.
The conversion of compounds of the formula IX above to the compounds of the formula X above, via reaction step (g), is carried out by treating the compound of the formula IX above with a dilower alkyl sulfate. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Among the conventional inert organic solvents which can be utilized are included lower alkanols, such as methanol or ethanol. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure or at elevated temperatures. Generally, it is preferred to carry out this reaction at the reflux temperature of the solvent.
The compound of formula X is converted to the compound of formula VIII via reaction step (h) by treating the compound of formula X above with an alkali. Any conventional alkali such as an alkali metal hydroxide or an alkali metal lower alkoxide, can be utilized in carrying out this reaction. Among the preferred alkali are included sodium hydroxide, potassium hydroxide, sodium methoxide, etc. This reaction is carried out in the presence of an inert organic solvent. Among the solvents that can be utilized are the lower alkanols, such as methanol or ethanol. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and at atmospheric pressure. If desired, elevated temperatures such as 80°C. can be utilized in carrying out this reaction.
The compound of formula VIII above is converted into the compound of formula I above by treating the compound of formula VIII above, as in reaction step (e), with liquid ammonia. This reaction is generally carried out a temperature of from minus 70°C. or below. It is preferred to carry out this reaction at a temperature of from minus 70°C. to minus 120°C. This reaction is carried out by dissolving the compound of formula VIII above in liquid ammonia. After the compound of formula VIII is dissolved in liquid ammonia, the resulting solution is slowly warmed to room temperature so as to produce the compound of formula I above. This warming should take place within a period of time of at least one hour. Generally, it is preferred to carry out this warming step within a period of from 4 to 24 hours.
Another means of converting the compound of formula VIII above into the compound of the formula I above is by treating the compound of the formula VIII above with a saturated aqueous solution of ammonium hydroxide. This reaction is carried out in an aqueous medium and by heating the aqueous mixture containing the compound of formula VIII and ammonium hydroxide to a temperature of from about 80°C. to 100°C.
This invention will be more fully understood from the specific examples which follow. These examples are intended to illustrate the invention and are not to be construed as limitative thereof. All temperatures are in degrees centigrade.
EXAMPLE 1
Dehydrogenation of dimethylaminopropionitrile to dimethylaminoacrylonitrile
The catalytic dehydrogenation of dimethylaminopropionitrile was carried out under the following conditions:Hydrogen Reaction ReactionAcceptor Catalyst Temperature Time__________________________________________________________________________Air 10% Raney nickel Reflux: about 6 hours 115°C.Air 30% CuCr 2 O 4 3-24 hoursCH 2 =CHOCH 2 CH 3 palladium on carbon 50°C. 24 hours (10%)Dihydropyran palladium on carbon Reflux: about 24 hours (10%) 80°C.Dihydropyran palladium on carbon Reflux 40 hours (10%)__________________________________________________________________________
In the above reaction, a reaction mixture was prepared containing the catalyst and dimethylaminopropionitrile. Where an ether hydrogen acceptor was utilized, the hydrogen acceptor was present in a molar amount of ten times the moles of dimethylaminopropionitrile in the reaction mixture and the reaction was carried out under nitrogen. In the cases where air was used, the reaction was carried out by exposing the reaction mixture to the atmosphere. The catalyst was present in an amount of about 10% by weight or 30% by weight based upon the weight of the dimethylaminopropionitrile as indicated above. The final product obtained by vapor phase chromatography was dimethylaminoacrylonitrile. This product distilled at 115°C. at 3mm Hg.
EXAMPLE 2
Preparation of 3-dimethylaminoacrylonitrile
173.0 g. of the diethylacetal of dimethylformamide (1.18 moles) and 400 ml. of acetonitrile were placed in a 1200 ml. autoclave. Air was removed from the autoclave by flushing with nitrogen, and after purging charged to 50 p.s.i. with nitrogen. The reaction was carried out for 36 hours at 150°C. Upon completion of the reaction, excess acetonitrile was removed by vacuum distillation using a rotary evaporator at a vacuum of 135 mm Hg. and a waterbath temperature of 60°C. maximum. The remaining residue was fractionated using a 24 inch Vigreaux column. After discarding a small first fraction, the material boiling at 115°C. and 3.0 mm Hg was collected. This material was 3-dimethylaminoacrylonitrile.
EXAMPLE 3
Preparation of (3-dimethylamino-2-cyano-2-propen-1-ylidene)-dimethylammonium perchlorate
10 ml. of N,N-dimethylformamide were stirred at -4° to -7° and 10 ml. of phosphoroxy chloride were added dropwise in such a rate as to maintain the reaction temperature below 0°. The resulting semi-solid reaction mixture was diluted with 80 ml. of 1,2-dichloroethane. On warming to room temperature, a clear amber solution was obtained. The solution was cooled to -8° to -10°C. and 5.91 g. of 3-dimethylamino-acrylonitrile, dissolved in 15 ml. of 1,2-dichloroethane were added dropwise with stirring within 15 minutes. After removal of the solvent in vacuo a semicrystalline residue was obtained. The material was dissolved in 20 g. of ice/water and 8.1 g. of sodium perchlorate were added to this solution. On cooling (3-dimethylamino-2-cyano-2-propen-1-ylidene)-dimethylammonium perchlorate as crystals, (m.p. 139°-142°) was obtained.
EXAMPLE 4
Preparation of 2-cyano-3-dimethylaminoacrolein
36 ml. (0.465 mole) of N,N-dimethylformamide were stirred at 0° and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0°). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25°), a clear solution resulted which was cooled to -7° with an icesalt bath. A solution of 30 ml. (0.293 mole) of β-dimethylaminoacrylonitrile in 90 ml. of 1,2-dichloroethane was added dropwise keeping the temperature between -4° to -7°. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A 100 g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 15°-20°. The resulting solution was extracted with ethyl acetate in a liquid-liquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3-dimethylaminoacrolein, as deep yellow prisms, m.p. 143°-144°. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms, m.p. 143°-144°.
EXAMPLE 5
Preparation of 2-cyano-3-dimethylaminoacrolein
Into a 250 ml. 3-neck-round-bottom flask were placed 7.3 g. (0.1m) of dimethylformamide and 150 ml. dichloromethane. The stirred solution was cooled in ice/water and phosgene was bubbled through for 30 minutes. A white solid formed. The solvent was removed in vacuo. The remaining solid was suspended in 120 ml. dichloromethane. The stirred suspension was cooled in an ice/salt bath to -10°C. A solution of 9.6 g. (0.1m) 3-dimethylaminoacrylonitrile in 40 ml. of dichloromethane was added dropwise, maintaining the temperature below 0°C. After completed addition a clear yellow solution resulted. The solution was evaporated in vacuo to dryness. The solid residue was dissolved in 20 ml. of water. The aqueous solution was cooled to 0°C. and adjusted to pH 8.5 with 5N sodium hydroxide solution. The alkaline solution was allowed to stand at room temperature for 4 hours, during which time a crystalline solid precipitated. The whole mixture was extracted with 5 × 100 ml. of dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness in vacuo. The crystalline residue consisted of 2-cyano-3-dimethylaminoacrolein, m.p. 140°-141°. After recrystallization from ethanol, the melting point was 142°-143.5°.
EXAMPLE 6
Preparation of dimethylaminomethylenemalononitrile
To a mixture of 10 g. of 2-cyano-3-dimethylaminoacrolein and 100 ml. of ethylene chloride was added in small portions with stirring 9 g. of 0-acetylhydroxylamine hydrochloride. The mixture was stirred at room temperature for 30 minutes and then heated at reflux temperature for 1 hour. On cooling, dimethylaminomethylenemalononitrile crystallized from the reaction solution, and was collected by filtration (m.p. 81°-82°).
EXAMPLE 7
Preparation of N-(3-dimethylamino-2-cyano-2-propene-1-ylidene)-N', N'- dimethylhydrazine hydrochloride
A solution of 12.4 g. of 2-cyano-3-dimethylaminoacrolein and 9.6 g. of 1,1-dimethylhydrazine hydrochloride in 50 ml. of methanol was heated to reflux temperature for 90 minutes. On cooling the reaction mixture a first crop of N-(3-dimethylamino-2-cyano-2-propene-1-ylidene)-N', N'-dimethylhydrazine hydrochloride (m.p. 173°) precipitated in crystalline form and was filtered off. A second crop (m.p. 170°-172°) was obtained from the mother liquor on concentrating.
EXAMPLE 8
Preparation of N-(3-dimethylamino-2-cyano-2-propene-1-ylidene)-N', N'-dimethylhydrazine
5 g. of the N-(3-dimethylamino-2-cyano-2-propene-1-ylidene)-N', N'-dimethylhydrazine hydrochloride was dissolved in the minimum required amount of water. The pH was adjusted to 8 by addition of 10% sodium hydroxide solution. The desired product N-(3-dimethylamino-2-cyano-2-propene-1-ylidene)-N', N'-dimethylhydrazine precipitated and was filtered off (m.p. 130°-134°).
EXAMPLE 9
Preparation of N-(3-dimethylamino-2-cyano-2-propen-1-ylidene)-N', N', N'-trimethylhydrazinium methyl sulfate
3.3 g. of N-(3-dimethylamino-2-cyano-2-propen-1-ylidene)-N', N'-dimethylhydrazine were dissolved in 20 ml. of absolute ethanol. The solution was heated on a steambath, and 1.9 ml. of dimethyl sulfate was added. The resulting mixture was allowed to cool to room temperature and was then refrigerated. The product N-(3-dimethylamino-2-cyano-2-propen-1-ylidene)N',N', N'-trimethylhydrazinium methyl sulfate was collected by filtration (m.p. 147°-149°).
EXAMPLE 10
Preparation of dimethylaminomethylenemalononitrile
To a solution of 2.92 g. of N-(3-dimethylamino-2-cyano-2-propen-1-ylidene)N', N', N'-trimethylhydrazinium methyl sulfate in 20 ml. of methanol was added in small portions at room temperature 540 mg. of sodium methoxide. The resulting mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated under reduced pressure. The residue was dissolved in hot water. On cooling dimethylaminomethylenemalononitrile crystallized out and was collected by filtration (m.p. 81°-83°).
EXAMPLE 11
Preparation of dimethylaminomethylenemalononitrile
To a slurry of 12.4 g. of 2-cyano-3-dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamine-O-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0° and adjusted to pH 6.0 by addition of approximately 26 ml. of 5N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at 70°. A pH 3 was maintained over this period by dropwise addition of 5N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3 × 100 ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 93°-95°.
EXAMPLE 12
Preparation of dimethylaminomethylenemalononitrile from 3-dimethylaminoacrylonitrile
Into a 250 ml. 3-neck-round-bottom flask are placed 7.3 g. (0.1m.) of dimethylformamide and 150 ml. of dichloromethane. The stirred solution is cooled in ice/water and phosgene is bubbled through for 30 minutes. A white solid forms. The solvent is removed under reduced pressure. The remaining solid is suspended in 120 ml. of dichloromethane. The stirred suspension is cooled in an ice/salt bath to -10°. A solution of 9.6 g. (0.1m) of 3-dimethylaminoacrylonitrile in 40 ml. of dichloromethane is added dropwise, maintaining the temperature below 0°. After completed addition a clear yellow solution results. The solution is evaporated to dryness under reduced pressure. The remaining yellow solid is dissolved in 20 ml. of water. The aqueous solution is cooled to 0° and adjusted to pH 8 with 5N sodium hydroxide (˜15 ml). The alkaline solution is allowed to stand at room temperature for 90 minutes. A crystalline solid precipitates. The slurry is diluted with 20 ml. of water, and, while stirring 12.5 g. (0.1m) of hydroxylamino-0-sulfonic acid (91-93% pure) is added as a solid. A clear solution results. After 10 minutes stirring at room temperature, the solution is cooled in ice/water and the pH is adjusted to 7 with 5N sodium hydroxide (˜26 ml.). The neutral solution is heated briefly to 75° (˜3-4 min.). On cooling the main fraction of dimethylaminomethylenemalononitrile precipitates in crystalline form. The aqueous mother liquor is readjusted to pH 7 and extracted with 3 × 100 ml. of dichloromethane. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 50 ml. of isopropanol. The resulting solution is treated with activated charcoal and filtered hot. On concentration of the solution an additional crop of dimethylaminomethylenemalononitrile is obtained.
EXAMPLE 14
Preparation of Aminomethylenemalononitrile
Into a flask, cooled in a dry ice/acetone bath was placed 200 mg. of dimethylaminomethylenemalononitrile. 30 ml. of ammonia was condensed into the flask. The resulting solution was allowed to come slowly to room temperature and to evaporate over a period of ca. 10 hours. The dry residue was recyrstallized from water. Thus, aminomethylenemalononitrile (m.p. 139°-144°) was obtained. | A process for preparing dialkyl amino acrylonitrile by condensing acetonitrile and an acetal of dimethyl formamide. The dialkyl amino acrylonitrile is an intermediate for aminomethylene malononitrile, a valuable intermediate for thiamine. | 2 |
FIELD OF THE INVENTION
[0001] The invention relates to skate boots, in particular to skate boots featuring an exterior toe protector, and to a method of manufacturing skate boots.
BACKGROUND OF THE INVENTION
[0002] Toe protectors are not new to the field of sports equipment and hockey in particular. Hockey skates are provided with a shell-like reinforcement in the toe region of the skate to prevent injuries. Canadian patent No. 839,484 discloses a skate boot construction including a toe cap. A molded convex dome-like shell is placed over the last and stapled to the insole of the boot; an upper toe covering flexible material is then placed over the last and over the toe cap and secured to the insole of the boot. This is the typical method of manufacturing a skate boot having a protective toe cap.
[0003] Most skate boots are normally manufactured in the following manner: A toe-cap is positioned on the last of the skate boot. A last is a three-dimensional shape of the inside cavity of the boot or shoe. A pre-assembled boot consisting of various pieces of fabric and/or leather is placed over the last and over the toe-cap. An insole is then placed on the bottom part of the last. The pre-assembled boot is stretched over the last and over the toe cap in order for the preassembled boot to conform to the specific shape of the last. The toe cap is therefore located inside the boot. The stretched material is then nailed or tacked and glued to the insole to maintain the desired shape. Once the upper part of the skate boot is completed, a rigid outsole is glued to the insole of the boot to complete the skate boot. An ice blade holder or an in-line roller chassis is then mounted to the rigid outsole to complete the skate.
[0004] More recently, skate boots have been made with the toe cap outside the skate boot. This method has the advantage of eliminating all material covering the toe cap of the skate boot. However, the stretching part of the manufacturing process had to be modified. The pre-assembled boot no longer required a toe cap covering material since it was no longer necessary to stretch this material over the toe cap. A tongue was sewn to the toe cap. The protective toe cap and tongue assembly was inserted between the sides of the pre-assembled boot and sewn to each side of the boot. The stretching over the last was done only along the sides and at the rear of the pre-assembled boot where material was then glued and nailed or tacked to the insole. Finally, an outsole was nailed and glued to the bottom of the skate boot covering the bottom of the toe cap previously installed.
[0005] The above described method of manufacturing a skate boot using an exterior toe cap produced an inferior formfitting skate boot in the frontal area of the foot. Skaters using skate boots having an exterior toe cap often complained about poor frontal fitting of this type of skate boot. The frontal area of the skate boot was not being stretched properly and the result was a somewhat awkward fitting skate, which was either too tight or too loose.
[0006] Thus, there is a need in the industry for a skate boot featuring an outside toe protector which has equal formfitting qualities as a traditionally made skate boot.
OBJECTS AND STATEMENT OF THE INVENTION
[0007] It is thus an object of the invention to provide a skate boot having an outside toe protector that has equal formfitting qualities as a traditionally made skate boot.
[0008] It is another object of the invention to provide a skate boot construction adapted to increase the frontal formfitting of a skate boot.
[0009] It is a further object of the invention to provide a method of making a skate boot having an outside toe protector which has a good frontal form fit.
[0010] As embodied and broadly described herein, the invention provides a skate boot comprising an upper for supporting and enclosing a skater's foot. The upper has a heel counter, an ankle support, a medial quarter and a lateral quarter, each quarter having a frontal edge; the medial and lateral quarters extending forwardly from the heel counter and the ankle support. An insole forms the bottom of the upper and a toe cover defining a toe box for covering the toe area of the skater's foot, is connected to the frontal edges and to the insole. A tongue is connected to the toe cover for cushioning and covering the upper frontal part of the skater's foot and ankle. The skate boot also comprises a preformed toe protector overlying the toe cover and secured to the upper. The toe protector has a convex upper portion covering the front, the top and the sides of the toe cover. The toe protector also has an anchoring portion for securing the toe protector to the upper.
[0011] Preferably, the toe protector further comprises a tab extending inwardly from each lateral extensions for fastening the toe protector to the insole of the upper. Also, the toe protector comprises cut-out areas adapted to surround the frontal edges of the medial and lateral quarters to allow some degree of motion to these quarters.
[0012] Advantageously, the toe cover comprises at least two superposed layers: a first layer of smooth material facing the inside of the skate boot and a second layer of a textile material over the first layer and adapted to resist tension.
[0013] As embodied and broadly described herein, the invention also provides a method of making a skate boot comprising the steps of:
[0014] a) stretching over a last an upper having a toe cover, a heel counter, an ankle support, an insole, a medial quarter and a lateral quarter;
[0015] b) folding the edges of said upper underneath said insole on said last and fastening said edges to said;
[0016] c) affixing a preformed toe protector over said toe cover, said toe protector having a convex upper portion covering the front, the top and the sides of said toe cover and an anchoring portion for securing said toe protector to said insole;
[0017] d)simultaneously urging both sides said toe protector toward said medial and lateral quarters and fastening said anchoring portion of said toe protector to said insole.
[0018] Other objects and features of the invention will become apparent by reference to the following description and the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] A detailed description of the preferred embodiments of the present invention is provided herein below, by way of example only, with reference to the accompanying drawings, in which:
[0020] [0020]FIG. 1 is a perspective view of the first step of a method of making a skate boot according to the invention;
[0021] [0021]FIG. 2 is a front elevational view of the second step of a method of making a skate boot according to the invention;
[0022] [0022]FIG. 3 is a rear elevational of the second step of a method of making a skate boot according to the invention;
[0023] [0023]FIG. 4 is a bottom plan view of the third step of a method of making a skate boot according to the invention;
[0024] [0024]FIG. 5 is a perspective view of the fourth step of a method of making a skate boot according to the invention;
[0025] [0025]FIG. 6 is an inside perspective view of a toe protector according to the invention;
[0026] [0026]FIG. 7 is a bottom plan view of the fourth step of a method of making a skate boot according to the invention;
[0027] [0027]FIG. 8 is a bottom plan view of the fifth step of a method of making a skate boot according to the invention;
[0028] [0028]FIG. 9 is a top plan of view of a skate boot after the fifth step is completed according to the invention;
[0029] [0029]FIG. 10 is a perspective view of the sixth and final step of a method of making a skate boot according to the invention; and
[0030] [0030]FIG. 11 is perspective view of the completed skate boot made according to the invention.
[0031] [0031]FIG. 12 is a perspective view of the completed ice skate made according to the invention.
[0032] [0032]FIG. 13 is a perspective view of the completed in-line roller skate made according to the invention.
[0033] In the drawings, preferred embodiments of the invention are illustrated by way of examples. It is to be expressly understood that the description and drawings are only for the purpose of illustration and are an aid for understanding. They are not intended to be a definition of the limits of the invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0034] [0034]FIG. 1 illustrates a pre-assembled upper 20 for making a skate boot. Preassembled upper 20 basically comprises a heel counter 61 , an ankle support 62 , a medial quarter 63 and a lateral quarter 64 . Each quarter 63 and 64 has a frontal edge 28 and 29 and extends from the heel counter 61 and the ankle support 62 to the front of the upper 20 . At the front, a toe cover 26 made of a soft textile material covers the toe area of the skater's foot and is sewn on each side to frontal edges 28 and 29 . A tongue 31 , for cushioning and covering the upper frontal part of the skater's foot and ankle, is also sewn to the upper edge of toe cover 26 in a manner enabling tongue 31 to be flipped up and down to open the skate boot and allow the skater to easily insert his or her foot into upper 20 .
[0035] Pre-assembled upper 20 is made of various pieces of leather, fabric or textile sewn and glued together prior to being formed as pre-assembled upper 20 . FIG. 1 illustrates the first step of the making of a skate boot once preassembled upper 20 is completed. A Last 25 is inserted into pre-assembled upper 20 and an insole 36 is positioned over the lower end of last 25 once last 25 is inside pre-assembled upper 20 . Medial and lateral quarters 63 and 64 have a sufficient marginal edge 33 that exceeds all around last 25 to provide a gripping and pulling means to stretch upper 20 over last 25 . Similarly, toe cover 26 has a marginal edge 34 that exceeds the front portion of last 25 to provide the necessary gripping and pulling means to stretch toe cover 26 over the front portion of last 25 . Marginal edges 33 and 34 provide the necessary hold for preassembled upper 20 to be stretched over a last 25 .
[0036] [0036]FIG. 2 and 3 illustrate the second step of making of a skate boot and shows last 25 inside upper 20 and insole 36 in position. Glue is first applied along the sides of insole 36 . Marginal edges 33 and 34 of pre-assembled upper 20 are then pulled and stretched tightly over last 25 and folded underneath insole 36 as depicted by the arrows A. Once folded, marginal edges 33 and 34 adhesively bond to insole 36 with the glue that was previously laid on insole 36 . Note that toe cover 26 is made of a material strong enough to resist the traction force of the stretching. Toe cover is preferably constructed of three layers of material: A first layer of smooth textile material on the inside of the boot which will be in contact with the skater's foot, a second layer consisting of a thin plastic sheet adapted to retain the shape given by the last 25 , and a third layer of a nylon textile which can resist the traction force during the lasting process. The addition of toe cover 26 to the construction of a skate boot having a external toe protector enables the entire pre-assembled upper 20 to be properly stretched over last 25 which will provide a good fitting of the final product. The pulling and stretching may be accomplished by hand using traditional shoe maker tools or can be automated to provide an even tension of the material over last 25 which results in a better quality skate boot.
[0037] As shown in FIG. 4, while being stretched and pulled, marginal edges 33 and 34 are further nailed or tacked all around insole 36 with nails or tacks 38 . Nails 38 provide the necessary mechanical grip to remove the pulling forces and allow the glue to properly set between marginal edges 33 and 34 and insole 36 . Once marginal edges 33 and 34 are fully stretched and firmly attached to insole 36 , a light sanding of the marginal edges 33 and 34 is performed to partially even the lower surface of upper 20 and provide a flat surface on which an outsole can later be glued and nailed.
[0038] [0038]FIG. 5 shows upper 20 in its final form. Toe cover 26 is stretched around insole 36 and shaped to define a toe box covering the toe area of the foot. Both lateral and medial quarters 63 and 64 are also stretched around insole 36 and shaped to support each side of the foot. A toe protector 40 is then positioned over toe cover 26 as represented by arrow 50 . Prior to positioning toe protector 40 , a layer of glue may be applied to toe cover 26 to ensure that cover 26 adheres to the interior wall of toe protector 40 . However toe cover 26 may also not be glued to the interior surface of toe protector 40 and remain loose inside the skate boot. As shown in FIG. 5 and 6 , toe protector 40 is a convex structure made of a highly resistant plastic such as nylon or polyurethane which are both rigid and light. Toe protector 40 features a generally planar lower insole contacting portion 42 or anchoring portion conforming to the frontal lower surface of upper 20 and flanked by a pair of tabs 44 extending from lower portion 42 . Lower portion 42 preferably extends over the entire frontal area of insole 36 but may also only extend along the edge of insole 36 leaving the center portion uncovered. In this manner, toe protector 40 is more flexible and can adapt to various widths.
[0039] The upper portion 45 that will cover the toe area of pre-assembled upper 20 features an upper extension 46 and two lateral extensions 48 . Each lateral extension 48 preferably includes a tab 44 adjacent lower portion 42 of toe protector 40 . Cutout areas 43 are provided in between lateral extensions 48 and upper extension 46 to enable toe protector 40 to surround edges 28 and 29 . Toe protector 40 is of course hollow to fit over toe cover 26 of pre-assembled upper 20 .
[0040] [0040]FIG. 7 illustrates the same sequence as FIG. 5 but viewed from underneath. A layer of glue is also applied to marginal edge 34 . Toe protector 40 is slipped over the toe area of pre-assembled upper 20 and more specifically over toe cover 26 and the frontal part of insole 36 . Toe protector 40 is bonded to marginal edge 34 underneath pre-assembled upper 20 and is sometime glued to toe cover 26 . As shown In FIG. 8, once toe protector 40 has been positioned over toe cover 26 , mechanical pressure, depicted by arrows 51 , is applied on both sides of toe protector 40 to each lateral extension 48 . While the mechanical pressure 51 is applied, tabs 44 are tacked onto insole 26 through marginal edge 33 . This step results in lateral extensions 48 being tightly pressed against the exterior of each frontal edge 28 and 29 of pre-assembled upper 20 .
[0041] As shown in FIG. 9 and 10 , toe protector 40 is installed onto pre-assembled upper 20 in such a way that lateral extensions 48 overlap each frontal edge 28 and 29 . Since the entire pre-assembled upper 20 has been stretched to provide a proper form fit, toe protector 40 cannot be inserted between toe cover 26 and edges 28 and 29 . Cutout areas 43 of toe protector 40 are provided to surround frontal edges 28 and 29 and allow some degree of lateral motion to medial and lateral quarters 63 and 64 .
[0042] Finally, as shown in FIG. 10, an outsole 30 is nailed and glued to the bottom of pre-assembled upper 20 in order to complete the skate boot. It must be noted that the use of outsole 30 is optional since an ice blade holder or an in-line roller chassis having an integrated rigid platform conforming to the lower surface of upper 20 may be affixed to pre-assembled upper 20 rendering the outsole redundant. Outsole 30 is used when the blade holder or the in-line roller chassis requires a rigid platform for fastening.
[0043] [0043]FIG. 11 illustrates a finished skate boot 21 . The only step left to complete the skate is to mount an ice blade assembly or an in-line roller chassis assembly to outsole 30 by fastening it to the outsole 30 as shown in FIG. 12 and 13 . It should be noted that toe cover 26 further provides a more comfortable toe area for the skater. A normal skate boot does not have a textile cover in the toe region of the boot so the toes of the skater are directly in contact with the plastic toe cap.
[0044] The above description of preferred embodiments should not be interpreted in a limiting manner since other variations, modifications and refinements are possible within the spirit and scope of the present invention. The scope of the invention is defined in the appended claims and their equivalents. | A skate boot featuring an exterior toe protector and a method of manufacture. The skate boot is provided with a toe cover adapted to be pulled and stretched over a last allowing the skate boot to be formed in a similar fashion as a skate boot featuring an interior toe protector. The toe protector has a pair of lateral extensions which overlap the frontal edges of the lateral supporting portions of the skate boot and a pair of cutout areas to surround the same lateral supporting portions of the skate boot. | 0 |
RELATED APPLICATIONS
This application, pursuant to 37 C.F.R. § 1.78(c), claims priority based on provisional application serial No. 60/284,551 filed Apr. 18, 2001 and provisional application serial No. 60/350,199 filed Jan. 18, 2002.
FIELD OF THE INVENTION
The invention relates to improved tungsten-carbide dies made by metal injection molding (“MIM”).
BACKGROUND OF THE INVENTION
Tungsten-carbide dies are currently made from cylindrical blanks produced by the press and sinter method known as Powder Metallurgy or “PM.” Cobalt, in various volume percentages, is blended with tungsten-carbide. A mixture of various powders are used in the process. Our process allows us to make our dies with lower percentages of cobalt (which is an advantage in itself because cobalt is expensive). This results in increased hardness and abrasion resistance when compared to dies with higher cobalt content. It is also possible to add other metals and alloys to our feedstock to give the resulting metal improved characteristics and performance.
Powder Metallurgy (“PM”) uses oblong or shard-shaped powders for various reasons. To begin with, they are typically less expensive than spherical powders. More importantly, spherical powders do not work well (if at all) in PM. When the tungsten-carbide and cobalt powders are pressed into the cylindrical die, they are compressed, which gives the part its stability during the sintering process. The shard particles of various sizes, “interlock” to a certain extent. Pressing spherical powders in a PM process does not provide that interlocking.
Further, the use of spherical powders would substantially exacerbate the deformation that occurs during the sintering of PM parts. The deformation is caused primarily when the cobalt particles melt and fall through the spaces between the tungsten-carbide particles. Such deformation is already a significant problem in producing tungsten-carbide dies by PM.
In the PM process, a selected powder is pressed into a die or mold at high pressures. The pressed part is then sintered at high temperature to fuse the powders into “solid” metal. The part is not really solid, however. It has porosity, which is measured as its density (expressed as a percentage of the theoretical 100% density of wrought metal).
It is well known in the PM field that, in general, increasing the density of a sintered powdered metal item (i.e. reducing its porosity) will significantly improve its strength and durability. At high levels of porosity (i.e. low density), the metal is brittle and of low fatigue strength. Accordingly, considerable effort is expended (and significant cost incurred) in trying to increase the density of the PM blanks, which typically have a density of approximately 85% after sintering. Some of the methods include hot forging, double pressing, double sintering, hot isostatic pressing (“HIPing”) and pressure assisted sintering (“PASing”). While higher densities (typically, 88% to 92%) are achievable by these methods, it is often at the cost of dimensional precision. And, there is the additional cost of those secondary processes. The blanks need further machining in order to make them into blanks ready for their inside diameter (“I.D.”) profiles. Typically, the outside diameters (“O.D.”) need to be brought within specifications (the ends need to be squared off and the outside surface ground down) and then the pilot hole running down the center of the blank needs to be made to a specific diameter and concentric to the O.D. The result is referred to as a “semi-finished” blank, which is ready to be made into a finished die.
Making the finished die involves cutting the I.D. profile into the blank. This is done by various means such as drilling, reaming, grinding, EDMing, etc. Tungsten carbide is very hard, so it is difficult (time-consuming and/or costly) to cut in the I.D. profile. The difficulty increases with the complexity of the I.D. profile, the tolerances that must be met and the hardness of the tungsten-carbide blank. Frequently, blanks with lower hardness and/or density are selected in order to overcome or reduce these difficulties.
The present invention provides improved tungsten-carbide dies, with improved physical properties, improved chemical properties and enhanced performance, and an improved method of manufacturing those dies. This invention relates to both the blanks and the finished dies as well as other fastener industry tools.
SUMMARY OF THE INVENTION
The present invention produces improved tungsten-carbide blanks and finished dies using MIM. MIM is an established manufacturing process. Heretofore, fine powdered metals (typically spherically-shaped) are mixed with various binders to form a feedstock. This feedstock is then heated and molded under pressure in an injection molding machine to produce a “green” part or preform. After molding, the binders are removed from the green part in a process called “debinding,” producing a “brown” part or preform. The debound part is then sintered, which fuses the powdered metal particles into a densified matrix. While there is porosity in an MIM part, substantially higher densities are achievable by MIM than by PM. However, we have found that significantly improved results are obtained by using polygonal-shaped powder instead of spherical, oblong, or shard-shaped particles, as defined in Powder Metallurgy Science by Randall M. German, 1994, Chapter 2 and pages 29 and 30, which are herein incorporated by reference.
The green part shrinks substantially during debinding and sintering (typically between 11% and 30%, depending upon the formula of the feedstock and the debinding and sintering parameters). The shrinkage amount, however, is predictable in all dimensions and, once the optimum feedstock formula and parameters are determined, the process is highly consistent and repeatable. The amount of shrinkage that occurs (which is expressed as a percentage equal to one minus the ratio of the size of the finished part to the size of the green part) is referred to as the “shrink factor” and the amount by which the green part must be “over-sized” in order to produce a sintered part of specified dimensions (which is expressed as a percentage that is approximately equal to the ratio of the size of the finished part to the size of the green part) is referred to as the “form factor.”
Once an appropriate tungsten-carbide feedstock is developed, and its shrink factors and form factors are determined, a mold is fabricated. The mold will produce a blank or finished die with a specified O.D. and length. A pin or pins is then fabricated to be suspended in the mold cavity, which will form the pilot hole (for a blank) or the I.D. profile (for a finished die). Both the mold cavity and the pin(s) are over-sized to take into account the shrinkage that will occur during debinding and sintering. The feedstock is then molded around the pin(s). When the pin or pins are removed, the pilot hole or I.D. profile has been formed in the green part, and when that green part has been debound and sintered, the blank or finished die has been produced with near net shape.
Producing tungsten-carbide dies by this method offers many advantages. Eliminating most if not all of the secondary operations to produce the blanks and the finished dies saves time and expense. In addition, the dies themselves have improved characteristics. The metal powders used to make tungsten-carbide MIM feedstocks are in the present invention polygonal powders. This produces substantially higher densities in the metal (in excess of 99%, compared to 85% by PM) without the need for secondary processes. The polygonal powders also produce an improved microstructure of the metal, with more uniform bonding. This results in increased transverse rupture strength, which is a widely-accepted method used to determine load-bearing properties. The polygonal powders also make it easier to cut in the I.D. profiles into the blanks than the shard-shaped powders used in PM. This allows the use of harder grades of tungsten-carbide to make the same die. All of these improvements result in enhanced performance and/or utility of the die. One additional benefit of these dies is that, when the die wears so that it is no longer within required tolerances, it can easily be reamed to a larger I.D. and re-used.
DESCRIPTION OF THE INVENTION
An improved tungsten-carbide die, including finished dies and blanks for dies, can be made according to the present invention using polygonal-shaped tungsten-carbide particles with metal injection molding (“MIM”) and has many advantages over the prior art. The MIM process is a known fabrication process as taught in, for example U.S. Pat. No. 4,113,480, the disclosure of which is incorporated herein by reference. The die has a cylindrical shape (although it can also be of other shapes) and is flat on both ends. The die has a hole down its middle, extending from one of the flat ends to the other (although the hole can also extend through only a portion of the length of the die). It also could have no hole, in which case it is a blank for a die. The hole is round (a die with a round hole of uniform diameter all the way through its length is referred to a “straight hole” die). The hole can be of any diameter and can also of more than one diameter (e.g. for an extrusion die). Straight hole dies are used as is, or are used as a starting point to make dies with different internal diameter (“I.D.”) profiles by various secondary operations. The dies of the present invention can also have an I.D. profile that is other than round.
The hole in the die can be formed by drilling the green part, but it is preferably formed by suspending a pin or pins in the cavity of the mold, and molding the MIM feedstock around the pin(s). The hole in the die is formed by removing the pin(s) from the molded part prior to the debinding and sintering operations (although the pin(s) can also be removed after debinding and prior to sintering). The outside diameter (“O.D.”) profile of the pin(s) is round for a straight hole die. In order to produce a die with an I.D. profile that is other than round, the pin(s) are made with the corresponding non-round O.D. profile.
The MIM feedstock contains, in addition to the binders that serve to carry the metal powders into the mold, 85% by weight tungsten-carbide (WC) and 15% by weight cobalt (although the percentages of each can vary widely and metallic binders other than cobalt (e.g. nickel) can be used, as well). In addition, other alloying metals or compounds can be added to the feedstock as additives (e.g. tantalum, tantalum-carbide, titanium-carbide, niobium-carbide, chromium-carbide, cobalt-nickel, nickel-tantalum, titanium-nitride, and diamond dust), which produce different chemical and physical properties in the resulting cemented carbide. In general, the additive (or mixtures thereof) may be present in an amount in the range of from about 0% to about 7% by weight of the sintered article, with about 1% to about 5% being preferred.
By way of example, a die with finished dimensions of 0.625″×0.625″ was made using a binder system having just over 50% by weight wax in the binder system offered by the AQUAMIM Division of Planet Polymer Technologies Ltd. of San Diego, Calif. which may be described in Planet Polymer's two patents. No. 5,977,230, issued Nov. 2, 1999, and No. 6,008,281, issued Dec. 28, 1999). Water debinding was unsuccessful with the tungsten-carbide feedstock used for an 85% WC-15% Co feedstock as the parts developed bubbles and blisters in the debinding process.
After considerable effort, we determined that the binders could be removed by dissolving in a hydrocarbon solvent, preferably mineral spirits. We subsequently determined that the mineral spirits should be maintained at a temperature of 80°-120° F. for best results. We have also found that n-propyl bromide is not only an acceptable solvent, but is presently preferred. In general, any liquid linear hydrocarbon such as an alkane solvent may be used, including hexane, heptane, octane or various mixtures of the alkanes. Depending on the thickness of the part, a sufficient amount of the primary binder such as a wax (minimum 70%, and preferably 80% or more) is removed during the rebinding process. The balance of the binders, such as a high molecular weight polyolefin of more than 5,000 gram molecular weight, which give the part its support prior to and during the sintering process, are removed during sintering.
The shrink factor of a particular feedstock and its corresponding form factor are determined by measuring the sintered part and comparing those measurements to those of the green part. It will vary with each feedstock formulation. We provide our toolmaker with the dimensions of the finished part and the form factor for the feedstock that we intend to use. Any toolmaker with reasonable knowledge and skills in the art of making molds could design and fabricate a mold that will produce a green part of the required size. The means to suspend a pin in the mold cavity, and the fabrication of that pin, are also within the toolmaker's purview. One important part of our invention, however, is the concept of using such a suspended pin (or multiple pins) to form the I.D. profile. Not only does this eliminate the secondary operations to cut in the I.D. profile, but it allows the mold that produces a die blank with certain O.D. dimensions to be used to produce an unlimited number of dies (both finished and semi-finished) with different I.D. profiles.
The tungsten-carbide feedstock with polygonal-shaped particles is molded in a conventional injection molding machine. The only modification is that the barrel and screw of the molding machine is made of harder metal than those used in molding plastics. In the barrel, which is heated, the feedstock softens to a toothpaste-like consistency. The optimum temperature of the feedstock will depend upon the formulation of the binders. In the present case, we maintain the barrel temperature within a range from 350° to 400° F. The polygonal-shaped particle feedstock is injected into the mold cavity, and a packing pressure is applied by the molding machine while the feedstock cools and the binders “set up”. Sufficiently high molding and packing pressures should be applied in order to achieve the greatest density in the green part, such as for instance 2000-2400 psi. The amount of the holding time depends upon the feedstock formulation, the molding temperature and the size of the part. In the present case, our hold time is 60 seconds. A person of ordinary skill in the operation of an injection molding machine can arrive at the appropriate combination of molding parameters (temperature, shot size, injection speed, injection pressure, packing pressure, hold time, etc.) to produce good molded “green” parts, which is also a function of the molding machine itself.
After the molded part has cooled, we remove as much of the vestiges of the gate and runner system with a saw (in a production mold, most of that vestige will be removed by the mold itself). After a sufficient number of parts have been molded and de-gated, the debinding process is commenced. The green parts are placed in the debinding tank. After the requisite amount of primary binders (as determined by the binder supplier) have been removed producing the brown preform or part (we determine that by drying and weighing the parts from time to time), the parts are placed in a high temperature sintering furnace. An appropriate sintering profile is developed, depending on the size of the part, the quantity and nature of the secondary binders and the characteristics of the metal powders all as is well known in the powder metallurgy art. Typically, the temperature is initially increased gradually so that the secondary binders can melt and/or evaporate without deforming the part. The temperature is then ramped up more rapidly to a higher temperature level, held at that level for a certain period of time, and then ramped up to a higher level, held again, etc., until the part reaches the optimum sintering temperature. The temperature is held at that level for a certain period of time. During that process, the metal powders fuse together forming a coherent, densified matrix. The temperature in the furnace is then brought down, typically in stages, as in the ramp-up phase. The temperatures, ramp rates and hold times of a complete sintering cycle are referred to as the sintering profile. A person of ordinary skill in the art of sintering tungsten-carbide can devise an appropriate profile, which is also a function of the furnace itself. Table 1 is a current profile used to sinter the 0.625″×0.625 die with the current formulation of our feedstock.
TABLE 1
Segment # (1 to 100)
1
2
3
4
5
6
7
8
9
10
Segment Type (ramp/soak)
ramp
soak
ramp
soak
ramp
soak
ramp
ramp
soak
soak
Target Setpoint (0-1650)
275
275
475
475
1050
1050
1350
1370
1370
75
Ramp in Deg C./Min (Soak in Min)
3
60
3
90
3
60
5
2
60
5
Guaranteed Flag (Y/N)
n
n
n
n
n
n
n
n
n
y
Positive Deviation (0-1650)
0
0
0
0
0
0
0
0
0
0
Negative Deviation (0-1650)
0
0
0
0
0
0
0
0
0
75
PID #1 = Ramp, 2-Soak (1-2)
1
2
1
2
1
2
1
1
1
2
Debind Cycle (Y/N)
y
y
y
y
n
n
n
n
n
n
Heaters On (Y/N)
y
y
y
y
y
y
y
y
y
n
Sinter Cycle (Y/N)
n
n
n
n
y
y
y
y
y
n
Partial Pressure Setpoint (0-760)
300
300
300
300
300
300
300
300
300
700
H2 Hot Zone Setpoint* (0-35)
2
2
2
2
2
2
2
2
2
0
H2 Retort Setpoint* (0-35)
12
12
12
12
6
6
6
6
8
0
Process Gas* (Off. N2/Ar/Air/bub)
off
off
off
off
off
off
off
off
off
Ar
Proc. Gas Hot Zone Setpoint (0-35)
0
0
0
0
0
0
0
0
0
30
Proc. Gas Retort Setpoint (0-35)
0
0
0
0
0
0
0
0
0
30
High Vacuum Cycle (Y/N)
n
n
n
n
n
n
n
n
n
n
High Vacuum Hold (Y/N)
n
n
n
n
n
n
n
n
n
n
Cool Down Event (Y/N)
n
n
n
n
n
n
n
n
n
y
Cool Down Pressure (0-760)
0
0
0
0
0
0
0
0
0
760
Cool Down Temperature (0-1000)
0
0
0
0
0
0
0
0
0
1000
N2 Quench (Y/N)
n
n
n
n
n
n
n
n
n
n
Retort Shutters (Y/N)
n
n
n
n
n
n
n
n
n
y
Profile Name
Ryerwcl
Configured Date
1/26/01
Developer
BCS
*Warning: During an air or bubbler event DO NOT set the furnace temperature greater than 320° C.
After an Air or Bubbler or before a Hydrogen Event insert a segment to evacuate the chamber
The inventive process is very consistent and highly repeatable. While the following is typical but not as good as the best results achieved, our most recent dies (which are made of 85% by volume tungsten-carbide and 15% by volume cobalt) consistently exhibit the following characteristics, based upon tests by an independent testing laboratory [the numbers in the brackets are the corresponding figures for a PM sample, which turned out to be 84% WC-16% Co]:
1. Density (as a percentage of theoretical), based on ASTM B-276-91: 99.3%. We have densities as high as 99.7% [88%];
2. Microhardness: 86-87 Ra [85-86 Ra],
3. Transverse Rupture Strength (TRS), based on ASTM B-406-96: 275,000-325,000 psi [350,000-425,000 psi].
According to an independent testing service, the lower TRS for our dies is not necessarily a bad thing, especially for an impact application. The microstructure of the metal of our dies, because of the polygonal powders and higher densities, will likely make that metal tougher than the PM die, and more resistant to cracking. This latter condition also dictates the approximate atmosphere within the furnace chamber. Our dies have greater reamability than comparable PM dies. Our tungsten-carbide dies with 15 weight percent cobalt can be reamed with standard reaming tools used for tungsten-carbide die, but PM dies must have at least 20 weight percent cobalt to be reamed with standard tools.
In our process, we use polygonal metal powders. Typically, but not necessarily, that means a mean particle size of less than 15 μm, preferably 2 to 6 μm. However, submicron particles to particles having a mean particle size of 0.1 microns have been used. Mean particle diameters of up to about 30 microns have been used with the preferred range being between about 1.5 to about 5 microns. We vary the composition and the particle sizes of our feedstocks, depending on the application to which the die will be put. Some applications (such as header dies) produce better results with dies made from smaller particles. We also vary the distribution of particle sizes around the mean.
The dies made in accordance with the present invention have many applications, in many different industries. We have initially targeted applications in the fastener industry. In that industry, the inventive dies can be used in so-called “cold heading” machines, and would be referred to as “header dies”, but we can also use the inventive dies in so-called “hot heading”. Header dies are typically used in the fastener industry to form the body of a screw, nail, rivet or other fastener. There are many other “tools” used in the fastener industry that are currently made from tungsten-carbide, and still others that would be better if made from tungsten-carbide. These other types of tools include punches, upsets, hammers, fingers, transfer fingers, quills, cutters, trim dies, draw dies, saws, pinch point dies, forging dies and roll thread dies. Our dies can also be used in stamping applications. The method of our invention can be used to make all of these tools out of tungsten-carbide with or without an additive, as previously disclosed, using our injection molding process. As in the case of our dies, the metallurgical properties of the injection molded metals will result in improved tools.
We have varied the cobalt concentration from about 3 to about 35 percent by weight. At 6% by weight cobalt we have achieved greater than 99% of theoretical density without hipping. At 3% by volume cobalt, we have achieved abut 85% of theoretical density without hipping. Tools have been made using both 15% and 25% by weight cobalt as a percentage of the final article.
Moreover, we have made header dies (cylinders with a central aperture) with both inner and outer diameters with little shrinkage and superior densities.
While there has been disclosed what is considered to be the preferred embodiment of the present invention it is understood that various changes in the details may be made without departing from the spirit or sacrificing any of the advantages of the present invention. | A process of making an article of a tungsten-carbide-cobalt alloy with or without an additive of one or more of tantalum, cobalt-nickel, nickel-tantalum, tantalum-carbide, titanium-carbide, niobium-carbide, chromium-carbide, titanium-nitride and diamond dust. The method includes forming a homogeneous mixture of polygonal-shaped powder tungsten-carbide-cobalt and a polygonal-shaped powder additive and a binder including wax and a high molecular weight polyolefin polymer and injecting the mixture under heat and pressure into a metal injection mold to form a green preform of the article. The green preform is immersed in a linear hydrocarbon or a halogenated hydrocarbon or mixtures to dissolve and remove the wax and convert the green preform into a brown preform which is sintered to remove the remainder of the binder and to densify the brown preform into an article having a density not less than 98%. Various tungsten-carbide articles are disclosed. | 1 |
FIELD OF THE INVENTION
The present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
DESCRIPTION OF THE RELATED ART
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation.
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
The receptor-type tyrosine kinases (RTKs) comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. A more detailed discussion of receptor and non-receptor tyrosine kinases is provided in Cowan-Jacob Cell Mol. Life Sci., 2996, 63, 2608-2625.
There are a number of examples where RTK kinases, have been found to be involved in cellular signaling pathways leading to pathological conditions, including wet age-related macular degeneration (Ni et al. Opthalmologica 2009 223 401-410; Chappelow et al. Drugs 2008 68 1029-1036), diabetic retinopathy (Zhang et al Int. J. Biochem. Cell Biol. 2009 41 2368-2371), cancer (Aora et al. J. Path. Exp. Ther. 2006, 315, 971), psoriasis (Heidenreich et al Drug News Perspective 2008 21 97-105) and hyper immune response. In ophthalmic diseases such as neovascular age-related macular degeneration and diabetic retinopathy aberrant activation of VEGF receptors can lead to abnormal blood vessel growth. The importance of VEGFR signaling in the neovascular age-related macular degeneration disease process is evident by the clinical success of multiple anti-VEGF targeting agents including Lucentis®, Avastin®, and EYLEA™ (Barakat et al. Expert Opin. Investig. Drugs 2009, 18, 637). Recently it has been suggested that inhibition of multiple RTK signaling pathways may provide a greater therapeutic effect than targeting a single RTK signaling pathway. For example in neovascular ocular disorders such as neovascular age-related macular degeneration and diabetic retinopathy the inhibition of both VEGFR and PDGFRβ may provide a greater therapeutic effect in by causing regression of existing neovascular blood vessels present in the disease (Adamis et al. Am. J. Pathol. 2006 168 2036-2053). In cancer inhibition of multiple RTK signaling pathways has been suggested to have a greater effect than inhibiting a single RTK pathway (DePinho et al. Science 2007 318 287-290; Bergers et al. J. Clin Invest. 2003 111 1287-1295).
The identification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation is therefore desirable and one object of this invention.
Certain small compounds are disclosed in PCT publication No. WO/1999/062890, PCT publication No. WO/2005/082001 and PCT publication No. WO/2006/026034 as useful for the treatment of diseases related to unregulated TKS transduction.
SUMMARY OF THE INVENTION
The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction by blocking the VEGF and/or PDGF receptors. Such compounds are useful for the treatment of diseases related to unregulated PTKs transduction, including cell proliferative diseases such as cancer; vascular (blood vessel) proliferative disorders such as mesangial cell proliferative disorders and metabolic diseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma, melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetic mellitus, wound healing and inflammation and preferably ophthalmic diseases, i.e. diabetic retinopathy, retinopathy of prematurity, macular edema, retinal vein occlusion, exudative or neovascular age-related macular degeneration, high-risk eyes (i.e. fellow eyes have neovascular age-related macular degeneration) with dry age-related macular degeneration, neovascular disease associated with retinal vein occlusion, neovascular disease (including choroidal neovascularization) associated with the following: pathologic myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidal rupture, central serous retinopathy, cystoid macular edema, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, Central and branch retinal vein occlusions, inflammatory/infectious retinal, neovascularization/edema, comeal neovascularization, hyperemia related to an actively inflamed pterygia, recurrent pterygia following excisional surgery, post-excision, progressive pterygia approaching the visual axis, prophylactic therapy to prevent recurrent pterygia, of post-excision, progressive pterygia approaching the visual axis, chronic low grade hyperemia associated with pterygia, neovascular glaucoma, iris neovascularization, idiopathic etiologies, presumed ocular histoplasmosis syndrome, retinopathy of prematurity, chronic allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs host disease, etc.
In one aspect, the invention provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
wherein:
R 1 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , OC 3 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 )C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 8 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 9 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 10 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 11 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 12 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 13 is substituted or unsubstituted C 1-8 alkyl, hydrogen;
R 14 is substituted or unsubstituted C 1-8 alkyl, hydrogen; and
a is 0, 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)N)(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 )C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 )N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 8 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 9 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 10 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 11 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 12 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 13 is substituted or unsubstituted C 1-8 alkyl, hydrogen;
R 14 is substituted or unsubstituted C 1-8 alkyl, hydrogen; and
a is 0, 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 )N(R 13 R 14 ) 2 ;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 8 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 9 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 10 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 11 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 12 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 13 is substituted or unsubstituted C 1-8 alkyl, hydrogen;
R 14 is substituted or unsubstituted C 1-8 -alkyl, hydrogen; and
a is 0, 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O) N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 )OR 12 , OC 3-8 alkyl, (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, halogen, hydrogen, (CR 10 R 11 ) a C(O)OR 12 , (CR 10 R 11 ) a OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)R 12 , (CR 10 R 11 ) a C(O)N(R 13 R 14 ) 2 , (CR 10 R 11 ) a N(R 13 )C(O)OR 12 , (CR 10 R 11 ) a N(R 13 )C(O)N(R 13 R 14 ) 2 or (CR 10 R 11 ) a N(R 13 R 14 ) 2 ;
R 8 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 9 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 10 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 11 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 12 is substituted or unsubstituted C 1-8 alkyl or hydrogen;
R 13 is substituted or unsubstituted C 1-8 alkyl, hydrogen;
R 14 is substituted or unsubstituted C 1-8 alkyl, hydrogen; and
a is 0, 1, 2, 3 or 4.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle;
X is
R 2 is substituted or unsubstituted aryl;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen.
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted aryl;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen; R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen.
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle;
X is
R 2 is substituted or unsubstituted heterocyle;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle;
X is
R 2 is substituted or unsubstituted aryl;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted heterocycle;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen; and
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted aryl;
X is
R 2 is substituted or unsubstituted aryl;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 8 is hydrogen; and
R 9 is hydrogen.
In another aspect, the invention provides a compound represented by Formula I wherein:
R 1 is substituted or unsubstituted heterocycle;
X is
R 2 is substituted or unsubstituted heterocyle;
R 3 is hydrogen;
R 4 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 5 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 6 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen;
R 7 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, halogen.
R 8 is hydrogen; and
R 9 is hydrogen.
The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (—CH 2 —) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can have one or more chiral centers. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups, ester groups, ketone groups.
The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C 1-8 alkyl groups, sulfoxide C 1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, —OC 1-8 alkyl groups, —SC 1-8 alkyl groups, —C 1-8 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.
The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (—CH 2 —) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups, as defined above or by halogen atoms.
The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One methylene (—CH 2 —) group, of the alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S and N heteroatoms can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-8 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, alkylamino groups, amide groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom. Aryl can be substituted by halogen atoms, sulfonyl C 1-6 alkyl groups, sulfoxide C 1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C 1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, —OC 1-6 alkyl groups, —SC 1-6 alkyl groups, —C 1-6 alkyl groups, —C 2-6 alkenyl groups, —C 2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups. Aryls can be monocyclic or polycyclic.
The term “hydroxyl” as used herein, represents a group of formula “—OH”.
The term “carbonyl” as used herein, represents a group of formula “—C(O)—”.
The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —C(O)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “ester” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as —C(O)OR x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “amine” as used herein, represents a group of formula “—NR x R y ”, wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.
The term “sulfonyl” as used herein, represents a group of formula “—SO 2 − ”.
The term “sulfate” as used herein, represents a group of formula “—O—S(O) 2 —O—”.
The term “sulfonate” as used herein, represents a group of the formula “—S(O) 2 —O—”.
The term “carboxylic acid” as used herein, represents a group of formula “—C(O)OH”.
The term “nitro” as used herein, represents a group of formula “—NO 2 ”.
The term “cyano” as used herein, represents a group of formula “—CN”.
The term “amide” as used herein, represents a group of formula “—C(O)NR x R y ,” or “NR x R y C(O)—,” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “sulfonamide” as used herein, represents a group of formula “—S(O) 2 NR x R y ” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
The term “sulfoxide” as used herein, represents a group of formula “—S(O)—”.
The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”.
The term “phosphoric acid” as used herein, represents a group of formula “—OP(O)(OH) 2 ”.
The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”.
The formula “H”, as used herein, represents a hydrogen atom.
The formula “O”, as used herein, represents an oxygen atom.
The formula “N”, as used herein, represents a nitrogen atom.
The formula “S”, as used herein, represents a sulfur atom.
Other defined terms are used throughout this specification:
“DCM” refers to dichloromethane
“DMF” refers to dimethylformamide
“EDC” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
“PDGFRβ” refers to platelet derived growth factor receptor beta
“PTK” refers to protein tyrosine kinase
“RTK” refers to receptor tyrosine kinase
“THF” refers to tetrahydrofuran
“VEGF” refers to vascular endothelial growth factor
“VEGFR” refers to vascular endothelial growth factor receptor
Compounds of the invention are:
2-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide;
2-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indole-3-carboxamide;
2-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide;
2-[4-({[(3-ethylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide;
2-{4-[(3-methyl-2-furoyl)amino]phenyl}-1H-indole-3-carboxamide;
2-{4-[(2-fluoro-5-methylbenzoyl)amino]phenyl}-1H-indole-3-carboxamide;
2-[3-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide;
2-{3-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indole-3-carboxamide;
2-{3-[(3-methyl-2-furoyl)amino]phenyl}-1H-indole-3-carboxamide;
2-{3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}-1H-indole-3-carboxamide.
Compounds of formula I are useful as kinase inhibitors. As such, compounds of formula I will be useful for treatment of diseases related to unregulated tyrosine kinase signal transduction, for example, mesangial cell proliferative disorders and metabolic diseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma, melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabetic mellitus, wound healing and inflammation and preferably ophthalmic diseases, i.e. diabetic retinopathy, retinopathy of prematurity, macular edema, retinal vein occlusion, exudative or neovascular age-related macular degeneration, high-risk eyes (i.e. fellow eyes have neovascular age-related macular degeneration) with dry age-related macular degeneration, neovascular disease associated with retinal vein occlusion, neovascular disease (including choroidal neovascularization) associated with the following: pathologic myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidal rupture, central serous retinopathy, cystoid macular edema, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, rubeosis iridis, retinopathy of prematurity, Central and branch retinal vein occlusions, inflammatory/infectious retinal, neovascularization/edema, corneal neovascularization, hyperemia related to an actively inflamed pterygia, recurrent pterygia following excisional surgery, post-excision, progressive pterygia approaching the visual axis, prophylactic therapy to prevent recurrent pterygia, of post-excision, progressive pterygia approaching the visual axis, chronic low grade hyperemia associated with pterygia, neovascular glaucoma, iris neovascularization, idiopathic etiologies, presumed ocular histoplasmosis syndrome, retinopathy of prematurity, chronic allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs host disease, etc.
Some compounds of Formula I and some of their intermediates may have at least one asymmetric center in their structure. This asymmetric center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form.
The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).
The base addition salt form of a compound of Formula I that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).
Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Pharmaceutical compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
The ingredients are usually used in the following amounts:
Ingredient Amount (% w/v)
active ingredient about 0.001-5
preservative 0-0.10
vehicle 0-40
tonicity adjustor 0-10
buffer 0.01-10
pH adjustor q.s. pH 4.5-7.8
antioxidant as needed
surfactant as needed
purified water to make 100%
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of one or more of the above-described compounds and a pharmaceutically acceptable carrier or excipient, wherein said compositions are effective for treating the above diseases and conditions; especially ophthalmic diseases and conditions. Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
More particularly, the compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, rosacea, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as exudative age related macular degeneration and diabetic retinopathy.
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient. Such a composition is believed to modulate signal transduction by a protein kinase, tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
The present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered orally, subcutaneously, intravenously, intrathecally or some suitable combination(s) thereof.
In addition to the common dosage forms set out above, the compounds of this invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and 5,366,738.
For use where a composition for intravenous administration is employed, a suitable daily dosage range for anti-inflammatory, anti-atherosclerotic or anti-allergic use is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of this invention per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of this invention per kg of body weight per day. For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of this invention in an acceptable ophthalmic formulation may be used.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The magnitude of prophylactic or therapeutic dose of a compound of this invention will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. It will also vary according to the age, weight and response of the individual patient. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment to slow progression of an existing condition, and a prophylactically effective amount, e.g., for prevention of condition.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.001 mg to about 500 mg. In one embodiment, the quantity of active compound in a unit dose of preparation is from about 0.01 mg to about 250 mg. In another embodiment, the quantity of active compound in a unit dose of preparation is from about 0.1 mg to about 100 mg. In another embodiment, the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 100 mg. In another embodiment, the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 50 mg. In still another embodiment, the quantity of active compound in a unit dose of preparation is from about 1.0 mg to about 25 mg.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.01 mg/day to about 2000 mg/day of the compounds of the present invention. In one embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 1000 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 500 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 100 mg/day to 500 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 250 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 100 mg/day to 250 mg/day. In still another embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 100 mg/day. In still another embodiment, a daily dosage regimen for oral administration is from about 50 mg/day to 100 mg/day. In a further embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 50 mg/day. In another embodiment, a daily dosage regimen for oral administration is from about 25 mg/day to 50 mg/day. In a further embodiment, a daily dosage regimen for oral administration is from about 1 mg/day to 25 mg/day. The daily dosage may be administered in a single dosage or can be divided into from two to four divided doses.
In one aspect, the present invention provides a kit comprising a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluents, and directions for the use of said kit.
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claims.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects and responses to the extracellular microenvironment).
It has been shown that tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced by such proteins. More particularly, the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
The present invention concerns also processes for preparing the compounds of Formula I. The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. Synthetic Schemes set forth below, illustrate how the compounds according to the invention can be made.
At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. Details of certain specific chemical transformations are provided in the examples.
Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention only. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one kinase inhibitor as described herein.
In another aspect, the invention provides the use of at least one kinase inhibitor for the manufacture of a medicament for the treatment of a disease or a condition mediated by tyrosine kinases in a mammal.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of hydrogen 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
Compound names were generated with ACDLabs version 12.5. Some of the intermediate and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.
In general, characterization of the compounds is performed according to the following methods; NMR spectra are recorded on 300 or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
Usually the compounds of the invention were purified by medium pressure liquid chromatography, unless noted otherwise.
Synthetic Routes to Said Compounds are Illustrated Below
Intermediate 5
2-(4-aminophenyl)-1H-indole-3-carboxamide
To the stirring solution of indole-2-boronic acid pinacol ester (2 g, 7.8 mmol, 1 eq) in anhydrous dichloromethane (100 mL) at room temperature undemitrogen atmosphere was added dropwise chlorosulfonyl isocyanate (0.694 mL, 1 eq). After the reaction was continued at room temperature for one hour, it was subject to reduced pressure to remove the solvent dichloromethane. The resulting solid residue was dissolved in acetone-water (5:1, 60 mL) and to this stirring solution was added slowly aqueous sodium hydroxide (1 M) to adjust the pH to approximately 8. The solution was again subjected to evaporation under reduced pressure to remove acetone. The aqueous mixture was extract first with ethyl acetate then with EtOAc-THF (5:1) for the second time. The two organic layers were combined, dried with anhydrous sodium sulfate. The upper clear liquor was decanted, concentrated, and the resulting solid residue was triturated with EtOAc-Hex (1:1). Upon filtration, Intermediate 1 was obtained as slightly yellow solid in amount of 510 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.62 (s, 1H) 8.26 (d, J=8.22 Hz, 1H) 7.66 (br. s., 1H) 7.46 (d, J=8.22 Hz, 1H) 7.18 (ddd, J=8.07, 7.04, 1.03 Hz, 1H) 7.04-7.15 (m, 2H) 1.38 (s, 12H)
To the seal tube placed with Intermediate 1 (500 mg, 1.75 mmol, 1 eq) and tert-butyl-N-(4-iodophenyl)-carbamate (558 mg, 1 eq) under nitrogen atmosphere was added 1,2-dimethoxyethane (10 mL) and aqueous sodium carbonate (2 M, 2.62 mL, 3 eq) with stirring. Nitrogen was bubbled through the resulting mixture for 10 minutes followed by the addition of tetrakis(triphenylphosphine)palladium (0) (101 mg, 0.05 eq). The tube was sealed and the reaction mixture was stirred and heated at 99° C. for an hour. Next, the dark reaction mixture was cooled to room temperature and it was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer isolated was further washed with saturated aqueous sodium bicarbonate and brine, and dried with anhydrous sodium sulfate. The upper solution was decanted and concentrated down with silica gel. A chromatography (EtOAc-hex 1:4 to 2:1) was conducted and the solid which was obtained from the chromatography was further triturated with EtOAc-Hex (1:5). Intermediate 2 was isolated as a white solid in amount of 413 mg upon filtration.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.58 (s, 1H) 9.52 (s, 1H) 7.79 (d, J=7.92 Hz, 1H) 7.60-7.63 (m, 2H) 7.55 (d, J=8.80 Hz, 2H) 7.38 (d, J=7.92 Hz, 1H) 7.12-7.15 (m, 1H) 7.06-7.10 (m, 2H) 6.84 (br. s., 1H) 1.50 (s, 9H)
To the mixture of Intermediate 2 (400 mg, 1.14 mmol, 1 eq) in anhydrous dichloromethane (5 mL) under nitrogen atmosphere at 0° C. was added dropwise trifluoroacetic acid (1.76 mL, 20 eq) and the resulting yellow reaction solution was stirred at room temperature for two hours. The solution was then poured into a mixture of dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted once more with i-PrOH-DCM (1:5). All organic layers were combined, washed with brine, and dried with anhydrous sodium sulfate. The upper clear liquor was decanted, concentrated, and the resulting solid residue was treated with EtOAc-Hex (1:4). After the mixture was stirred at room temperature for 30 minutes, it was filtered through Buchner funnel was obtained as white powder in amount of 219 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.39 (s, 1H) 7.82 (d, J=7.63 Hz, 1H) 7.37-7.40 (m, 2H) 7.33 (d, J=7.92 Hz, 1H) 7.09 (td, J=7.56, 1.32 Hz, 1H) 7.02-7.06 (m, 1H) 6.97 (br. s., 1H) 6.64-6.66 (m, 2H) 6.55 (br. s., 1H) 5.42 (s, 2H)
Intermediate 4
2-(3-aminophenyl)-1H-indole-3-carboxamide
To the stirring solution of indole-2-boronic acid pinacol ester (4 g, 15.6 mmol, 1 eq) in anhydrous dichloromethane (100 mL) under nitrogen atmosphere at 0° C. was added dropwise chlorosulfonyl isocyanate (1.5 mL, 1.1 eq) and the brown reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to remove the solvent dichloromethane. To the resulting solid residue was added acetone-water (5:1, 120 mL) and the pH of this stirring solution was adjusted to about 7-8 by a slow addition of aqueous sodium hydroxide (1 M). After the solution was stirred over night at ambient temperature, it was evaporated under reduced pressure to remove the solvent acetone. The solid, which crashed out during this process, was filtered through a Buchner funnel and washed with water. The yellow solid obtained was further triturated in EtOAc-Hex (1:1) and upon a filtration, Intermediate 3 was obtained as an off-white solid in amount of 887 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.65 (br. s., 1H) 10.00 (s, 2H) 7.93 (d, J=7.92 Hz, 1H) 7.67 (br. s., 2H) 7.53 (d, J=8.22 Hz, 1H) 7.21 (t, J=7.34 Hz, 1H) 7.13-7.17 (m, 1H)
To the seal tube placed with Intermediate 3 (204 mg, 1.0 mmol, 1 eq) and 3-iodoaniline (0.123 mL, 1 eq) was added 1,2-dimethoxyethane (5 mL) and aqueous sodium carbonate (2 M, 2.0 mL, 4 eq) followed by a bubbling of anhydrous nitrogen for 10 minutes. Then was added tetrakis(triphenylphosphine)palladium (0) (57.8 mg, 0.05 eq). The tube was sealed and the reaction mixture was stirred and heated at 99° C. for two hours. After the reaction mixture was cooled to room temperature, it was partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer isolated was washed with saturated aqueous sodium bicarbonate and brine, followed by drying with anhydrous sodium sulfate. The upper solution was decanted and concentrated down with silica gel. A chromatography (DCM to MeOH-DCM 1:25) rendered Intermediate 4 in amount of 150 mg as a brown oil which became a foam in vacuo.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.58 (s, 1H) 7.89 (d, J=7.63 Hz, 1H) 7.36 (d, J=7.92 Hz, 1H) 7.11-7.16 (m, 2H) 7.06-7.10 (m, 1H) 7.00 (br. s., 1H) 6.86 (t, J=1.91 Hz, 1H) 6.80 (d, J=7.63 Hz, 1H) 6.63-6.66 (m, 1H) 6.50 (br. s., 1H) 5.27 (s, 2H)
Compound 1
2-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide
The reaction solution of Intermediate 5 (37.7 mg, 0.15 mmol, 1 eq) and m-tolyl isocyanate (0.02 mL, 1 eq) in anhydrous THF (1.5 mL) was stirred at room temperature for 2 hours. It was then subject to a partition between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (1:4). Compound 1 was obtained as white solid upon filtration in amount of 58 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.59 (s, 1H) 8.85 (s, 1H) 8.66 (s, 1H) 7.79 (d, J=7.92 Hz, 1H) 7.64-7.67 (m, 2H) 7.55-7.58 (m, 2H) 7.39 (d, J=7.92 Hz, 1H) 7.32 (s, 1H) 7.24 (d, J=8.22 Hz, 1H) 7.17 (t, J=7.78 Hz, 1H) 7.14 (ddd, J=8.00, 7.12, 1.03 Hz, 1H) 7.10 (br. s., 1H) 7.07-7.10 (m, 1H) 6.90 (br. s., 1H) 6.81 (d, J=7.63 Hz, 1H) 2.29 (s, 3H).
Compound 2
2-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 1.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.61 (s, 1H) 9.12 (s, 1H) 9.00 (s, 1H) 8.04 (s, 1H) 7.79 (d, J=7.92 Hz, 1H) 7.66-7.69 (m, 2H) 7.57-7.61 (m, 3H) 7.51-7.55 (m, 1H) 7.39 (d, J=7.92 Hz, 1H) 7.33 (d, J=7.63 Hz, 1H) 7.14 (ddd, J=7.92, 7.04, 0.88 Hz, 1H) 7.06-7.12 (m, 2H) 6.93 (br. s., 1H)
Compound 3
2-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 1.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.61 (s, 1H) 9.25 (s, 1H) 8.55 (d, J=2.64 Hz, 1H) 8.01 (dd, J=7.63, 1.76 Hz, 1H) 7.79 (d, J=7.92 Hz, 1H) 7.66-7.69 (m, 2H) 7.56-7.58 (m, 2H) 7.39 (d, J=7.92 Hz, 1H) 7.07-7.16 (m, 4H) 6.93 (br. s., 1H) 6.80-6.83 (m, 1H) 2.28 (s, 3H)
Compound 4
2-[4-({[(3-ethylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 1.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 11.62 (s, 1H) 8.87 (s, 1H) 8.71 (s, 1H) 7.78 (d, J=7.91 Hz, 1H) 7.62-7.68 (m, 2H) 7.54-7.60 (m, 2H) 7.32-7.42 (m, 2H) 7.04-7.29 (m, 5H) 6.96 (br. s., 1H) 6.84 (d, J=7.62 Hz, 1H) 2.58 (q, J=7.52 Hz, 2H) 1.18 (t, J=7.62 Hz, 3H)
Compound 5
2-{4-[(3-methyl-2-furoyl)amino]phenyl}-1H-indole-3-carboxamide
The mixture of Intermediate 5 (25.1 mg, 0.1 mmol, 1 eq), 3-methyl-furan-2-carboxylic acid (12.6 mg, 1 eq), EDC (23 mg, 1.2 eq), and DMAP (2.44 mg, 0.2 eq) in anhydrous dichloroethane (1 mL) under nitrogen atmosphere was stirred and heated at 60° C. for two hours. The reaction mixture was then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed sequentially with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. After the upper liquor was decanted and concentrated, the oily residue was treated with small amount of dichloromethane. The solid that appeared during the process was filtered. The yellow solid obtained was subject to a column chromatography (DCM to MeOH-DCM 1:25) to yield Compound 5 as a white solid in amount of 15 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.63 (s, 1H) 10.21 (s, 1H) 7.88-7.91 (m, 2H) 7.82 (d, J=1.76 Hz, 1H) 7.78 (d, J=7.92 Hz, 1H) 7.67-7.70 (m, 2H) 7.40 (d, J=8.22 Hz, 1H) 7.13-7.16 (m, 1H) 7.12 (br. s., 1H) 7.09 (ddd, J=7.92, 7.04, 0.88 Hz, 1H) 6.97 (br. s., 1H) 6.61 (d, J=1.47 Hz, 1H) 2.37 (s, 3H)
Compound 6
2-{4-[(2-fluoro-5-methylbenzoyl)amino]phenyl}-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 5.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.65 (s, 1H) 10.53 (s, 1H) 7.83 (d, J=8.51 Hz, 2H) 7.79 (d, J=7.92 Hz, 1H) 7.70-7.73 (m, 2H) 7.49 (dd, J=6.75, 1.76 Hz, 1H) 7.37-7.42 (m, 2H) 7.25 (dd, J=9.68, 8.51 Hz, 1H) 7.14-7.17 (m, 1H) 7.12 (br. s., 1H) 7.08-7.11 (m, 1H) 6.96 (br. s., 1H) 2.36 (s, 3H)
Compound 7
2-[3-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-3-carboxamide
The reaction solution of Intermediate 4 (37.7 mg, 0.15 mmol, 1 eq) and m-tolyl isocyanate (0.02 mL, 1 eq) in anhydrous THF (1.5 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. It was then subjected to a partition between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and finally dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (1:3). Compound 7 was obtained as white solid upon filtration in amount of 46 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.68 (s, 1H) 8.81 (s, 1H) 8.63 (s, 1H) 7.82 (d, J=7.92 Hz, 1H) 7.77 (t, J=1.76 Hz, 1H) 7.57-7.59 (m, 1H) 7.39-7.42 (m, 2H) 7.29-7.32 (m, 2H) 7.24 (d, J=8.22 Hz, 1H) 7.14-7.18 (m, 2H) 7.08-7.12 (m, 2H) 6.91 (br. s., 1H) 6.80 (d, J=7.63 Hz, 1H) 2.28 (s, 3H)
Compound 8
2-{3-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 7.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.69 (s, 1H) 9.10 (s, 1H) 8.97 (s, 1H) 8.04 (s, 1H) 7.82 (d, J=7.92 Hz, 1H) 7.79 (t, J=1.91 Hz, 1H) 7.57-7.60 (m, 2H) 7.50-7.54 (m, 1H) 7.40-7.44 (m, 2H) 7.30-7.35 (m, 2H) 7.17 (ddd, J=7.92, 7.04, 1.17 Hz, 1H) 7.08-7.13 (m, 2H) 6.93 (br. s., 1H)
Compound 9
2-{3-[(3-methyl-2-furoyl)amino]phenyl}-1H-indole-3-carboxamide
The mixture of Intermediate 4 (25.1 mg, 0.1 mmol, 1 eq), 3-methyl-furan-2-carboxylic acid (20 mg, 1.5 eq), EDC (29 mg, 1.5 eq), and DMAP (2.5 mg, 0.2 eq) in anhydrous tetrahydrofuran (1.5 mL) was stirred under nitrogen atmosphere and heated at 60° C. for two hours. The reaction mixture was then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, washed sequentially with saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. After the upper liquor was decanted and concentrated, the solid residue was triturated with EtOAc-Hex (1:1) and Compound 9 was obtained as a white solid upon filtration in amount of 21 mg.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.68 (s, 1H) 10.20 (s, 1H) 8.15 (t, J=1.76 Hz, 1H) 7.84 (d, J=7.92 Hz, 1H) 7.80-7.82 (m, 2H) 7.43-7.46 (m, 1H) 7.39-7.42 (m, 2H) 7.17 (ddd, J=8.07, 7.04, 1.03 Hz, 1H) 7.11 (ddd, J=7.92, 7.19, 1.03 Hz, 1H) 7.08 (br. s., 1H) 6.85 (br. s., 1H) 6.61 (d, J=1.47 Hz, 1H) 2.36 (s, 3H).
Compound 10
2-{3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}-1H-indole-3-carboxamide
Synthesized using a procedure similar to the synthesis for Compound 9.
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 11.71 (s, 1H) 10.55 (s, 1H) 8.05-8.07 (m, 1H) 7.83 (d, J=7.92 Hz, 1H) 7.78 (d, J=7.63 Hz, 1H) 7.45-7.49 (m, 2H) 7.40-7.44 (m, 2H) 7.38 (ddd, J=7.92, 5.14, 2.20 Hz, 1H) 7.24 (dd, J=9.83, 8.66 Hz, 1H) 7.17 (ddd, J=7.92, 7.04, 1.17 Hz, 1H) 7.11 (ddd, J=7.85, 7.12, 0.88 Hz, 1H) 7.08 (br. s., 1H) 6.89 (br. s., 1H) 2.35 (s, 3H).
Biological data for the compounds of the present invention was generated by use of the following assays.
VEGFR2 Kinase Assay
Biochemical KDR kinase assays were performed in 96 well microtiter plates that were coated overnight with 75 μg/well of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates were washed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA, then washed with 2 mls per well PBS-T prior to starting the reaction. Reactions were carried out in 100 μL reaction volumes containing 2.7 μM ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 20 ul per well of kinase buffer containing 200-300 ng purified cytoplasmic domain KDR protein (BPS Bioscience, San Diego, Calif.). Following a 15 minute incubation at 30° C., the reactions were washed 2 mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to the wells for 30 minutes. Following a 2 mls per well wash with PBS-Tween-20, 100 μl of O-Phenylenediamine Dihydrochloride in phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7-10 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100 μl of 2.5N H 2 SO 4 to each well and read using a microplate ELISA reader set at 492 nm. IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
VEGFR2 Cellular Assay
Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of VEGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. HUVEC (human umbilical vein endothelial cells) (Clonetics) were seeded in 384-well fibronectin coated black-walled plates overnight @37° C./5% CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cells were washed 2 times (Elx405, Biotek Instruments) to remove extracellular dye. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.0001 to 10.0 uM followed by VEGF 165 stimulation (10 ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 384 wells using a cooled CCD camera. Data were generated by determining max-min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
PDGFRβ Kinase Assay
Biochemical PDGFRβ kinase assays were performed in 96 well microtiter plates that were coated overnight with 75 μg of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates were washed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked by incubation with PBS containing 1% BSA, then washed with 2 mls per well PBS-T prior to starting the reaction. Reactions were carried out in 100 μL reaction volumes containing 36 μM ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 VO 4 ). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 20 ul per well of kinase buffer containing 200-300 ng purified cytoplasmic domain PDGFR-b protein (Millipore). Following a 60 minute incubation at 30° C., the reactions were washed 2 mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to the wells for 30 minutes. Following a 2 mls per well wash with PBS-Tween-20, 100 μl of O-Phenylenediamine Dihydrochloride in phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7-10 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of 100 μl of 2.5N H 2 SO 4 to each well and read using a microplate ELISA reader set at 492 nm. IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
The biological results for the various compounds are shown in Table 1 below.
TABLE 1
In vitro VEGFR2 and PDGFRβ data
VEGFR2
PDGFRβ
Compound
Kinase
Kinase
Number
Structure
IC 50 (nM)
IC 50 (nM)
1
13
140
2
7
61
3
17
267
4
7
37
5
>10,000
NA
6
>10,000
NA
7
>10,000
NA
8
>10,000
NA
9
>10,000
>10,000
10
>10,000
NA | This invention is directed to a compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined herein. The compounds of Formula I are useful as receptor tyrosine kinase (RTK) inhibitors and can be used to treat such diseases as cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Application No. 60/067,009 filed Dec. 1, 1997.
BACKGROUND OF THE INVENTION
The present invention relates to hubcaps for wheels, and more particularly, to hubcap assemblies for automotive vehicle wheels.
Push-through hubcaps--hubcaps which are inserted into hub bores of wheels from the back side of a wheel--are generally known in the art. Typical push-through hubcaps are generally decorative in nature and are usually made of a relatively light synthetic resin material, such as plastic. A problem associated with such push-through hubcaps is that the fit between the main body of the cap and the hub bore can be loose, or can loosen over time, allowing the hubcap to move within the bore. In either case, though, this movement has a tendency to produce an undesirable rattling noise during rotation of the associated wheel.
In general, the reason for an initially loose fit is that the hubcaps are designed to have a clearance fit within the wheel bore rather than a friction fit. As a result of this clearance fitting, minor dimensional discrepancies between different wheels and the associated hubcaps can result in the fit of some hubcaps being somewhat looser than others when they are mounted on a wheel.
The reason for such looseness which occurs over time is somewhat more complex. The resin material from which most hubcaps are fabricated has a tendency to shrink when exposed to heat. Since these hubcaps are disposed in the hub bore of an automobile wheel, they are often exposed to a great deal of radiant and kinetic heat. During normal conditions, the shrinkage of the hubcap due to this heat is relatively negligible and poses few problems. However, when the hubcap is subjected to extreme heat due to exposure to direct radiant sunlight or extended rotation at high rates of speed, the hubcap shrinkage may reach a point where it becomes problematic. This, shrinkage causes the hubcap to pull away from the wall of the hub bore, thus loosening the engagement between the hubcap and the hub bore.
Accordingly, there is a need for a push-through hubcap assembly that overcomes some of the above identified deficiencies associated with conventional push-through hubcaps, that maintains a tight fit engagement with an associated hub bore, that prevents the rattling noise associated with conventional push-through hubcaps, and that is cost efficient to manufacture.
SUMMARY OF THE INVENTION
The present invention provides a push-through hubcap assembly which overcomes some of the deficiencies of prior art push-through hubcaps by including a resilient member between the body of the hubcap and the hub bore of an associated wheel. It has been found that by using a resilient member in accordance with the present invention, a tight fit between the hub cap and the hub bore is able to be maintained even when the hubcap shrinks due to exposure to radiant and kinetic heat.
The hubcap assembly of the present invention includes a wheel having a central hub bore and an associated push-through hubcap. Preferably, the hub bore is annular in shape and includes an inner annular surface for engaging a flange on an associated push-through hubcap. The push-through hubcap preferably is composed of an annular body having a flange disposed at the bottom thereof. Preferably, a chamfer is formed on the inner annular surface of the hub bore for engaging the flange on the hubcap body and the flange includes an annular channel formed around the top edge thereof for receiving a resilient member. Thus, when the hubcap is inserted into the hub bore, the resilient member engages the chamfer of the inner annular surface and maintains the hubcap in a tight fit engagement with the hub bore, thereby maintaining a snug fit and preventing rattling of the hubcap, even when the hubcap shrinks from heat exposure. In a preferred embodiment, the hubcap assembly of the present invention is assembled by inserting the hubcap body through the hub bore of the associated wheel such that the resilient member engages and is biased against the chamfered inner surface of the bore.
Accordingly, it is an object of the present invention to provide a push-through hubcap which includes a resilient member on its external surface to maintain a tight fit engagement between the hubcap and the hub bore of an associated wheel; a push-through hubcap assembly which decreases the potential for the hubcap to become loose and move within the hub bore, thus decreasing the potential for the hubcap to rattle within the hub bore; a push-through hubcap assembly which is cost efficient to manufacture; and a method for assembling a hubcap and wheel wherein the push-through hubcap has a significantly reduced potential for rattling within a hub bore of an associated wheel.
Other objects and advantages of the invention will be apparent from the following description, the accompanying drawing and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of a preferred embodiment of the push-through hubcap of the present invention;
FIG. 2 is a cross section taken at line 2--2 of FIG. 1; and
FIG. 3 is a detail in section of the hubcap of FIG. 1, mounted in the hub bore of an associated wheel.
DETAILED DESCRIPTION
The term "push-through hubcap" is used to describe a hubcap which is shaped to be inserted into a hub bore of a wheel from the inside (inboard side) of a wheel prior to mounting the wheel on a hub of an associated vehicle. The push-through hubcap is inserted into the hub bore of the wheel so that a face of the hubcap is visible from the outside (outboard) side of the wheel.
As best shown in FIGS. 1 and 2, in accordance with a preferred embodiment of the present invention, a push-through hubcap, generally designated 10, includes a cup-shaped body generally designated 12. In a preferred embodiment, the body 12 is made of plastic, or more specifically plateable ABS. However, those skilled in the art will appreciate that other suitable materials can be used without departing from the scope of the invention. The body 12 includes an outboard end 14 and an inboard end 16. The outboard end 14 includes a spherical face 18 and the inboard end 16 includes a radially outwardly flared annular flange 20 having a lower surface 21 to fix the position of the body 12 within a hub bore relative to an associated wheel. Those skilled in the art will appreciate that other structures, such as spaced projections, could be used to prevent axial outward movement of the hubcap 10 and these structures are considered to be within the scope of the present invention.
The body 12 includes an outwardly tapered, cylindrical wall 22 having an annular outer surface 23 and an annular inner surface 24. The taper facilitates the insertion of the hubcap 10 into an associated hub bore. It is desirable that the hubcap 10 be shaped to slide freely into an associated hub bore. Therefore, the largest outer diameter of the wall 22 is preferably less than the outer diameter of an associated hub bores so that the hubcap 10 can be substantially received within the hub bore.
As best shown in FIG. 3, the body 12 includes an annular channel 26, and the hubcap 10 includes a resilient member 28, preferably an O-ring, shaped to fit within the channel. Preferably, the O-ring is made of a resilient material, such as rubber, or the like. The purpose of the O-ring is to maintain a tight fit engagement between the hubcap 10 and an associated wheel. Such a tight fit engagement prevents rattling and vibration of the hubcap 10 within the wheel. The annular channel 26 is positioned in proximity to the inboard end 16, preferably at the transition point between the outer wall 22 of the body 12 and the annular flange 20 to receive the resilient member 28.
The push-through hubcap 10 can be used to form a hubcap assembly, generally designated 30, shown in FIG. 3. The hubcap assembly 30 of the present invention includes the push-through hubcap 10 and a wheel, generally designated 32. The wheel 32 includes an outboard side 34, an inboard side 36, and a hub bore 38. The hub bore 38 extends through the center of the wheel 32 and includes an outer diameter defined by an inner annular surface 40 which preferably includes an inner annular chamfer 42. The dimensions of the outer diameter of the hub bore 38 are sized such that a hubcap 10 can be inserted into the hub bore 38. Preferably, when the hubcap 10 is positioned within the hub bore 38, the flange 20 and resilient member 28 securely engage the inner annular chamfer 42 around the entire circumference of the hubcap 10, thereby restricting both radial and axial outward movement of the hubcap 10 within the hub bore 38. In an alternate embodiment, the resilient member 28 is positioned farther out on the body 12 so that it engages the inner annular surface 40 of the wheel 32 outboard of the inner annular chamfer 42.
The hubcap 10 of the present invention is inserted into the hub bore 38 from the inboard side 36 of the wheel 32. The employment of the flange 20 with the wheel 32 acts as a stop, which positions the hubcap 10 relative to the hub bore 38. Preferably, the lower surface 21 of the flange 20 is shaped to engage a surface of a brake drum or rotor 41 so that when the wheel 32 is bolted to a hub (not shown), the lower surface 21 of the flange 20 engages the caliper 41 thereby preventing the hubcap 10 from sliding in an inboard direction. Preferably, the flange 20 of the hubcap 10 is also shaped to engage the chamfer 42 of the annular surface 40. More preferably, the resilient member 28 engages the chamfer 42 of the annular surface 40 such that the hubcap 10 is held in tight fit engagement with the hub bore 38 and its associated wheel 32. In a preferred embodiment, the cylindrical wall 22 is not in contact with the annular surface 40 of the hub bore 38 once the hubcap 10 is received by the hub bore 38.
The method of assembling the hubcap assembly 30 of the present invention is as follows. A wheel 32 having a hub bore 38 extending through a central axis thereof is selected. Preferably, the hub bore 38 of the wheel 32 includes an outer diameter that is defined by an annular surface 40 having a an annular chamfer 42 on a lower portion thereof. Next, a push-through hubcap 10 having a body 12 which is capable of being received by the hub bore 38 is selected. Preferably, the body 12 of the hubcap 10 further includes a resilient member 28 positioned thereon that is capable of engaging the annular chamfer 42 of the hub bore 38. Finally, the push-through hubcap 10 is inserted through the hub bore 38 such that the resilient member 28 engages the annular chamfer 42 of the hub bore 38. In a preferred embodiment, the lower surface 21 of the flange 20 is pressed flush against a brake pad or caliper 41 when the wheel 32 is bolted to an associated hub (not shown), thereby preventing inboard movement of the hubcap 10.
Having described the invention in detail and by reference to the drawings, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the following claims. | A hubcap assembly that includes a push-through hubcap having a resilient member disposed on its external surface to maintain a tight fit engagement between the hubcap and a hub bore of an associated wheel. The hubcap assembly of the present invention decreases the potential for the hubcap to become loose and move within the hub bore, thus decreasing the potential for the hubcap to rattle within the hub bore. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to and the benefit of Korean Patent Application No. 10-2005-0124968 filed in the Korean Intellectual Property Office on Dec. 17, 2005, the content of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] (a) Field of the Invention
[0003] The present invention relates to a cruise control system and method for a vehicle.
[0004] (b) Description of the Related Art
[0005] With increased number of vehicles and congestion on the roadways, the need for more intelligently designed safety mechanisms is greater than ever before. In particular, efforts have been directed to creating improved anti-collision systems and methods. While adaptive cruise control (ACC) systems can help ensure the safety and comfort of the driver and his passengers even under complex road conditions, conventional cruise control systems cannot reliably avoid a collision or for warning against a collision.
[0006] In conventional ACC systems, once a running speed is set on a host vehicle, the ACC system on the host vehicle takes in certain load conditions and the running speed of the preceding vehicle as detected by sensors and, based on these parameters, controls the throttle actuator or brake actuator to maintain the host vehicle at a fixed predetermined running speed. The host vehicle is equipped with a distance detection unit mounted at the front which sends its signals to a computer that calculates a relative velocity and relative distance from the preceding distance. The computer also executes an algorithm that calculates and sets a time gap for determining a safety distance to leave between the host vehicle and the preceding vehicle based on the current running speed of the host vehicle. The safety distance is derived by multiplying the time gap by the current running speed of the host vehicle.
[0007] In this manner, if the relative distance and relative velocity indicate that the host vehicle is in danger of colliding with the preceding vehicle, the ACC system will apply the brakes and thereby control the vehicular distance to the preceding vehicle based on the predetermined time gap. When the threshold braking distance of the host vehicle as it corresponds to the current running speed thereof is less than the calculated safety distance, the ACC system operates the brake actuator or the throttle actuator until the distance from the preceding vehicle exceeds the predetermined safety distance.
[0008] Once the distance from the preceding vehicle exceeds the calculated safety distance due to the reduced running speed of the host vehicle, the ACC system will increase the running speed of the host vehicle to the original fixed running speed by recovering an engine torque.
[0009] One of the reasons for the imperfect anti-collision mechanisms of conventional ACC system is the manner by which the time gap is determined. As those of skill in the art will recognize, the time gap in conventional ACC systems cannot be readily modulated by a driver. Even in conventional systems that allow the driver to select the time gap to be one of three phases, Far, Med, and Close, the mechanism for control is such that it presents difficulty and danger for a driver attempting to adjust the time gap while driving. The simple fashion by which the time gap is determined is also a cause for concern. Assuming the predetermined time gaps of a host vehicle running at a speed of 100 km/h to be 2.0, 1.5, and 1.0 s, the distance from the preceding vehicle to be maintained would be 55 m, 42 m, and 28 m, respectively, using conventional ACC systems. The time gap is set with the assumption that the friction coefficient between each tire and a road is 1.0 and the maximum deceleration of the host vehicle is 9.8 m/s 2 . With these oversimplified conditions, the minimum braking distance for a host vehicle at a running speed of 100 km/h is 38 m and would appear well within the calculated safety distance of 55, 42, and 28 m.
[0010] Unfortunately, the assumption relied upon in conventional ACC system can be a fatal one as the friction coefficient between each tire and the road is not always 1.0. As shown in FIG. 6 , the friction coefficient between each tire and the road can vary significantly depending on road/weather conditions. The friction coefficient between each tire and the road can also vary considerably due to the type of road surface, e.g. asphalt, concrete road, unpaved, etc.), thread design or degree of wearing on each tire. For example, the friction coefficient and the maximum deceleration for a vehicle on a concrete road with a new tire on a sunny day is about twice as large as the friction coefficient and the maximum deceleration for the same vehicle on an asphalt road with an old tire on a rainy day.
[0011] Conventional ACC systems fail to account for variations in the friction coefficient between each tire and the road when calculating the minimum safety distance. In addition, the maximum deceleration in the conventional ACC system is fixed to the value of 9.8 m/s 2 . As such, conventional ACC systems cannot be relied upon to provide the appropriate minimum safety distance and to avoid a collision between the host vehicle and the preceding vehicle in an emergency.
[0012] The above information is provided only to enhance understanding of the background of the invention and therefore it may contain information that does not form the prior art with respect to the present invention.
SUMMARY OF THE INVENTION
[0013] The present invention provides an adaptive cruise control system and method for a vehicle having advantages of maintaining an appropriate safety distance between a host vehicle and a preceding vehicle.
[0014] An exemplary method for an adaptive cruise control of a vehicle according to an embodiment of the present invention includes: calculating a maximum friction coefficient of a road; calculating a minimum safety distance to a preceding vehicle based on the calculated maximum friction coefficient and a current running speed of a host vehicle; setting a reference safety index in accordance with the calculated minimum safety distance; calculating a current safety index in accordance with a relative distance to the preceding vehicle; and controlling a vehicular distance by comparing the current safety index with the reference safety index and accordingly operating an actuator.
[0015] The safety index may include a time gap that is defined as a time it would take the host vehicle to travel the minimum safety distance at the current running speed thereof.
[0016] In a further embodiment, the calculating the maximum friction coefficient of the road includes: calculating a brake gain; calculating a traction force applied on each tire; calculating a normal force applied on each tire; calculating a friction coefficient of the road on which the host vehicle is running; detecting tire and road information; calculating a slip ratio and detecting a gradient thereof; and estimating the maximum friction coefficient based on the friction coefficient and the gradient of the slip ratio.
[0017] The maximum friction coefficient increases with an increasing slip ratio of the tire. However, if the slip ratio is excessive, the maximum friction coefficient decreases with an increasing slip ratio.
[0018] The brake gain may be calculated from a brake pressure and an angular velocity of each wheel. The brake pressure is applied by a brake actuator.
[0019] The traction force may be calculated from a transmission torque and the brake gain.
[0020] The transmission torque may be calculated from a torque converter torque and the angular velocity of each wheel.
[0021] The torque converter torque may be calculated from an engine torque, a carrier speed, and a gear condition.
[0022] Furthermore, the engine torque may be calculated from a degree of throttle opening and an engine speed.
[0023] The normal force may be calculated from an entire vehicular weight and dynamics of the host vehicle.
[0024] The tire information includes information of the brake gain, the traction force, the normal force, and a tire effective radius.
[0025] The tire effective radius is defined as a distance between the road and a center of each wheel.
[0026] The road information includes a wheel speed of each wheel, the current running speed of the host vehicle, and the slip ratio of each wheel.
[0027] The wheel speed of each wheel may be detected by an angular velocity detector mounted on each wheel.
[0028] The current running speed of the host vehicle may be detected by a vehicular speed detector mounted on an output shaft of a transmission.
[0029] The slip ratio may be calculated from the angular velocity of each wheel, the current running speed, and the tire effective radius.
[0030] An exemplary system for an adaptive cruise control of a vehicle according to an embodiment of the present invention includes: a friction coefficient calculator for calculating a friction coefficient of a road; a slip ratio calculator for calculating a slip ratio between the road and each tire; a vehicular distance detector for detecting a current vehicular distance to a preceding vehicle; a slip ratio gradient detector for detecting a gradient of the slip ratio based on the friction coefficient and the slip ratio, the slip ratio gradient detector receiving a signal of the friction coefficient from the friction coefficient calculator and a signal of the slip ratio from the slip ratio calculator; a maximum friction coefficient calculator for calculating a maximum friction coefficient between the road and each tire based on the gradient of the slip ratio, the maximum friction coefficient calculator receiving a signal of the gradient of the slip ratio from the slip ratio gradient detector; a minimum safety distance calculator for calculating a minimum safety distance corresponding to the current running speed of the host vehicle based on the maximum friction coefficient, the minimum safety distance calculator receiving a signal of the maximum friction coefficient from the maximum friction coefficient calculator; a safety index calculator for calculating a reference safety index and a current safety index corresponding to the minimum safety distance and the current vehicular distance to the preceding vehicle respectively, the safety index calculator receiving a signal of the minimum safety distance from the minimum safety distance calculator and a signal of the current vehicular distance from the vehicular distance detector; a processor for comparing the current safety index with the reference safety index and generating a control signal thereby, the processor receiving a signal of the reference safety index and the current safety index from the safety index calculator; and an actuator for controlling the current running speed of the host vehicle, the actuator receiving the control signal from the processor.
[0031] The present ACC system may comprise a processor, memory and associated hardware and software as may be selected and programmed by persons of ordinary skill in the art based on the teachings of the present invention contained herein.
[0032] The friction coefficient calculator may include: a traction force calculator for calculating a traction force applied on each tire; and a normal force calculator for calculating a normal force applied on each tire.
[0033] The slip ratio calculator may include: a tire effective radius detector for detecting a distance between the road and a center of each tire; an angular velocity detector mounted on each wheel for detecting an angular velocity thereof; and a vehicular speed detector for detecting the current running speed of the host vehicle.
[0034] The traction force calculator may include: a brake gain calculator for calculating a brake gain based on brake pressure and the angular velocity of each wheel; and a transmission torque calculator for calculating a transmission torque based on a torque converter torque and the angular velocity of each wheel.
[0035] The angular velocity detector may include an angular velocity sensor mounted on each wheel.
[0036] The vehicular speed detector may include a vehicular speed sensor mounted on an output shaft of the transmission.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 shows a block diagram of an adaptive cruise control system for a vehicle according to an exemplary embodiment of the present invention.
[0038] FIG. 2 shows a block diagram for calculating traction force in an adaptive cruise control system for a vehicle according to an exemplary embodiment of the present invention.
[0039] FIG. 3 shows a flowchart of an adaptive cruise control method according to an exemplary embodiment of the present invention.
[0040] FIG. 4 shows a flowchart for estimating the maximum friction coefficient in an adaptive cruise control method according to an exemplary embodiment of the present invention.
[0041] FIG. 5 is a graph of the change in estimated maximum friction coefficient over time as determined by an adaptive cruise control method according to an exemplary embodiment of the present invention as a vehicle moves from a wet road surface to a dry road surface.
[0042] FIG. 6 is a graph showing the friction coefficient and slip ratio for various road conditions.
[0000]
<Legend of Reference Numerals for Elements Appearing in the Drawings>
10: friction coefficient calculator
11: brake gain calculator
12: traction force calculator
13: normal force calculator
14: tire effective radius detector
15: slip ratio calculator
16: vehicular distance detector
17: angular velocity detector
18: vehicular speed detector
19: slip ratio gradient detector
20: maximum friction coefficient
21: minimum safety distance
calculator
calculator
22: safety index calculator
23: processor
24: actuator
25: transmission torque calculator
26: torque converter table
27: engine map
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0043] Exemplary embodiments of the present invention will hereinafter be described in detail with reference to the accompanying drawings.
[0044] As illustrated by the embodiment in FIG. 1 , an adaptive cruise control system for a vehicle includes a friction coefficient calculator 10 for calculating a friction coefficient; a slip ratio calculator 15 for calculating a slip ratio between a road and each tire; a vehicular distance detector 16 for detecting a current vehicular distance to a preceding vehicle; a slip ratio gradient detector 19 for detecting a gradient of the slip ratio based on the calculated friction coefficient and the slip ratio; a maximum friction coefficient calculator 20 for calculating a maximum friction coefficient between the road and each tire; a minimum safety distance calculator 21 for calculating a minimum safety distance based on the calculated maximum friction coefficient and the current running speed of a host vehicle; a safety index calculator 22 for calculating a reference safety index and a current safety index corresponding to the minimum safety distance and the current vehicular distance to the preceding vehicle respectively; a processor 23 for comparing the reference safety index with the current safety index and generating a control signal thereby; and an actuator 24 for controlling the current running speed of the host vehicle corresponding to the control signal received from processor 23 .
[0045] The friction coefficient calculator 10 calculates the friction coefficient between the road and each tire based on a traction force that is applied horizontally on each tire and a normal force that is applied vertically on each tire. The friction coefficient calculator 10 outputs a signal of the friction coefficient to the slip ratio gradient detector 19 . The friction coefficient calculator 10 can either include a traction force calculator 12 and a normal force calculator 13 or, in the alternative, take as inputs values generated by calculators 12 and 13 .
[0046] The traction force calculator 12 , as shown in greater detail in FIG. 2 , can include a brake gain calculator 11 and a transmission torque calculator 25 or, in the alternative, take as inputs values generated by calculators 11 and 25 . The traction force calculator 12 calculates the traction force that is applied horizontally on the tire of each wheel FL (“front left”), FR (“front right”), RL (“rear left”), and RR (“rear right”) from a brake gain K B and a transmission torque T S . The traction force calculator 12 outputs a value of the traction force to the friction coefficient calculator 10 .
[0047] The brake gain calculator 11 calculates the brake gain K B from a wheel speed that is detected by an angular velocity detector 17 mounted on each wheel and a brake pressure that is applied by a brake actuator. The brake gain calculator 11 then outputs a value of the brake gain to the traction force calculator 12 .
[0048] The transmission torque calculator 25 includes an engine map 27 and a torque converter table 26 . The transmission torque calculator 25 calculates a transmission torque T S from a torque converter torque T t and the wheel speed of each wheel.
[0049] As shown in FIG. 2 , the engine map 27 detects an engine torque T net based on a degree of throttle opening and an engine speed, and outputs a signal of the engine torque T net to the torque converter table 26 . The torque converter table 26 detects a torque converter torque T t based on the engine torque T net , a gear condition, and a carrier speed. The torque converter table 26 outputs the value of the torque converter torque T t to the transmission torque calculator 25 .
[0050] In addition, the transmission torque calculator 25 calculates a transmission torque T S from the torque converter torque T t and the wheel speed of each wheel, and outputs a signal of the transmission torque T S to the traction force calculator 12 . The traction force calculator 12 calculates the traction force applied on each tire based on the transmission torque T S and the brake gain K B .
[0051] The normal force calculator 13 calculates a normal force that is applied vertically on each wheel based on the total vehicular weight, including weight of the driver, passengers, and cargo, and dynamics of the host vehicle. The normal force calculator 13 outputs the value of the normal force to the friction coefficient calculator 10 .
[0052] The slip ratio calculator 15 includes a tire effective radius detector 14 , the angular velocity detector 17 , and a vehicular speed detector 18 . The slip ratio calculator 15 calculates a slip ratio of each wheel based on the wheel speed of each wheel, the current running speed of the host vehicle, and a tire effective radius, as determined by any of various algorithms known in the art. The slip ratio calculator 15 outputs the value of the slip ratio to the slip ratio gradient detector 19 .
[0053] The tire effective radius detector 14 detects a tire effective radius that is defined as a distance between the road and a center of each wheel based on the normal force applied on each wheel. The tire effective radius detector 14 outputs the value of the tire effective radius to the slip ratio calculator 15 .
[0054] The angular velocity detector 17 includes an angular velocity sensor mounted on each wheel. The angular velocity detector 17 estimates a wheel speed of each wheel from the angular velocity of each wheel, and outputs the value of the wheel speed to the slip ratio calculator 15 .
[0055] The vehicular speed detector 18 includes a vehicular speed sensor mounted on an output shaft of the transmission. The vehicular speed detector 18 detects the current running speed of the host vehicle according to the rotational speed of the output shaft of the transmission. The vehicular speed detector 18 outputs a signal of the current running speed to the slip ratio calculator 15 .
[0056] The vehicular distance detector 16 detects a relative distance and a relative velocity between the host vehicle and the preceding vehicle. The vehicular distance detector 16 outputs the relative distance and the relative velocity to the safety index calculator 22 .
[0057] The slip ratio gradient detector 19 analyzes the friction coefficient received from the friction coefficient calculator 10 and the slip ratio received from the slip ratio calculator 15 , the values of which are determined according to one of various algorithms known in the art. Through numerical analysis, the slip ratio gradient detector 19 detects a gradient of the slip ratio as illustrated by the slip ratio graph of FIG. 6 , and outputs the value of the gradient of the slip ratio to the maximum friction coefficient calculator 20 .
[0058] The maximum friction coefficient calculator 20 calculates a maximum friction coefficient between the road and each tire according to an initial gradient of the slip ratio and the friction coefficient. The maximum friction coefficient calculator 20 outputs a signal of the maximum friction coefficient to the minimum safety distance calculator 21 .
[0059] The maximum friction coefficient calculator 20 calculates the maximum friction coefficient according to the relation between the slip ratio and the friction coefficient. As shown in FIG. 6 , the maximum friction coefficient increases with an increasing slip ratio. However, if the slip ratio is excessive, the maximum friction coefficient decreases with an increasing slip ratio.
[0060] Generally, the maximum friction coefficient of a dry road is estimated to be 1.0, and therefore the maximum deceleration thereof is determined to be 9.8 m/s 2 by equation 1 under this condition.
[0000] maximum deceleration=friction coefficient×acceleration of gravity (Equation 1)
[0061] The minimum safety distance calculator 21 calculates a minimum safety distance to the preceding vehicle based on the current running speed of the host vehicle and the maximum friction coefficient.
[0062] The safety index calculator 22 calculates a reference safety index and a current safety index corresponding to the minimum safety distance and the vehicular distance to the preceding vehicle respectively. The safety index calculator 22 outputs the value of the reference safety index and the current safety index to the processor 23 .
[0063] The safety index can be indicated in various forms, e.g. by distance or time, but a time gap is widely used as the safety index. The time gap is defined as the time it would take the host vehicle to travel the minimum safety distance at the current running speed thereof.
[0064] The processor 23 compares the reference safety index with the current safety index and accordingly operates the actuator 24 to control the vehicular distance from the preceding vehicle when the current safety index is less than the reference safety index.
[0065] The actuator 24 decelerates the current running speed of the host vehicle to ensure the minimum safety distance is maintained from the preceding vehicle. Generally, a brake actuator or a throttle actuator is used as the actuator 24 .
[0066] An exemplary method for an adaptive cruise control of a vehicle according to an embodiment of the present invention is explained as follows.
[0067] As shown in FIG. 3 , an ACC system operates while the host vehicle is at a running state in step S 105 . When a driver sets a vehicular running speed of the host vehicle at step S 110 , the safety index calculator 22 calculates a reference safety index which corresponds to the vehicular running speed thereof at step S 115 . The reference safety index enables the host vehicle to ensure the minimum safety distance is maintained away from the preceding vehicle under a dry road condition, wherein the maximum friction coefficient is 1.0.
[0068] The maximum friction coefficient calculator 20 then calculates a maximum friction coefficient of a road according to road surface and tire conditions, and outputs the value of the maximum friction coefficient to a minimum safety distance calculator 21 at step S 120 . As those of ordinary skill in the art will appreciate, the present invention can find application in vehicles having any number of tires. Each tire may have a different friction coefficient. The ACC system accounts for this variation between the tires by taking the highest friction coefficient to calculate the minimum safety distance.
[0069] Referring to FIG. 4 , a process of calculating the maximum friction coefficient is explained in detail as follows.
[0070] An angular velocity of each wheel is detected by an angular velocity detector 17 mounted thereon, and a brake gain K B is calculated from brake pressure of a brake actuator at step S 205 .
[0071] Subsequently, a traction force that is applied horizontally on each wheel is calculated from the brake gain K B and a transmission torque T S at step S 210 . A normal force that is applied vertically on each wheel is calculated according to an entire vehicular weight and the dynamics of the host vehicle at step S 215 . Then, the friction coefficient of the road is calculated from the relation of the traction force and the normal force at step S 220 .
[0072] After that, tire and road information is detected at step S 225 . The tire information includes the brake gain K B , the traction force of each wheel, the normal force of each wheel, and a tire effective radius. The tire effective radius is defined as a distance between a center of each wheel and the road. The brake gain K B is calculated from the angular velocity of each wheel and the brake pressure. The traction force that is applied horizontally on each wheel is calculated from a transmission torque T S , and the normal force that is applied vertically on each wheel is calculated from the total vehicular weight and dynamics of the host vehicle.
[0073] In addition, the road information includes the wheel speed of each wheel, the current running speed of the host vehicle, and the slip ratio of each wheel. The wheel speed is detected by the angular velocity detector 17 mounted on each wheel, and the current running speed of the host vehicle is detected by the vehicular speed detector 18 mounted on an output shaft of a transmission
[0074] After the road and tire information is detected, a gradient of the slip ratio is detected from the friction coefficient and the slip ratio at step S 230 . Then, the maximum friction coefficient is calculated from the gradient of the slip ratio at step S 235 .
[0075] After the maximum friction coefficient between the road and each tire is calculated, the maximum deceleration is calculated from the maximum friction coefficient and the current running speed of the host vehicle at step S 125 . Subsequently, the minimum safety distance from the preceding vehicle is calculated corresponding to the maximum deceleration at step S 130 .
[0076] After that, the reference safety index, which was set under the assumption that the friction coefficient between the road and each tire is 1.0, is adjusted so as to correspond with the minimum safety distance at step S 135 . To elaborate, the reference safety index is set under the assumption that the friction coefficient between the road and each tire is 1.0 at the step S 115 , but if the maximum friction coefficient calculated based on the actual conditions of the road surface and of each tire is less than 1.0, the reference safety index that is set at the step S 115 would not be effective to ensure the minimum safety distance is kept. As such, the reference safety index of the present invention can be modified to reflect the actual tire and road conditions.
[0077] After the reference safety index is modified as described above, the presence of a preceding vehicle is checked at step S 145 using one of various methods known in the art. If no preceding vehicle is detected, the ACC system enters speed control mode at step S 150 , and a predetermined speed is maintained by modulating a throttle actuator control at step S 155 .
[0078] However, if a preceding vehicle does exist, the relative distance in consideration of the relative velocity between the host vehicle and the preceding vehicle is detected by the vehicular distance detector 16 , and a current safety index in accordance with the relative distance is calculated at step S 160 . Then, the processor 23 compares the reference safety index with the current safety index at step S 165 .
[0079] If the current safety index is greater than or equal to the reference safety index, the ACC system enters a speed control mode at step S 150 , and it maintains the predetermined running speed by performing a throttle actuator control at step S 155 .
[0080] However, if the current safety index is less than the reference safety index, that is, there is a risk of colliding with the preceding vehicle and the ACC system will give off a collision warning signal to the driver and perform a vehicular distance control at step S 170 .
[0081] The vehicular distance control is performed by a braking control or an engine torque decelerating control, wherein the relative distance between the host vehicle and the preceding vehicle is controlled so as to exceed the minimum safety distance by decelerating the current running speed of the host vehicle at step S 175 .
[0082] The following example is put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methodology of the present invention works and is not intended to limit the scope of what is regarded as the invention.
EXAMPLE
[0083] The circumstances under which the time gap is used as the safety index will hereinafter be described in detail. The minimum safety distance given a dry road surface where the maximum friction coefficient is 1.0 is about 38 m if the host vehicle is running at a speed of 100 km/h. In contrast, the minimum safety distance given a wet road surface where the maximum friction coefficient is 0.7 is about 56 m under the same conditions. Therefore, even if a driver sets the reference time gap to be 1.5 seconds in order to maintain the distance between the vehicles in excess of 41 m (1.5 sec×vehicular speed (100 km/h)=41 m), the reference time gap may be modified to 2.02 seconds in order to prevent a collision between the vehicles because the actual minimum safety distance under the above conditions is 56 m (2.02 sec×100 km/h=56m).
[0084] On the other hand, if the relative distance between the host vehicle and the preceding vehicle is 45 m when the host vehicle is running at a speed of 100 km/h, the current time gap is 1.62 seconds (1.62 sec×100 km/h=45 m). The ACC system will therefore control the vehicular distance from the preceding vehicle until the current time gap is the same as the reference time gap, 2.02 seconds.
[0085] As described above, the ACC system according to the present invention calculates the maximum friction coefficient between the road and each tire according to the condition of the road and tire in real-time, and calculates the actual minimum safety distance in accordance with the estimated maximum friction coefficient and the current running speed of the host vehicle. The reference safety index is then modified accordingly based on the actual minimum safety distance.
[0086] In addition, the ACC system according to the present invention is designed to give off a warning signal to the driver should a collision be likely and automatically decelerate the current running speed if the current safety index according to the relative distance to the preceding vehicle is less than the modified reference safety index. Safety and reliability is thereby enhanced by the adaptive ACC system and method of the present invention.
[0087] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. | The present invention provides a vehicular adaptive cruise control system and method that can adapt in real-time to tire and road conditions, vehicular weight, dynamics of the host vehicle, as well as other factors, to offer improved collision avoidance and warning. | 1 |
This present application claims the benefit of French Application No. 09-58137 entitled “Active Medical Device Comprising Means of Capture Test by Analysis of the Cardiac Vectrogram” and filed Nov. 18, 2009, which is hereby incorporated by reference in its entirety.
FIELD OF INVENTION
The present invention relates to “active implantable medical devices” as defined by the 20 Jun. 1990 Directive 90/385/EEC of the Council of the European Communities, and more particularly to devices that continuously monitor a patient's heart rhythm and deliver to the heart, if necessary, electrical pulses for stimulation, resynchronization and/or defibrillation in response to a rhythm disorder detected by the devices.
BACKGROUND
Antibradycardia stimulation involves the delivery of controlled stimulation pulses to an atrium and/or a ventricle, using a single or dual chamber device. In the case of cardiac resynchronization therapy (“CRT”), a multisite device delivers the stimulation pulses jointly to both ventricles. In general, after stimulating a cardiac cavity, a test known as a “capture test” is performed to determine whether the stimulation induced a depolarization wave in the cavity (also referred to as an “evoked wave”). A capture test is particularly useful for adjusting the amplitude and/or the width of the stimulation pulses, or the energy delivered to the stimulation site.
There are many techniques for implementing a capture test. For example, a capture test described in WO 93/02741 A1 and its counterpart U.S. Pat. No. 5,411,533 (Sorin CRM, previously known as ELA Medical) uses an automated testing algorithm that measures the efficiency threshold of the stimulation referred to as a “pacing threshold”, at regular intervals, for example, every six hours. The amplitude of the stimulation pulse is then adjusted, based on the measured pacing threshold increased by a safety margin taking into account the various uncertainties in determining the pacing threshold.
It has been discovered that this capture test algorithm in known devices can be misled by some atypical situations, such as an occurrence of a fusion event, in which a stimulation is triggered concomitantly by a spontaneous QRS event, at the time the capture test is performed.
Various proposals have been made to overcome this difficulty, including EP 1216722 A1 and its counterpart U.S. Pat. No. 6,711,441 (Sorin CRM, previously known as ELA Medical), which describes detecting a suspected fusion event and disregarding suspected events in the capture test.
Nevertheless, clinical follow-ups of patients show that the different conventional techniques for performing a capture test remain sensitive to various rhythm abnormalities occurring erratically, which deceive the test algorithm and lead to both false positive and false negative results. These anomalies may lead to an incorrect adjustment of the stimulation energy. If the stimulation energy is set too high, more power is consumed than is needed, thus the lifetime of the implant is reduced. If the stimulation energy is set too low, it presents a potential risk to the patient.
It also is known, as disclosed in EP 1287849 A1 and its counterpart U.S. Pat. No. 6,714,820 (Sorin CRM, previously known as ELA Medical), to perform a capture test, and readjust the stimulation energy continuously by checking on each cycle whether the stimulation was effective. These “cycle-to-cycle” adjustment techniques, despite their much higher reactivity, are very sensitive to the occurrence of a fusion event or an isolated atypical cycle, such as a post-atrial ventricular detection, a too short cycle, or an extrasystole, which may be misinterpreted as a loss of a capture, even though the pacing threshold did not naturally increase.
Moreover, in case of a multisite device, it is necessary to run as many capture tests as there are existing test sites. With the recent trend of increasing the number of stimulation sites, this leads to a substantial increase in a test time needed to perform a capture test on all the stimulation sites.
OBJECT AND SUMMARY
The present invention is directed to obtaining relevant parameters for detecting an evoked wave from endocardial electrogram (EGM) signals collected concurrently on two distinct channels from a single cavity, for example, a ventricle. The two distinct EGM channels may be, for example, a unipolar signal (e.g., a signal collected between the device housing and one of the distal or proximal lead electrodes), or a bipolar signal (e.g., a signal collected between a distal electrode and a proximal electrode of the lead).
Characteristically, the analysis of the EGM signals is a two-dimensional analysis of a “cardiac loop” or “vectogram” (“VGM”), which is a representation of one of the two signals relative to the other in a two-dimension space. This two-dimensional space is typically defined by a “unipolar channel” (in ordinate) vs. a “bipolar channel” (in abscissa), and each beat or significant fraction of a beat is represented by its vectogram in the two-dimensional space-eliminating the temporal dimension.
It shall be appreciated by a person of ordinary skill in the art that the “two-dimensional” analysis, or “in two dimensions” (2D) discussed herein is exemplary only, thus should not be seen as restrictive in itself. Rather, the invention may also apply to analysis in a higher order multidimensional space, e.g., 3D or more, by extrapolation of the teachings of the present description to a situation in which EGM signals collected from a cavity are simultaneously collected on three or more channels.
The invention therefore is broadly directed to the detection of an evoked wave by analysis of a recorded VGM during a cardiac cycle, particularly from a measure of the similarity or difference between the recorded VGM during a cardiac cycle under test and that recorded during a reference cardiac cycle corresponding to a well defined and known situation (e.g., proven capture, no capture, fusion). The cardiac cycle under test is also referred to herein as a “stimulated cardiac cycle,” as contrasted with the aforementioned “reference cardiac cycle.”
More specifically, one aspect of the present invention is directed to an active medical device of a known type including: stimulation means such as circuits that deliver electrical stimulation pulses of low energy to an electrode implanted in a cardiac chamber of a patient; means for detecting (collecting) the patient's heart electrical activity that includes means for producing at least two distinct temporal components from two distinct endocardial electrogram EGM signals of a cavity, and mean for performing a capture test on a stimulated cardiac cycle to detect an occurrence of a depolarization wave induced by the stimulation to the cavity.
Preferably, the means for performing a capture test includes: means for determining a non-temporal 2D characteristic representative of said stimulated cardiac cycle, based upon the variation of one of the temporal components as a function of the other of the temporal components, and means for performing a bi-dimensional analysis for delivering at least one descriptor parameter of said non-temporal 2D characteristic, and for determining a presence or loss of a capture based on said at least one descriptor parameter.
In one embodiment, the means for detecting a patient's electrical heart activity is connected to two or more electrodes of a lead placed in the patient's cardiac chamber(s), and to the device housing, and obtains a bipolar signal and a monopolar signal as said two distinct EGM signals respectively.
In a preferred embodiment, the means for determining the non-temporal 2D characteristic determines the 2D characteristic over time of the components of a fraction of the stimulated cardiac cycle, for example, in a time window including the QRS complex of the stimulated cardiac cycle.
In another embodiment, the means for bi-dimensional analysis compares the 2D characteristic of the stimulated cardiac cycle to at least one reference 2D characteristic, using a descriptor parameter that is representative of a degree of similarity or difference between the stimulated cardiac cycle 2D characteristic and the reference 2D characteristic. In yet another embodiment, the means for bi-dimensional analysis includes means for discriminating a fusion situation based on the at least one descriptor parameter.
According to one embodiment, the descriptor parameter generated by the means for bi-dimensional analysis is a geometric descriptor. For example, the geometric descriptor is:
the angle of a tangent vector to the 2D characteristic considered in a plurality of points of the vectogram. In this case, the means for bi-dimensional analysis includes a means for evaluating a correlation coefficient between the respective angle of the tangent vectors of the stimulated cardiac cycle 2D characteristic and a reference 2D characteristic;
the norm of the tangent vector to the 2D characteristic considered in a plurality of points of the vectogram. In this case, the means for two-dimensional analysis includes means for evaluating a correlation coefficient between the norms of the respective tangent vectors of the stimulated cardiac cycle 2D characteristic and a reference 2D characteristic;
the curvature of the 2D characteristic considered in a plurality of points. In this case, the means for bi-dimensional analysis includes means for evaluating a correlation coefficient between the respective curvatures of the stimulated cardiac cycle 2D characteristic and a reference 2D feature, and/or
the area defined by the stimulated cardiac cycle 2D characteristic.
According to one embodiment, several of these parameters are concurrently used when performing an analysis based on a combination of parameters, such as a combination of the norm and the angle of the tangent vector.
In an alternative embodiment, the means for determining a two-dimensional non-temporal characteristic (VGM) includes means for analyzing the principal components and producing the descriptor parameter(s).
The device may be a multisite device, wherein: the stimulation means includes means for selectively delivering pacing to a plurality of stimulation sites, or only to some of the stimulation sites, and the means for detecting includes means for producing, at each site, at least two distinct EGM components, and the means for performing a capture test includes means for discriminating situations among: a presence of capture on all the stimulated sites; a presence of capture only on a subset of the stimulated sites; and a loss of a capture on all the stimulated sites.
BRIEF DESCRIPTION OF THE DRAWINGS
Further features, characteristics and advantages of the present invention will become apparent to a person of ordinary skill in the art from the following detailed description made with reference to the drawings annexed, in which like reference characters refer to like elements and in which:
FIG. 1 is a schematic view of a bipolar lead located at an apex of the ventricle;
FIG. 2 illustrates exemplary EGM signals obtained respectively from the ventricular bipolar and unipolar channels according to the configuration of FIG. 1 ;
FIG. 3 shows a vectogram obtained from the two EGM signals of FIG. 2 ;
FIG. 4 illustrates exemplary parameters characterizing a vectogram at a given point, including the curvature and the tangent vector;
FIG. 5 shows an exemplary surface electrocardiogram illustrating, during successive beats, various situations that are taken into account by a detection algorithm; and
FIGS. 6-11 respectively illustrate, for various consecutive situations illustrated in the exemplary electrocardiogram of FIG. 5 , the left plot corresponding to the vectogram and the right plot corresponding to the position of a descriptor evaluated by a characterization algorithm over a decision boundary between a capture and a loss of capture.
DETAILED DESCRIPTION
With reference to FIGS. 1-11 , an embodiment of a device according to the present invention will now be described.
According to one embodiment, the present invention is implemented in an appropriate programming of a controlling software of a known device, for example, a cardiac pacemaker or a defibrillator/cardioverter, including hardware circuits and a control logic for collecting signals from endocardial leads and/or one or more implanted sensors. The present invention may particularly be implemented in an implantable device such as those of the Reply, Paradym, Ovatio, Esprit or Rhapsody device family manufactured and marketed by Sorin CRM, Clamart France (formerly known as ELA Medical, Montrouge, France).
A suitable implantable device such as those mentioned above includes a programmable microprocessor to receive, format, and process electrical signals collected (detected) by implanted electrodes, and to generate and deliver stimulation pulses to the implanted electrodes. It is possible to transmit by telemetry software and store it in a memory of the implantable device, and execute the software to implement various functions and features of the present invention that are described herein. The adaptation and modification of a device to implement these functions and features of the present invention is believed to be within the abilities of a person of ordinary skill in the art, and therefore will not be described in detail.
As indicated above, the present invention is directed to providing an improved analysis for detecting an evoked wave following a stimulation of a cavity from electrogram signals (EGM) collected on two different channels in a two-dimensional space.
FIG. 1 illustrates a conventional “single chamber” configuration for providing stimulation pulses to a cardiac cavity. A pulse generator 10 is connected to a lead 12 located in a patient's right ventricle 14 . The lead 12 has two electrodes including a distal electrode 16 and a proximal electrode 18 for collecting a first electrogram V bip corresponding to the potential difference between the distal electrode 16 and the proximal electrode 18 , and a second electrogram V uni , corresponding to the potential difference between one of the electrodes, e.g., the proximal electrode 18 and the metal housing of the pulse generator 10 .
This single chamber configuration was shown because of its simplicity to describe the present invention, but is in no way intended to be limiting as to the scope of the present invention. The present invention may be applied to the detection of a capture during stimulation of an atrium by a suitable electrode, or to the concomitant stimulation of both right and left ventricles in the case of multisite devices, especially biventricular devices designed to restore synchronization between the two ventricles. In general, the term “cavity” as used herein should be understood to mean either the atrium or ventricle, in the right or left cardiac cavities.
FIG. 2 shows exemplary plots of electrograms V bip and V uni obtained respectively from the bipolar ventricular channel ( FIG. 2 a ) and the unipolar ventricular channel ( FIG. 2 b ) according to the configuration shown in FIG. 1 .
After these EGM signals are collected in the time domain, one of the EGM signals is traced with respect to the other. FIG. 3 shows an exemplary relative tracing characteristic of the EGM signals, referred to as a “cardiac loop” or “vectogram” (VGM). It should be understood that the vectogram VGM is distinguished from the “vectocardiogram” VCG that is obtained from external electrocardiogram ECG signals, and not from endocardial EGM signals.
The VGM is therefore representative of a heartbeat in a non-temporal space. It may be unnecessary to analyze the entire beat because the analysis of a significant fraction of the beat (typically the one centered on or about the corresponding QRS complex) is generally sufficient to detect an evoked wave.
More specifically, the beat that follows each stimulation pulse is isolated by a fixed window, for example, a window of a 100 ms width (corresponding to 100 points for a sampling frequency of 1000 Hz) shifted by 10 ms from the moment of the stimulation. The typical value of 100 ms allows for good isolation of the QRS complex to analyze its morphology, without including much surrounding noise, said noise corresponding to the baseline wave after the QRS period ends. The beats are simultaneously recorded on the ventricular bipolar channel (V bip ) and the ventricular unipolar channel (V uni ). The fraction of each of these beats contained within the window is displayed as a vectogram in a two-dimensional plane consisting of the bipolar channel in abscissa and the unipolar channel in ordinate. It should be understood that in this case the corresponding vectogram may not be a closed loop because it is only a part of the complete cardiac loop, i.e., the QRS complex isolated inside the window.
According to one embodiment, the present invention is directed to performing a capture test for detecting an evoked wave, by analyzing the vectogram. This analysis does not involve any temporal parameter. Instead, it involves measuring a level of capture (e.g., total capture, fusion, absence of capture) of the cavity or cavities stimulated by the device by:
ensuring that the therapy has been delivered on the different stimulated sites, particularly in the case of a CRT therapy in which it is essential that both ventricles are stimulated together;
assessing how the therapy has been delivered, for the purpose of patient monitoring especially if it is desirable to know if, by the application of optimized stimulation delays on hemodynamics characteristics of the patient, the optimization produces an effective capture or induces a fusion situation;
adapting the stimulation energy to be at the minimum level necessary, to reduce the energy consumption of the device and therefore increase its lifespan;
if necessary, adapting the pacing intervals.
Measuring a level of capture in accordance with the present invention may be done cycle by cycle, with an adjustment (or not) of the stimulation energy or the pacing intervals (e.g., atrioventricular delay (AVD) and/or interventricular delay (VVD)), depending on the stimulation response. These potential adjustments may be made at regular intervals, e.g., every six hours.
For a multisite device, in accordance with one embodiment of the present invention the presence of a capture is tested simultaneously on all stimulation sites. This is in contrast to known techniques that require ensuring a presence of a capture on each stimulated site, a capture measurement made separately at each programmed stimulation site.
According to one embodiment, the analysis of the vectogram for a capture test is an intrinsic analysis of the properties of the cardiac loop obtained from a stimulation cardiac cycle. Alternatively, the analysis is a comparative analysis that seeks a correlation between the characteristics of a vectogram of obtained from a stimulation cardiac cycle and the characteristics obtained from one or more reference cardiac cycles with known and determined conditions (e.g., capture, no capture, fusion).
The following description is made in the context of a comparative analysis, but it should be understood that the present invention is not intended to be limited thereto, thus the present invention may be applied to an intrinsic analysis. In this embodiment, the vectogram is characterized by a descriptor based on a tangent vector {right arrow over (e)} T at a point P of the vectogram VGM, as shown in FIG. 4 . It is possible to use other types of descriptors including the angle and a norm of the tangent vector {right arrow over (e)} T .
The tangent vector {right arrow over (e)} T at a given point can be determined by a known technique, especially with a discrete filter that approximates the first derivative, for example, on four points at a sampling frequency of 1000 Hz.
Another descriptor that can be used is the curvature c (i.e., the inverse of the radius r) at a point P of the vectogram, for successively sampled points of the vectogram.
The tangent vector obtained for a stimulated cardiac cycle, i.e., a cardiac cycle to be analyzed, is compared to the corresponding vector of a reference curve that has been previously obtained for a reference cardiac cycle, for the same length, under reference conditions, preferably:
a complete capture on all stimulation sites in response to a stimulation pulse at high energy (i.e., an energy level that is high enough to ensure a capture), or by subsequent confirmation of the capture by a physician in light of the recorded reference cycles;
a partial capture of some of the stimulation sites: i.e., a stimulation pulse at high energy is delivered to selected sites where capture is wanted, with no stimulus or a stimulus at zero volts being delivered to the remaining sites; and
a complete loss of a capture at all stimulation sites: i.e., by a stimulation at zero volts for all stimulation sites.
Any other situation that does not correspond to these three situations is considered a fusion situation.
Reference fusion curves may be created by adapting pacing intervals to spontaneous electrical events present in the considered cavity.
The reference vectograms are obtained either manually, by a test triggered by a practitioner who validates each reference type, or automatically, for the vectograms corresponding to a complete capture, a partial capture, and/or a complete loss of capture. In the latter case, the device regularly performs (e.g., every four hours, weekly . . . ) stimulation tests at high energy or at zero volts on different sites and updates the reference vectograms.
The method to make the comparison between a vectogram of a stimulation cardiac cycle and a reference vectogram will now be explained. This comparison uses a criterion derived from one or more descriptors to assess the degree of similarity or difference between the curves of each cardiac loop: e.g., the area circumscribed by the vectogram, the angle or norm of a tangent vector, the direction of travel, principal component analysis, or any other criterion for describing the morphology and orientation of the curve in the vector space. Depending on the degree of similarity observed, the device diagnoses a total capture, a partial or null capture, the degree of similarity being evaluated against a threshold that may or may not be linear. Preferably, the descriptor is the angle and/or the norm of the tangent vector {right arrow over (e)} T as shown in FIG. 4 .
For a biventricular device, the acquisition and the prior memorization of a reference vectogram is performed by the following sequence of steps:
acquiring a reference cardiac cycle vectogram in a complete biventricular capture;
delivering biventricular pacing pulses over stimulation cardiac cycles (for example, eight cycles) at maximum energy;
acquiring a combined EGM for each of these stimulation cardiac cycles;
averaging the combined EGMs;
calculating a corresponding descriptive criteria; and
storing the descriptive criteria of the complete biventricular capture.
The same technique is used for each type of reference vectogram: a right capture, a left capture, and a complete loss of a right and left capture. To ensure a capture, maximum energy is delivered to the selected site(s); to the contrary, to miss a capture, stimulation pulses are delivered with zero energy to the selected site(s).
Once a reference electrogram is acquired and stored, a capture test on a stimulation cardiac cycle is performed as follows:
stimulating the selected site(s);
acquiring a vectogram on the stimulated cardiac cycle event;
calculating a descriptive criteria of the vectogram so acquired;
comparing the descriptive criteria of the vectogram versus the reference vectogram in the complete biventricular capture.
If any discrepancies are found, a comparison is made with other reference vectograms (e.g., right capture alone, left capture alone), and if a difference still persists, it is determined to be a loss of a capture. At a loss of a capture, a security back-up stimulation of higher energy may be delivered.
The comparison of vectograms between a stimulated cardiac cycle with reference vectogram(s) is made by an algorithm such as those described in EP 2105843 A1 and its counterpart U.S. Pat. Pub. No. 2010/0249626 (assigned to Sorin CRM, previously known as ELA Medical), which describes various techniques for comparative analysis of electrograms in a specific application including a technique for discriminating between ventricular tachycardia and supraventricular tachycardia in a tachycardia classifier. EP 2105843 A1 and its counterpart U.S. Pat. Pub. No. 2010/0249626 are incorporated herein by reference. The vectogram comparison techniques described in EP 2105843 A1 and its counterpart U.S. Pat. Pub. No. 2010/0249626 are readily transferable to the implementation of the present invention, and they may be referred to for more details on the implementation of those vectogram comparison algorithms.
FIGS. 5-11 illustrate exemplary results of a capture test according to the present invention.
FIG. 5 is a representation of a surface electrocardiogram (ECG) captured during an episode showing different situations such as a capture, a loss of a capture, a fusion, etc., each being representative of a typical situation encountered in real conditions.
FIGS. 6-11 show the electrocardiogram of FIG. 5 . The left plot is the corresponding vectogram. The position of a descriptor X, evaluated by an characterization algorithm, is shown on the right plot in comparison with a decision boundary F between a capture and a loss of capture.
In this example, the retained criterion is a dual descriptor X combining first (horizontal axis), the value of the correlation coefficient between the norms of the respective tangent vectors of the analyzed vectogram and reference vectogram, and second (vertical axis), the average angle between the same tangent vectors respectively. Using these criteria, a field corresponding to the decision boundary F is defined such that if the dual descriptor X is within this area, it is considered to be a capture and if not, it is considered to be a loss of a capture. The area is represented by a rectangle corresponding to the criteria, for example, correlation coefficient >0.5 and average angle <70°.
FIGS. 6 and 7 correspond to a situation of a complete capture of stimulated beats (beats No. 84 and 88 of the ECG in FIG. 5 ). It shows that the VGM has a regular shape, just before a loss of a capture (e.g., at beat No. 89). The dual descriptor X is situated within the decision boundary F.
FIG. 8 illustrates a stimulated beat with a loss of a capture, corresponding to beat No. 89 of the ECG shown in FIG. 5 . With the absence of a capture, the VGM is reduced to a very small loop. It is determined that a descriptor X is located substantially outside of the decision boundary F, including a correlation coefficient represented by the norms of tangent vectors being close to zero.
FIG. 9 shows a situation in which the absence of a capture is linked to the emergence of a fusion, corresponding to beat No's. 90 and 91 of the ECG shown in FIG. 5 . In this situation ( FIG. 9 ), it is shown that the shape of the vectogram is quite different from that of stimulation with a capture ( FIGS. 6 and 7 ) and that of stimulation without a capture ( FIG. 8 ). The analysis reveals, despite a relatively high correlation coefficient between the norms of tangent vectors, an average angle between the vectors significantly exceeds a prescribed threshold. The algorithm in this case determines that a loss of capture is only apparent, since it does not result from a natural increase in the pacing threshold, but is simply masked by the occurrence of a fusion.
The distinction between a proven loss of a capture and a fusion situation may be obtained, for example, by applying a criterion related to the area circumscribed by the vectogram. This area may be significantly larger in the case of a fusion ( FIG. 9 ) than in the case of a true loss of a capture ( FIG. 8 ).
FIG. 10 illustrates a case of a beat in spontaneous rhythm, corresponding to beat No. 99 and following of the ECG shown in FIG. 5 . In this case, the algorithm inhibits any capture threshold test because it is meaningless.
FIG. 11 illustrates a situation after disappearance of a spontaneous rhythm and resumption of stimulation and a capture, corresponding to beat No. 107 and following of the ECG shown in FIG. 5 . The vectograms and descriptors X are somewhat similar to stimulation with a capture as shown in FIGS. 6 and 7 .
According to one embodiment, a capture test according to the present invention is used to determine a pacing threshold. To this end, the device applies stimulation pacing pulses of decreasing energy to a cardiac cavity, and monitors a presence or absence of an evoked wave according to the monitoring technique described above. If a capture is confirmed at a given energy, the device considers that the stimulation is effective. The energy applied at the next cycle is reduced, typically by a fixed amplitude step, for example, 0.25 V. Once a capture is lost in this cycle, the device considers that the stimulation is ineffective, therefore determines that the pacing threshold is higher than the latest value applied. In this case, a back-up stimulation at the maximum amplitude may be applied to cause a contraction of the cardiac cavity.
The pacing threshold thus determined may be stored in a memory of the device, transmitted to a data collection center, or used by the device to change the stimulation amplitude for pacing.
For further details on algorithms for adjusting the stimulation amplitude from successive capture tests, one is referred in particular to EP 1080744 A1 and its counterpart U.S. Pat. No. 6,487,451 (Sorin CRM, previously known as ELA Medical), which describes various techniques for measuring the pacing threshold, for controlling consistency of measures and for adjustment of the width and amplitude of stimulation pulses, all of which are incorporated herein by reference. The corresponding algorithms may be implemented in a capture test performed by a vectogram analysis according to the teachings of the present invention.
Techniques other than those described above can also be implemented to analyze a vectogram and determine a presence or absence of a capture. In one particular embodiment, a principal component analysis (“PCA”) may be applied to a vectogram. The PCA analysis is a technique in itself known that deduces the electrical axis of a heart and provides a general indicator of the direction taken by the electric wave when it propagates through the ventricle(s). The path with the highest dynamics is the one with the highest projection, the corresponding direction being called the “main axis.” The main axis is supplemented by two other axes called “secondary axes”, perpendicular to each other and to the main axis. In the present case, a two-dimensional analysis is performed, thus only one of the two secondary axes is considered. PCA is described in, for example, J. Shlens, “A Tutorial on Principal Component Analysis”, 25 Mar. 2003, Version 1.
According to one embodiment, the PCA allows one to define the orthonormal basis to represent the vectogram V uni =f (V bip ). If S 1 and S 2 designate signals on respective channels V bip and V uni representing a heartbeat, each signal consists of N points represented in the base of the electrodes (V bip , V uni ) in which the coordinates of the ith point is (S 1 (i), S 2 (i). For the principal component analysis, an assumption is made that these N points form an ellipse, and the axes of the ellipse that forms the PCA basis and the length of each axis are calculated. Using these two values, the main direction of the ellipse (i.e., the direction of spreading of the vectogram) is identified and, its size and area are quantified. The coordinates of these N points in the PCA base (P 1 , P 2 ) is sought by calculating a transition matrix from the base (V bip , V uni ) to the PCA base (P 1 , P 2 ).
According to one embodiment, the principal component analysis extracts various parameters including the following descriptors:
the main axis that is the eigenvector of the covariance matrix associated with the largest eigenvalue;
the secondary axis that is the eigenvector of the covariance matrix associated with the second eigenvalue;
the size of the main axis and the secondary axis; and
the angles between the two axes with respect to the axis OX, based on calculations of sines and cosines.
To extract the morphology of the vectograms from these PCA descriptors, each signal is projected on its own base. The corresponding one-dimensional signal is observed in the time domain and the forms are compared in order to detect a presence or absence of an evoked wave or to confirm indeterminacy because of a fusion situation.
One skilled in the art will appreciate that the present invention may be practiced by other than the embodiments described above, which are provided for purposes of illustration, and not of limitation. | Performing a capture test on a stimulated cardiac cycle based on the analysis of a cardiac vectogram using an active medical device including circuits and control logic for delivering electrical stimulation pulses to a heart chamber; collecting electrical activity of the heart chamber and producing two distinct temporal components (V bip , V uni ) from two distinct intracardiac electrogram EGM signals from the heart chamber. The capture test detects an occurrence of a depolarization wave induced by the stimulation of the heart chamber, and determines a two-dimensional non-temporal characteristic (VGM) representative of the stimulated cardiac cycle, from the variation of one of the temporal components (V uni ) versus the other temporal component (V bip ). A bi-dimensional analysis delivers at least one descriptor parameter of the two-dimensional non-temporal characteristic, and determines a presence or loss of a capture based on the at least one descriptor parameter. | 0 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority from U.S. Provisional Application Ser. No. 60,267,438, filed Feb. 9, 2001.
BACKGROUND OF THE INVENTION
[0002] Plants are sources of drugs and other useful materials. These materials are the products of plant metabolism, which is the total collection of biochemical pathways within a plant. Genes encode the enzymes that function in plant metabolic pathways and regulatory genes, in turn, control the activity of metabolic pathways by directing the expression of entire sets of enzyme-encoding genes specific to a given pathway. It follows that methods to identify any genes that govern the production of such plant metabolites are critical to enable the manipulation of pathways for elevating product yield and for increasing the diversity of these substances. The present invention provides methods to identify, in a relatively efficient and reliable manner, plant-genetic material required for production of metabolites which would ordinarily be difficult to identify. The invention is the realization of the successful merging of two distinct methodologies: activation-tagging mutagenesis and high-throughput screening. The present unique combination of these methodologies results in the ability to assign metabolic functionality to plant genes involved in the production of biologically active molecules and to create a means of compound discovery based on the genetic capabilities of a plant or group of plants.
[0003] This invention is therefore based on the following technical developments: 1) methodology which enables propagation and maintenance of mutagenized “microcallus” material in a “library” format in such a way as to permit large scale screening; 2) procedures to nondestructively sample the microcallus; 3) methodology to screen the microcallus sample in a miniaturized high throughput pharmacological screen.
[0004] Therefore, the invention is in the field of plant molecular biology, in particular, genetic methods for production and identification of useful compounds.
[0005] Identification of plant genes via activation mutagenesis has been used with success previous to the present invention. This technique involves incorporation of enhancer sequences from a plant viral promoter at random places into the plant genome via Agrobacterium mediated T-DNA transfer. When applied to single plant cells in culture, the resulting mutants are identified by positive selection, and the gene(s) in the vicinity of the T-DNA insert is cloned. However, elucidation of the effects of mutations in regulatory regions, or downstream effects from a mutagenized gene, are very difficult in cases where no positive selection schemes can be employed. Even with classical activation mutagenesis methods, Walden et al. conclude “this process is involved, labor-intensive and can only be effectively carried out with relatively limited numbers of segregating individuals.” Walden et al., Methods in Cell Biology, 49:455-469 (1995).
[0006] High-throughput screening has also been utilized in the pharmaceutical field.
[0007] Citation of the above document is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on subjective characterization of information available to the applicant and does not constitute any admission as to the accuracy of the dates or contents of these documents.
SUMMARY OF THE INVENTION
[0008] The present invention provides a method for identifying plant genetic material whose actions cause increased production of a metabolite or metabolites of interest in plant cells, said method comprising causing random integration into the plant genome in plant protoplasts of at least one enhancer-containing T-DNA genetic element harboring sequences to enable bacterial replication and selection; growing said protoplasts to the stage of callus cultures; sampling said callus cultures in such a manner as to retain viability of said clonal cultures; analyzing said samples to identify the callus cultures producing metabolite or metabolites of interest; and isolating and identifying the plant genetic material, the action of which has been stimulated by the enhancer-containing T-DNA genetic element in the sampled, identified callus cultures.
[0009] Preferred is a method wherein the plant genetic material, which is identified, is a plant gene whose action causes a plant cell to produce an increased amount of a metabolite or metabolites of interest. More preferred is a method wherein the plant genetic material, which is identified, is a regulatory gene. Also preferred is a method wherein the analysis of callus cultures detects the production of metabolites of interest having pharmacological properties. Most preferred is a method wherein said metabolites are detected via at least one radioligand displacement assay.
[0010] Methods of the present invention, which comprises the further step of propagating at least one callus, culture producing said metabolite or metabolites. Most preferred are methods, which involve a tobacco plant.
[0011] Most preferred are methods wherein said enhancer sequence is a plant viral enhancer sequence.
[0012] Most preferred are methods wherein said enhancer sequence is delivered to the plant via Agrobacterium tumefaciens.
[0013] Preferred are methods wherein said radioligand is a nicotinic acetylcholine agonist or a nicotinic acetylcholine antagonist. Most preferred is the radioligand [ 3 H]-epibatidine or [ 3 H]-methyllycaconitine.
[0014] The present invention provides a method for identifying plant genetic material whose actions cause increased production of a metabolite or metabolites of interest in plant cells, said method comprising co-cultivating plant protoplasts with Agrobacterium cells harboring an activation-tagging vector; embedding the plant protoplasts in agarose; transferring the embedded protoplasts to a larger surface area to allow further growth; excising individual, clonal calli resulting from said growth; partially macerating individual samples of tissue from said calli in multi-welled microtiter plates to establish a sample clonal library; removing supernatant liquid fractions from said macerated samples; subjecting said supernatant fractions to radioligand displacement assays to determine if metabolites in the liquid supernatant displace the radioligand; adding growth medium to remaining tissues in the microtiter plate; and isolating and identifying the plant genetic material, the action of which has been stimulated by the action of the activation-tagging vector, from the callus cultures which generated ligand displacement in the radioligand displacement assay.
[0015] The present invention provides methods for detecting a metabolite in a plant comprising: causing integration of at least one enhancer-containing T-DNA in a plant protoplast; growing said protoplast to the stage of callus culture; sampling said callus in such a manner so as to retain viability of said callus culture; and detecting a metabolite of interest. Those methods wherein said metabolite is detected via at least one radioligand displacement assay are preferred. More preferred are methods as described which further comprise the step of continuous propagation of at least one stably transformed culture.
[0016] In the present invention, methods wherein the plant is a tobacco plant are preferred. Those methods wherein said enhancer sequence is a plant viral enhancer sequence are also preferred. Most preferred are those methods, which utilize a viral enchancer sequence, delivered via Agrobacterium tumefaciens.
[0017] When the detection means is a radioligand displacement assay, methods wherein said radioligand is a nicotinic acetylcholine agonist or a nicotinic acetylcholine antagonist are preferred. In particular, those methods wherein said radioligand is [ 3 H]-epibatidine are more preferred.
[0018] Also provided are methods for detecting a metabolite in a plant comprising: co-cultivating protoplasts with Agrobacterial cells harboring an activation tagging vector; embedding the protoplasts in agarose; transferring protoplasts to a larger surface area to allow further growth; excising individual calli tissue; partially macerating individual calli tissue in a multi-welled microtitre plate; establishing a viable callus library; removing liquid supernatant; adding growth medium to tissues remaining in the microtitre plate; and conducting radioligand displacement assay to determine if a metabolite displaces the radioligand.
[0019] For the purposes of the present invention, the term “a” or “an” entity refers to one or more of that entity; for example, “a metabolite” or “a radioligand” or “an assay” refers to one or more of those compounds or at least one compound. As such, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably. Furthermore, a compound “selected from the group consisting of” refers to one or more of the compounds in the list that follows, including mixtures (i.e. combinations) of two or more of the compounds. According to the present invention, an isolated or biologically pure, protein or nucleic acid molecule is a compound that has been removed from its natural milieu. As such, “isolated” and “biologically pure” do not necessarily reflect the extent to which the compound has been purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using molecular biology techniques or can be produced by chemical synthesis.
[0020] These and other objects of the invention will be more fully understood from the following description of the invention, the referenced drawings attached hereto and the claims appended hereto.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The present invention will become more fully understood from the detailed description given herein below, and the accompanying drawing, which is given by way of illustration only, and thus is not limitative of the present invention.
[0022] FIG. 1 shows a protoplast isolation and transformation flowchart.
[0023] FIGS. 2 A-B. FIG. 2A shows a photograph taken through a bright field microscope (40× magnification) of freshly isolated protoplasts from tobacco leaves two days after isolation. At seven days the protoplasts are co-cultivated with Agrobacterium tumefacians (GV3101) to conduct transformation resulting in the insertion of the activation-tagging T-DNA. FIG. 2B shows a photograph of a cluster of clonal cells after several steps of incubation, washing, antibiotic selection and embedding of the multiplied protoplasts. The clusters of clonal cells become macroscopic (referred to as “microcalli”) as shown in the dish in the right of the figure. Diameter of the petri dish shown is 150 mm.
[0024] FIGS. 3 A-B. FIG. 3A shows a photograph of a plate of surface-embedded calli after propagation for approximately five weeks (compare to microcalli in FIG. 2 ). This is an example of the type of density used of mutagenized material used for sampling to conduct the pharmacological assay. FIG. 3B shows a photograph of a standard 48-well plate showing regrowth of the mutagenized callus tissue after sampling and extract preparation which took place in the same wells approximately three weeks previously.
[0025] FIG. 4 shows a photograph of an “activation-tagging mutagenesis” (ATM) library that harbors over 1300 individual mutant clones. This illustrates the workability of establishing a viable “master” library developed using the methods described herein.
[0026] FIGS. 5 A-B. FIG. 5A shows a photograph of an individual screen-positive callus clone that had been physically divided and propagated as approximately 20 clonal pieces of separate callus tissue. This is used for verification of the pharmacological phenotype, as each “daughter” individual is expected to have the same displacement activity as the “parental” tissue. FIG. 5B shows that such pieces are also used for plant regeneration from the calli (right half).
[0027] FIG. 6 shows a photograph of plants growing on synthetic media in Magenta boxes that had been regenerated from calli scored as positive in the screen.
[0028] FIG. 7 shows a graph of displacement data of a population of mutant (“ATM”) and wild type (“no ATM”) using 3 H-epibatidine as the ligand in the pharmacological screen. Non-mutated samples show average displacement of approximately 3% whereas the ATM population indicates two individuals with greater than 30 and 70% displacement activity, respectively. Note the log scale on the X-axis. These data are typical for many thousands of assays run to date.
[0029] FIG. 8 shows a summary of activities of positive mutant lines and wild-type controls expressed in terms of “nicotine displacement activity” or approximately equivalent to a given concentration of nicotine in the displacement assay. Note log scale on the Y-axis. The upper clone represents activity 10,000 times higher than that found in wild-type calli. This line is no. 7309. The line with the lowest activity (and regenerated and analyzed at the whole plant level) is no. 1402.
[0030] FIGS. 9 A-D. FIGS. 9A and 9B show initial activity characterization by displacement activity of line no. 1402 callus (See discussion text). The pure anabasine alkaoid and pure nicotine alkaloid are used here to standardize the system. FIGS. 9C and 9D show characterization of crude callus extracts performed in the same way as that in A. This difference in the shape of the profiles indicates that the activity in the 1402 extract is distinct from wildtype and is most likely a compound other than nicotine.
[0031] FIG. 10 shows a summary of the molecular characterization of cell line 1402.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention provides a method for identifying plant genetic material whose actions cause increased production of a metabolite or metabolites of interest in plant cells, said method comprising causing random or directed integration into the plant genome in plant protoplasts of at least one enhancer-containing T-DNA genetic element harboring sequences to enable bacterial replication and selection; growing said protoplasts to the stage of callus cultures; sampling said callus cultures in such a manner as to retain viability of said clonal cultures; analyzing said samples to identify the callus cultures producing metabolite or metabolites of interest; and isolating and identifying the plant genetic material, the action of which has been stimulated by the enhancer-containing T-DNA genetic element in the sampled, identified callus cultures.
[0033] Preferred is a method wherein the plant genetic material, which is identified, is a plant gene whose action causes a plant cell to produce an increased amount of a metabolite or metabolites of interest. More preferred is a method wherein the plant genetic material, which is identified, is a regulatory gene. Also preferred is a method wherein the analysis of callus cultures detects the production of metabolites of interest having pharmacological properties. Most preferred is a method wherein said metabolites are detected via at least one radioligand displacement assay.
[0034] Methods of the present invention may also comprise the further step of propagating at least one callus culture producing said metabolite or metabolites. Most preferred are methods, which involve a tobacco plant and wherein said enhancer sequence is a plant viral enhancer sequence.
[0035] Most preferred are methods wherein said enhancer sequence is delivered to the plant via Agrobacterium tumefaciens.
[0036] Preferred are methods wherein said radioligand is a nicotinic acetylcholine agonist or a nicotinic acetylcholine antagonist. Most preferred is the radioligand [ 3 H]-epibatidine or [ 3 H]-methyllycaconitine.
[0037] In a preferred embodiment, the present invention provides a method for identifying plant genetic material whose actions cause increased production of a metabolite or metabolites of interest in plant cells, said method comprising co-cultivating plant protoplasts with Agrobacterium cells harboring an activation-tagging vector; embedding the plant protoplasts in agarose; transferring the embedded protoplasts to a larger surface area to allow further growth; excising individual, clonal calli resulting from said growth; partially macerating individual samples of tissue from said calli in multi-welled microtiter plates to establish a sample clonal library; removing supernatant liquid fractions from said macerated samples; subjecting said supernatant fractions to radioligand displacement assays to determine if metabolites in the liquid supernatant displace the radioligand; adding growth medium to remaining tissues in the microtiter plate; and isolating and identifying the plant genetic material, the action of which has been stimulated by the action of the activation-tagging vector, from the callus cultures which generated ligand displacement in the radioligand displacement assay.
[0038] The present invention provides methods for detecting a metabolite in a plant comprising: causing integration of at least one enhancer-containing T-DNA in a plant protoplast; growing said protoplast to the stage of callus culture; sampling said callus in such a manner so as to retain viability of said callus culture; and detecting a metabolite of interest in the event that the metabolite of interest is present. Those methods wherein said metabolite is detected via at least one radioligand displacement assay are preferred. More preferred are methods as described which further comprise the step of propagating at least one daughter culture.
[0039] In the present invention, methods wherein the plant is a tobacco plant are preferred. Those methods wherein said enhancer sequence is a plant viral enhancer sequence are also preferred. Most preferred are those methods, which utilize a viral enhancer sequence, delivered via Agrobacterium tumefaciens.
[0040] When the detection means is a radioligand displacement assay, methods wherein said radioligand is a nicotinic acetylcholine agonist or a nicotinic acetylcholine antagonist are preferred. In particular, those methods wherein said radioligand is [ 3 H]-epibatidine are more preferred.
[0041] Also provided are methods for detecting a metabolite in a plant comprising: co-cultivation of protoplasts with Agrobacterial cells harboring an activation-tagging vector; embedding the protoplasts in agarose; transferring protoplasts to a larger surface area to allow further growth; excising individual calli tissue; partially macerating individual calli tissue in multi-welled microtitre plate; removing liquid supernatant; conducting radioligand displacement assay to determine if a metabolite displaces the radioligand; and adding growth medium to tissues remaining in the microtitre plate.
[0042] Other methods of transformation include: biolistic bombardment and polyethylene glycol-mediated DNA uptake. Plant cells may also be transformed with other sequences with the ability to cause the activation of genes such as enhancer sequences from different promoters and sequences encoding transcription factors that can function to activate gene expression or from the introduction of populations of genes in order to determine their impact on metabolite production.
[0043] The supernatant may be assayed for products of secondary metabolism with radiolabelled ligand binding assays. Preferred ligands are acetylcholine agonists and antagonists. More preferred are 3 H-methyllycaconitine, 3 H-spermidine. Most preferred is 3 H-epibatidine.
[0044] Preferred enhancer sequences include tissue-specific promoter enhancers and temporal-specific promoter enhancers. Most preferred is a constitutive plant viral promoter active in plant cells and undifferentiated callus tissue.
[0045] Enhancer sequences may be contained within vectors enabling the transfer of said sequences into the plant genome.
[0046] The term “antagonist” is intended to refer to that which is understood in the art. In general, the term refers to a substance that interferes with receptor function. Antagonists are of two types: competitive and non-competitive. A competitive antagonist (or competitive blocker) competes with the naturally occurring ligand for the same binding site. In the case of acetylcholine, an example of such an antagonist is bungarotoxin. A non-competitive antagonist or blocker inactivates the functioning of the receptor by binding to a site other than the acetylcholine-binding site.
[0047] Specifically, the radiolabeled ligand may bind nicotinic acetylcholine receptors. The preferred radiolabeled ligand is [ 3 H]-epibatidine, a nicotinic cholinergic receptor agonist. Cholinergic receptors play an important role in the functioning of muscles, organs and generally in the central nervous system. There are also complex interactions between cholinergic receptors and the function of receptors of other neurotransmitters such as dopamine, serotonin and catecholamines.
[0048] Acetylcholine (ACh) serves as the neurotransmitter at all autonomic ganglia, at the postganglionic parasympathetic nerve endings, and at the postganglionic sympathetic nerve endings innervating the eccrine sweat glands. Different receptors for ACh exist on the postganglionic neurons within the autonomic ganglia and at the postjunctional autonomic effector sites. Those within the autonomic ganglia and adrenal medulla are stimulated predominantly by nicotine and are known as nicotinic receptors. Those on autonomic effector cells are stimulated primarily by the alkaloid muscarine and are known as muscarinic receptors.
[0049] The nicotinic receptors of autonomic ganglia and skeletal muscle are not homogenous because they can be blocked by different antagonists. For example, d-tubocurarine effectively blocks nicotinic response in skeletal muscle, whereas hexamethonium and mecamylamine are more effective in blocking nicotinic responses in autonomic ganglia. The nicotinic cholinergic receptors are named the NM and NN receptors, respectively.
[0050] Acetylcholine receptors at any or all of the above mentioned locations may be assayed by radiolabeled ligand binding assays in the present invention.
EXAMPLES
[0051] The following examples illustrate the present invention without, however, limiting it. It is to be noted that the Examples include a number of molecular biology, microbiology and biochemistry techniques considered to be known to those skilled in the art. Disclosure of such techniques can be found, for example, in Sambrook et al., ibid., and related references.
Example 1
Leaf Protoplast Preparation
[0052] Growing Conditions: Tobacco plants ( Nicotiana tabacum SR1) were grown in sterile culture on MS media (One liter contains: 4.3 g MS basal salt mixture (Sigma), 0.5 g MES (2-[N-Morpholino]ethanesulfonic acid) (Sigma) for buffering, 10 g sucrose. The pH was adjusted to 5.8 with KOH. Media was solidified by adding Phytagel (Sigma) to 0.2%. Sterilization was by autoclaving in Magenta boxes. Magenta boxes contained lids with a vent provided by a 2 cm diameter hole covered with a single 0.45 μm pore size filter disc (Type HA, Millipore) and two pieces of “Micropore” surgical tape (3M). Plants grown for four to five weeks at 24° C. under approximately 110 μmol m −2 s −1 light intensity were used as a source of leaf material.
[0053] Leaf Preparation Procedure: Under sterile conditions, leaf tissue was removed from the plants and cut into approximately 1 cm 2 pieces using a sharp scalpel or razor blade. Approximately 5 g of leaf material was added to 20 ml filter-sterilized enzyme solution (1.5% cellulase, 0.5% pectinase, (Sigma)) in K3 plant culture media. K3 media contains 10 ml per liter of the following stock solutions: NaH 2 PO 4 (3 g/200 ml); CaCl 2 (18 g/200 ml); (NH 4 )2SO 4 (2.7 g/200 ml); MgSO 4 (5 g/200 ml); KNO 3 , (5 g/200 ml); NH 4 NO 3 (2.7 g/200 ml). Added directly to one liter of K3 media was inositol, 100 mg; xylose, 250 mg; and MES buffer, 2.0 g. In addition, K3 media also contained 10 ml per liter of a micronutrients solution and 1.0 ml per liter of a vitamin solution. The micronutrient solution was prepared by dissolving the following into one liter H 2 O: H 3 BO 3 , 6.2 g; MnSO 4 .4H 2 O, 22.3 g; ZnSO 4 .7H 2 O, 10.6 g; KI, 0.88 g; NaMoO 4 .2H 2 O, 0.25 g; CuSO 4 .5H 2 O, 0.025 g; and CoCl 2 .6H 2 O, 0.025 g. The vitamin stock solution was made by dissolving the following in 200 ml H 2 O: glycine, 400 mg; nicotinic acid, 400 mg; pyridoxin-HCl, 400 mg; thiamin-HCl, 20 mg. 5.0 ml of an Fe-EDTA solution was added from a stock, prepared by dissolving 5.57 g FeSO 4 .7H 2 O and 7.45 g Na 2 EDTA. To prepare K3 containing 0.4M sucrose, 136.92 g sucrose was added. 0.1M sucrose K3 media contains 34.23 g sucrose.
[0054] Protoplast Isolation: Leaves were digested overnight (no more than 19 h) by incubation at 26° C. in the dark. The following day, 250 ml beakers were mixed for 10 min on an orbital shaker (approximately 40 rpm), and the solution was passed through a 105 μm mesh sieve by pouring through a filtration apparatus. This was divided into 17×100 mm sterile plastic centrifuge tubes, which were then centrifuged at 2000 rpm in a swinging bucket rotor for 6 minutes at room temperature. Following the centrifugation, protoplasts, which float at the top of the media in the centrifuge tube, were removed from the pelleted debris by aspirating the lower contents of the tube. Protoplasts were washed by addition of 0.4M K3 media and recentrifuged. The protoplasts from these were pooled into one or two single screw cap sterile tubes. After adjusting protoplast cell density, cells were further incubated as 10 ml cultures in standard (60 mm) petri dishes. Dishes were wrapped with parafilm for incubation at 26° C. in the dark for two days.
Example 2
Activation-Tagging Mutagenesis: Protoplast Transformation
[0055] Materials: Agrobacterium tumefaciens strain GV3101, is described in Koncz and Schell, Mol Gen Genet 204:383-396. 1986, which is incorporated herein by reference in its entirety. The plasmid pPCVICEn4HPT containing the T-DNA tag was used. It was made as described in Fritze and Walden, Methods in Molecular Biology 44:281-294. 1995 and in Walden, Fritze and Harling, Methods in Cell Biology 49:455-469. 1995, which references are incorporated by reference herein in their entirety. pPCVICEn4HPT is derived from the pPCV vector (Koncz and Schell, Mol Gen. Genet 213:285-290, 1986) in which the T-DNA contains four tandemly repeated enhancer elements derived from the 35S RNA promoter of the Cauliflower mosaic virus, a hygromycin resistance marker for protoplast and plant selection and an E. coli plasmid sequence that contains an E. coli origin of replication and an ampicillin resistance gene.
[0056] Procedure: Transformation with the activator T-DNA tag was performed by co-cultivation with Agrobacterium tumefaciens harboring the T-DNA tagging element (strain GV3101, plasmid pPCVICEn4HPT). Freshly grown bacterial cells were added directly to six to eight day-old protoplast cultures in a ratio of 100:1 bacteria to protoplast cells. Co-cultivation was conducted at 26° C. in the dark for 48 hr. At the end of the incubation period, protoplasts were washed three times in W5 media by centrifugation in a swing-out rotor at room temperature. W5 media contained NaCl, 9.0 g/liter; CaCl 2 .2H 2 O, 18.38 g/liter; KCl, 0.373 g/liter; and glucose, 0.90 g/liter. The pH was adjusted to 5.6-6.0, with HCl. The medium was sterilized by autoclavation. Protoplasts were then resuspended in 0.4M K3 media to produce a final concentration of 106 protoplasts per ml. One ml of protoplast suspension was transferred to a standard (100 mm) petri dish and cultured in a final volume of 10 ml of 0.4 M K3 media containing antibiotic selection against Agrobacterium cells (cefotaxime 500 μg/ml) as well as the presence of hormones to maintain cells in a dedifferentiated state (auxin (NAA) 1.0 μg/ml and cytokinin (kinetin 0.2 μg/ml). Hygromycin (15 μg/ml) was also added to the incubation media to select for the protoplasts transformed with the activation-tagging vector.
Example 3
Propagation of Protoplasts and Calli
[0057] Culturing of Protoplasts: Transformed cells were embedded in 0.3% low gelling temperature agarose in 100 mm petri dishes. K4 media was then added to the petri dishes containing the soft agarose embedded microcalli. Following protoplast embedding, the K4 media was reduced in osmolarity in 0.1M increments, (starting at 0.4M sucrose, ˜580 mOsm) on a weekly basis by changing the liquid phase media over the soft agarose embedded cells. “K4” media contains 10 ml per liter of the following stock solutions: NaH 2 PO 4 (3 g/200 ml); CaCl 2 (18 g/200 ml); KCl (58.8 g/200 ml); glutamine (17.54 g/200 ml); asparagine (5.32 g/200 ml); arginine (3.52 g/200 ml); (NH 4 ) 2 SO 4 (2.7 g/200 ml); MgSO 4 (5 g/200 ml). Added directly to one liter of K4 media is inositol, 100 mg; xylose, 250 mg, and MES buffer, 2.0 g. In addition, K4 media also contains 10 ml per liter of a micronutrients solution and 1.0 ml per liter of a vitamin solution with the same composition as that used for the K3 media as well as 5.0 ml per liter of a Fe-EDTA solution and sucrose to 0.4 or 0.1M.
[0058] Transfer to Larger Areas for Additional Growth: Once microcalli were established (usually four to five weeks), they were released from the agarose by gentle maceration and dilution. Microcalli were further cultured by “surface plating” the transformed tissue onto 0.1M K4 media solidified with 0.8% agar in 150 mm dishes. The released microcalli were “re-embedded” in low gelling-temperature agarose and plated to the surface of solidified K4 media agar plates. This results in a 2 mm thick monolayer of embedded microcalli on the plate such that further growth forms an upward protrusion of the calli large enough for physical sampling. Dilutions were empirically made to adjust the number of individual microcalli on each dish to densities sufficient to enable continued growth of the microcalli up to the stage of sampling.
Example 4
Nondestructive Sampling and Library Establishment
[0059] The three steps of sampling, establishment of a viable working library and extract preparation of surface-grown macrocalli are combined into a single process to maximize throughput. Surface-embedded microcalli grown to sizes ranging from approximately 0.5 cm to 1.5 cm (“macrocalli”) are deemed sufficient for sampling and establishing the master library. Under sterile conditions, petri dishes containing the surface-grown macrocalli are opened and macrocalli are individually sampled using ring forceps (4.8 mm inner ring diameter, Fine Science Tools, Inc. Foster City, Calif.). This ring size enables a section of tissue weighing approximately 50 mg to be sampled. The removed tissue section is placed into the numbered well of a 48-well microtiter plate containing 0.4 ml fresh K4 media including required growth regulators. Once the 48-well dishes are loaded, a maceration pestle, custom made of Delrin™ plastic (12 cm in length×1-cm dia.) with the maceration end machined to a semi-circle (one-half of the 1-cm circular end) is used to partially macerate the tissue in the well of the plate. Partial maceration is conducted to break open a sufficient proportion of the cells within the 50 mg piece of callus tissue to release the cellular contents for analysis and to maintain an amount of this tissue (generally about ⅓ of each callus section) in the well to enable continued growth and recovery. Because the 3 H-epibatidine displacement assay (below) can be used with K4 callus growth media, recovery and growth of the microcalli within the wells is virtually 100%. Additional media is added to each well to increase the volume to 1.0 ml. 0.65 ml of the 1.0 ml volume of cellular fluid resulting from the partial callus maceration in each well is removed and transferred to standard 1.5 ml micro-centrifuge tubes. After sealing the lids of the 48-well dishes with surgical tape (3M), they are placed in a lighted 26° C. incubator for recovery and growth. The growing calli within the 48-well dishes establishes the working library.
Example 5
Extract Preparation
[0060] Micro-centrifuge tubes containing 0.65 ml of cell tissue fluid and K4 growth media are centrifuged at 13,000 rpm for ten minutes at room temperature. The supernatant is removed and placed into clean micro-centrifuge tubes and stored at −80° C. until used for displacement assays.
Example 6
[ 3 H]-epibatidine Screening
[0061] Tissue Preparation: Crude membrane preparations from brains of male adult Sprague-Dawley rats were prepared from methods modified after Houghtling R A, Davila-Garcia M I, Kellar K J, Mol Pharmacol 48(2):280-7, 1995, which reference is incorporated by reference herein in its entirety. Following sacrifice by rapid decapitation, the frontal cortex and hippocampus were rapidly dissected and homogenized in ice-cold sucrose buffer (0.32 M sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride, 0.01% wt/vol sodium azide; pH adjusted to 7.4) using a polytron tissue homogenizer. The homogenate was centrifuged at 1000×g at 4° C. for 10 min. The pellet was resuspended in sucrose buffer and the centrifugation repeated. The supernatant fractions were combined and the P2 membranes recovered as a pellet after centrifugation 15000×g at 4° C. for 20 min. The pellet was washed twice by resuspension in phosphate buffer (same as above, except 50 mM phosphate substituted for sucrose) and centrifuged at 15000×g at 4° C. for 20 min. The final pellet was resuspended in phosphate buffer. Protein was determined by the BCA Protein Assay kit from Pierce, Rockford Ill. Aliquots were stored at −80° C. until use.
[0062] Preparation of membrane homogenates: Fresh tissue (bovine brain) was procured immediately after euthanasia by exsanguination. Alternatively, standards and replication of results were confirmed in male Sprague-Dawley rat cerebrum homogenates derived from animals sacrificed by rapid decapitation. The preparation of these membranes was identical to bovine homogenates. Frontal cortex was blocked, then placed in ice-cold HEPES buffer (50 mM) for 10 min. Tissue was weighed, and 4 ml of “incubation” buffer was added. Tissue was homogenized in a 30 ml vol. glass hand-held tissue homogenizer with a teflon pestle. The crude homogenate was washed 3 times by centrifugation at 35,000×G for 20 min at 4° C. After each centrifugation, the homogenate was re-suspended in fresh, cold buffer. Following final washing, 1 ml aliquots were snap-frozen in liquid nitrogen and stored in a −20° C. freezer until use. Prior to use in binding assays, total protein concentration was determined using a modified Lowry method (Sigma Kit) for membrane bound proteins. Protein concentration effects and protein loss were investigated by preparing aliquots of known dilutions of membrane protein suspension into wells, filtering, and measuring the protein concentration remaining on the plate filters via the Lowry method.
[0063] Competition binding: To reduce binding of radiolabel to filters, 0.1% BSA was added to the assay buffer. Membranes were diluted with buffer to yield a final protein concentration of 600 μg/well (2 mg/ml). Membranes were added to the wells of a 96-well microtiter plate and incubated at room temperature with 10 nM [ 3 H]-MLA, and unlabelled ligand or unknown samples (100 μl each). Incubation was halted after 2 hr by the addition of ice-cold buffer. The contents of the microtiter plate were harvested onto a 96 well filterplate using a plate harvester (Packard, Inc). Filters were washed 5× with ice cold buffer and the filterplate dried overnight. Scintillation cocktail was then added to the filters and the entire plate counted using a TopCount™ 96-well plate scintillation counter, Packard Instruments, Meriden Conn.
[0064] Procedures for 3 H-epibatidine binding in 96-well filter plates: All procedures were performed at room temperature, unless noted. Assays were performed in standard (350 μl well volume) 96 well microtiter plates. Nicotine or a sample competitor was added to 8 wells at a time using an 8-channel multipipettor. Crude sample extracts were solubilized using 1N HCl, if necessary. Unknown samples were diluted with incubation buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, 1 nM MgCl 2 , 2 mM CaCl 2 , pH adjusted to 7.4) 1:10. This dilution allows an approximate weight:volume ratio of 100 mg/ml of unknown sample per well. 100 μl of a competitor was added to each respective well. Non specific binding for epibatidine was determined using 10 mM nicotine competition. Membrane homogenates were thawed on ice and diluted with incubation buffer for final protein concentration of each well equal to 4 mg/ml. Membrane homogenate preparation was added to 8 wells at a time, using 8-channel pipettor. A competitor was incubated within wells for 1 hr. at room temp. Following incubation of competitor, 3 H-epibatidine (New England Nuclear) was added to each well and incubated for 2 hr. Following incubation, the plate was harvested onto a 96 well GF/B filter plate using a Packard 96 well harvester, and rapidly washed 3× with 350 μl 50 mM Tris-HCl buffer (pH=7.4). The plate was then allowed to dry overnight, then 30 μl MicroScint20™ was added to each well before counting with a Packard Topcount™ 96-well plate scintillation counter. Each well was counted for 2 min. Specific binding in the presence of competitor was converted to percentage of total specific binding of 3 H-epibatidine alone. Significant differences were calculated from CPM averages using Student's 2 tailed t tests.
Example 7
Results
[0065] Screening of Activation-Tagged Microcalli: 4400 activation tagged microcalli were screened in a six month period. This was a 75% increase in efficiency over previous methodologies.
[0066] Identification of Microcalli with Significant Alkaloid-Displacing Activity: Two stable cell lines were identified that showed significant alkaloid-displacing activity. One of these, 1402, was examined at the whole plant level and showed a 7.5-fold increase in the level of displacement activity over the wild type in extracts prepared from leaf punches from nontransformed plants. The second identified isolate, 5094, showed displacement activity in callus tissue extracts equivalent to alkaloid levels of several orders of magnitude over the wild-type calli.
Example 8
Isolation and Replication of Activated Genes
[0067] Isolation: Molecular genetic techniques are conducted using standard methodologies. The analytical sequence is determined by isolating the plant genomic DNA activated by the T-DNA insert through Southern hybridization analysis, followed by polymerase chain reaction (PCR) to establish the insert number and structure. Cloning of the T-DNA along with flanking genomic plant DNA will depend on the structure of the insert, first utilizing plasmid rescue for single site T-DNA insertions. If there are multiple inserts, then genomic libraries will be prepared and screens conducted on these to obtain genomic clones linked to the T-DNA that contain different plant genomic DNA sequences. Resulting clones can be sorted first by Southern analysis and then functionally by reintroduction into wild-type protoplasts and scoring microcalli for the original phenotype. If necessary, subclones of the recovered flanking plant DNA can be prepared and tested for activity by fusing various fragments downstream of the 35S promoter of the Cauliflower mosaic virus, introducing these back into protoplasts and scoring these cells for the phenotype. Once the putative activated genomic DNA is identified, it is used as a probe to screen cDNA libraries of tobacco. In addition, functional analysis to determine nicotinic alkaloid pathway upregulation can be performed by reverse transcription PCR using oligonucleotide primer specific to the pmt gene of tobacco. This provides early molecular evidence if the alkaloid pathway was induced in callus tissue, for example.
Example 9
[0068] We have prepared extracts from about 8000 clonal cultures and have screened these for [3H]epibatidine-displacing activity. Approximately 12 of these produced activity that met the criteria of being “positive” in the first screen. Of these, only three have met the criteria that daughter cultures should continue to overproduce activity in the screen through several cycles of growth and separation. The extent of the increase in activity varies markedly between these three clones. Thus, the first clone isolated (#1402) producing a compound or compounds with a biological activity in the screen equivalent to a concentration of nicotine an order of magnitude higher than that produced by wild-type cultures (see FIG. 8 ). A very recent clone (#7309) is producing activity about 10,000× that of wild-type whereas the other clone (#5094) is intermediate between these ( FIG. 8 ). Because we isolated #1402 first we have spent most time characterizing this clone, and the specific findings will be described below.
[0069] The results show that ATM can be used to create a large library of mutant clonal cultures (see FIG. 4 ) that can be maintained by a small number of research workers. We have also shown that clones in this library can be repeatedly sampled and separated without destroying the individual cultures. Extracts from these cultures can therefore be sampled and screened serially to evaluate whether the genetically produced chemical phenotype is stable. We have also shown that it is possible to adapt pharmacological HTS techniques to evaluation of a clonal library produced by ATM, and that the amplitude of changes in secondary metabolites from wild-type or other control cultures that are produced by ATM can be detected by this HTS. We are thus able to combine ATM and HTS—the first requirement for proof of the Natural Products Genomics concept. Our results using this combination of techniques show that a small number of clones (currently around 1 in 2,700 mutants) can be regarded as stable alterations in genes that increase the synthesis of products with a biological activity similar to nicotine. These products may be nicotine itself, or some other chemical with activity in the screen, at this stage we do not know. Similarly, the genes that have been activated may have an impact on the nicotine metabolic pathway, or be completely unrelated to this. All we know is that they increase the production of natural compounds with potentially useful biological activity that is similar to that of nicotine. In fact, we may well be underestimating the numbers of clones that have this type of value. About 75% of the clones that give a positive result in the first screen eventually fail, sometimes after several generations of positive daughter cultures. Some cultures even recover activity after producing negative data for a while. In some cases, this may indicate that we have activated a gene that regulates the production of the natural product very indirectly, and that its effects can be over-ridden by other genes that may be activated by environmental or developmental factors beyond our control. However, such genes might still be useful as a means of regulating synthesis of the natural product. We have been deliberately conservative in our criteria to avoid the criticisms previously associated with unstable somatic mutations in plant cell culture. Considered together we believe that our results demonstrate that ATM and HTS have the potential to act as a discovery platform for those genes that regulate the synthesis of natural products in plants. As our characterization of clone 1402 has shown (see below) this Natural Products Genomics approach has utility as a drug discovery platform technology.
[0070] Clone 1402 has now consistently over-produced activity in the epibatidine displacement screen for about 18 months. This has been in various incarnations of the original clonal material that originated from a single protoplast subjected to ATM (see FIG. 8 ). Thus, daughter cultures of the original clone continued to overproduce activity in the screen. Some of these cultures were regenerated into intact plants which set seed. Extracts of the seed were screened, and these continued to show greater activity in the screen than wild-type N tabacum seed. Plants were grown from this seed and leaf punch extracts from young seedlings showed greater activity in the screen than leaf punches from wild-type seedlings. Leaf protoplasts from these plants were grown to the microcallus level and these microcalli were found to be still overproducing activity relative to wild-type cultures.
[0071] The only situation in which clone 1402 was not found to be an overproducer relative to wild-type was in leaf punches from relatively mature plants. At this stage nicotine production is rising rapidly in the wild-type plants and this might well eliminate the difference from the clonal plant. Additionally, assessing the production of nicotine-like alkaloids in leaf punches from mature plants is subject to the Heisenberg principle because leaf damage massively increases the synthesis and transport of nicotine. Our failure to observe a difference in the screen between clone 1402 and wild-type plants at the mature plant stage illustrates the potential difficulties of evaluating differences in natural products in a population of mutant intact plants. Metabolic profiling of the plants at this stage by GC/MS also did not reveal any differences in alkaloid material (see FIG. 7 ).
[0072] Since 1402 consistently overproduces activity in the epibatidine displacement screen it would seem to be a simple matter to establish what compound or compounds it is producing that account for this activity. Unfortunately this is more difficult than would be expected. The problem is one of sensitivity and quantitation. The screen is semi-quantitative at best, but it is extraordinarily sensitive, being easily able to respond to picogram quantities of nicotine in a culture extract. Chemical analytical methods such as GC/MS (as in FIG. 7 ) are about 1000× less sensitive, and to date we have not accumulated enough clonal culture material to be able to analyze extracts quantitatively for known and novel nicotine-like alkaloids. We have therefore used a combination of pharmacological analysis and separation techniques to investigate extracts of clone 1402 in comparison with extracts from wild-type microcallus.
[0073] Nicotine is the most pharmacologically alkaloid in the intact plant, and this alkaloid can be detected by GC/MS in extracts from wild-type cultures. Therefore, the most likely reason for the increased activity in extracts from clonal culture #1402 is that this is producing more nicotine than the wild-type cultures. This does not appear to be the case. Thus, this clonal culture was identified on the basis of greater displacement of epibatidine, a ligand with relative selectivity for alpha3-containing nicAChRs on brain membranes. In contrast, nicotine, and the partial agonist cytisine, have a higher affinity for nicAChRs on brain containing alpha4 subunits. If the active principle in clone #1402 is nicotine it should displace [3H]nicotine or [3H]cytisine from brain membranes to a greater extent than it displaces [3H]epibatidine. In fact the reverse is the case—the same extract from 1402 that is an order of magnitude more effective at displacing epibatidine is no more effective than that from wild-type cultures in displacing nicotine or (see FIG. 9 ). This suggests that whatever is responsible for the activity has a greater affinity for alpha3-containing nicAChRs, and this is inconsistent with this being nicotine or probably any of the other major alkaloids in tobacco (see below).
[0074] FIG. 9 also shows another important pharmacological characteristic of the culture extracts. The dilution/response relation in the screens is very similar to that for pure nicotine. This suggests that the displacement of the respective radioligands is by direct competition for the binding site, rather than by indirect or allosteric effects. This type of interaction suggests an alkaloid that is a structural relative of nicotine rather than a totally different type of compound. For example we know that the cultures produce polyamines (see below) and these compounds can affect nicAChR binding allosterically. The suggestion that the compound in clone 1402 is structurally similar to the known tobacco alkaloids is supported by results from serial fractionation of the extracts from #1402 and wild-type cultures. We compared these fractions for activity in the radioligand binding screens and also compared the recovery in each phase with that of standards representing the major alkaloids present in N tabacum . In general, the activity in extracts from #1402 showed a similar distribution to that from wild-type cultures and to that of alkaloid standards (not shown here).
[0075] Taken together, all this data is consistent with the production, by clone 1402, of an alkaloidal compound (or compounds) with structural similarity to nicotine, but which bind with high affinity to nicAChRs containing alpha3 subunits. Since none of the major alkaloids in the plant have exactly these characteristics, then we appear to have produced a stable mutation that causes “overproduction” either of a compound that is not normally found in the plant, or one that is normally produced in very small amounts. This finding, and the procedure we used to come to this conclusion, has some implications for drug discovery. Specifically, if the main purpose of this technology is to discover clones that are producing active compounds other than the major active principle in the plant, it is a simple matter to use differential activity in two related screens to do this. Those clones that are simply overproducing the “wild-type compound” will produce a characteristic ratio of activity in the two screens. Those that are producing some product with novel properties will usually produce a ratio of activity that differs from this.
[0076] Since the T-DNA that has been inserted into the N tabacum genome during the ATM procedure is “tagged” with bacterial DNA, it is a relatively simple method to rescue this material together with sections of the plant genes surrounding it. However, this does not guarantee that the piece of plant DNA that is obtained is responsible for the altered chemical phenotype. Thus the influence of the viral enhancer sequences inserted into the genome extends for as much as 10-Kb pairs in each direction from the insert, and it may be any gene within this range that is of value for natural product synthesis. Another potential problem is that there may be more than one insert. The important activation may be in one of these rather than the other or, possibly, it could require both. Fortunately clone #1402 has only one T-DNA insert and we have used plasmid rescue techniques to obtain genomic plant DNA from the region of this insert. To date we have isolated approximately 1.8-Kb pairs of this material (see FIG. 10 ), which is probably of insufficient length to encode a complete gene. However, the sequence analysis indicates very strongly suggests that the cloned genomic DNA does indeed encode intact genes in that the deduced amino acid sequence from this region reveals some homology with expressed genes when compared with existing gene databanks. In particular, there is homology with expressed sequence tags obtained from a soybean roots that represents a gene of unknown function ( FIG. 10 ). Since the nicotine alkaloids are synthesized in roots, this at least shows the expected tissue specificity.
[0077] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention specifically described herein. Such equivalents are intended to be encompassed in the scope of the following claims. | This invention provides materials and methods to manipulate the plant genome at the level of single plant cells in culture resulting in the ability to assign metabolic functionality to plant genes involved in the production of biologically active molecules and to create a means of product discovery based on the biosynthetic capacity of plants. The materials to create an activation mutagenesis include incorporation of enhancer sequences from a plant viral promoter at random places in the plant genome via Agrobacterium mediated DNA transfer (T-DNA). The usefulness is that genes in the immediate vicinity of the incorporation were activated which allows for immediate screening of the mutagenized plant cells. Additionally, the usefulness includes relevant areas of the genome were flanked by the inserted T-DNA which allows recovery of this area by standard molecular biology techniques. The method includes a procedure for screening large numbers of mutagenized plant cell cultures for activation of a relevant gene on the basis of the desired protein product on the basis of radioligand binding displacement assay. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel N-benzoyl N'-pyridyloxy phenyl ureas and the process for producing the same and the insecticidal composition containing the same.
2. Description of the Prior Arts
Almost of the conventional insecticides impart neurotoxicity and contact toxicity to all kinds of insects.
And, it has been required to find selective insecticidal compounds without toxicity to useful insects, N-benzoyl N'-phenyl ureas disclosed in U.S. Pat. No. 3,748,356 have such insecticidal properties.
The N-benzoyl N'-pyridyloxyphenyl ureas according to the present invention have a substantially better action than the above described known compounds.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel N-benzoyl N'-pyridyloxy phenyl ureas.
It is another object of the present invention to provide a process for producing N-benzoyl N'-pyridyloxy phenyl ureas.
It is the other objects of the present invention to provide selective insecticidal compositions which are remarkably effective to certain injurious insects without affecting useful insects in remarkably low toxicity to animals.
The novel compounds of the present invention are N-benzoyl N'-pyridyloxy phenyl ureas having the formula ##STR2## wherein X 1 represents a halogen atom; X 2 represents hydrogen or halogen atom; X 3 and X 4 respectively represent hydrogen or chlorine atom; X 5 represents hydrogen or halogen atom; and X 6 represents a halogen atom or nitro or trifluoromethyl group.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Suitable compounds having the formula (I) include:
N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-bromopyridyl-2-oxy) phenyl]urea m.p. 196° to 199° C.
N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-nitropyridyl-2-oxy) phenyl]urea m.p. 209° to 212° C.
N-(2-chlorobenzoyl)N'-[4-(3,5-dibromopyridyl-2-oxy) phenyl]urea m.p. 185° to 188° C.
N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dibromopyridyl-2-oxy) phenyl]urea m.p. 223° to 224° C.
N-(2-chlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 216° to 218° C.
N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 225° to 228° C.
N-(2-chlorobenzoyl)N'-[3,5-dichloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 221° to 223° C.
N-(2-chlorobenzoyl)N'-[4-(5-bromopyridyl-2-oxy) phenyl]urea m.p. 179° to 180° C.
N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-chloropyridyl-2-oxy) phenyl]urea m.p. 198° to 200° C.
N-(2-chlorobenzoyl)N'-[3,5-dichloro-4-(5-chloropyridyl-2-oxy) phenyl]urea m.p. 147° to 148° C.
N-(2-chlorobenzoyl)N'-[4-(5-trifluoromethylpyridyl-2-oxy) phenyl]urea
N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-trifluoromethylpyridyl-2-oxy) phenyl]urea
N-(2,6-dichlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 228° to 230° C.
N-(2,6-dichlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 214° to 216° C.
N-(2,6-dichlorobenzoyl)N'-[3,5-dichloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 273° to 275° C.
N-(2,6-difluorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 184° to 185° C.
N-(2,6-difluorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea m.p. 230° to 231° C.
N-(2,6-difluorobenzoyl)N'-[3-chloro-4-(5-chloropyridyl-2-oxy) phenyl]urea m.p. 210° to 212° C.
The N-benzoyl N'-pyridyloxy phenyl ureas having the formula (I) are produced by reacting a compound having the formula ##STR3## wherein X 1 represents a halogen atom; X 2 represents hydrogen or halogen atom; R 1 represents amino or isocyanate group with a compound having the formula ##STR4## wherein X 3 and X 4 are the same and different and respectively represent hydrogen or chlorine atom; X 5 represents hydrogen or halogen atom; X 6 represents halogen atom or nitro or trifluoromethyl group; and R 2 represents an amino or isocyanate group and R 2 is amino group in the case that R 1 is isocyanate group, R 2 is isocyanate group in the case that R 1 is amino group.
More particularly, the compounds having the formula (I) can be produced by the following processes (1) and (2).
(1) The reaction of benzoyl isocyanate having the formula ##STR5## with pyridyloxy aniline having the formula ##STR6## (wherein X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are defined above)
(2) The reaction of benzamide having the formula ##STR7## with pyridyloxy phenyl isocyanate having the formula ##STR8## (wherein X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are defined above).
The reaction is preferably carried out in the presence of a solvent. Suitable solvents include benzene, toluene, xylene, pyridine etc.
The reaction temperature is usually in a range of 20° to 120° C. and the reaction time is usually in a range of 0.5 to 24 hours. The reaction is preferably carried out at the temperature from 50° C. to a refluxing temperature for 1 to 5 hours.
Certain examples of preparations of the compounds of the present invention will be described.
EXAMPLE 1
Preparation of N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy) phenyl]urea
A solution prepared by dissolving 2.9 g of 3-chloro-4-(3,5-dichloro-pyridyl-2-oxy) aniline in 50 ml of toluene was heated at 80° C. A solution prepared by dissolving 1.8 g of 2-chlorobenzoyl isocyanate in 20 ml of toluene was added dropwise to the former solution under stirring it and the reaction was carried out for 1 hour. After the reaction, the reaction mixture was cooled and the precipitate was filtered and washed with toluene and then with petroleum ether and dried to obtain 3.2 g of N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea (m.p. 225° to 228° C.).
EXAMPLE 2
Preparation of N-(2,6-dichlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy) phenyl]urea
In accordance with the process of Example 1, except using 2.5 g of 4-(3,5-dichloropyridyl-2-oxy) aniline instead of 3-chloro-4-(3,5-dichloropyridyl-2-oxy) aniline and using 2.4 g of 2,6-dichlorobenzoyl isocyanate instead of 2-chlorobenzoyl isocyanate and reacting at 30° C. for 8 hours instead of 80° C. for 1 hour, the process was repeated to obtain 3.8 g of N-(2,6-dichlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy) phenyl]urea (m.p. 228° to 230° C.).
The compounds of the present invention impart excellent selective insecticidal effect as clearly understood from the following experiments.
Most of the conventional insecticides impart quick effect and neurotoxicity and contact toxicity. However, the compounds of the present invention impart the delayed effect that the compounds effect to molting (ecdysis) and metamorphosis of specific insects which orally take the compound with feeds or water whereby the death of the specific insects is caused.
The compounds of the present invention impart remarkable insecticidal effect to larvae of Lepidoptera, Coleoptera, Hymenoptera and Diptera, for example, larvae of the following insects:
diamondback moth (Plutella xylostella), common white (Pieris rapae crucivora), cabbage armyworm (Mamesta brassicae), cabbage looper (Plusia nigrisigma), tobacco cutworm (Prodenia litura), smoller citrus dog (Papilio xuthus), small blackfish cochlid (Seopelodes contracta), fall webworm (Hyphantria cunea), gypsy moth (Lymantria dispar), rice stem borer (Chilo suppressalis), bollworm (Heliothis zea), tobacco budworm (Heliothis virescens), bollweevil (Anthonomus grandis), confused flour beetle (Tribolium confusum), colorado potato beetle (Leptinotarsa decemlineata), sawfly (Neurotoma irdescens), Culex mosquito (Culex pipiens pallens).
The compounds of the present invention do not substantially impart insecticidal effect to adults and are ineffective to natural enemies as predatory insects and impart low toxicity to animals.
When the compounds are used as active ingredients of the insecticidal composition, it is possible to prepare various forms of the compositions such as dust, wettable powder, emulsifiable concentrate, invert emulsion, oil solution, aerosol preparation, etc. with adjuvants as the cases of agricultural compositions. The compositions can be applied with or without diluting them in suitable concentrations.
Suitable adjuvants include powdery carriers such as talc, kaolin, bentonite, diatomaceous earth, silicon dioxide, clay and starch; liquid diluents such as water, xylene, toluene, dimethylsulfoxide, dimethyl formamide, acetonitrile, and alcohol; emulsifiers dispersing agents spreaders etc.
The concentration of the active ingredient in the selective insecticidal composition is usually 5 to 80 wt.% in the case of the oily concentrate; and 0.5 to 30 wt.% in the case of dust; 5 to 60 wt.% in the case of wettable powder.
It is also possible to combine with the other agricultural ingredients such as the other insecticides, miticides, plant growth regulators. Sometimes synergetic effects are found.
The selective insecticides of the present invention are effective for inhibiting various injurious insects and they are usually applied at a concentration of the active ingredients of 5 to 10,000 ppm preferably 20 to 2,000 ppm.
EXPERIMENT 1
The active ingredients were respectively dispersed in water to prepare dispersions having specified concentrations. Leaves of cabbage were dipped into the dispersions for about 10 seconds and taken out and dried under passing air.
A piece of moistened filter paper was put on each Petri dish (diameter 9 cm) and the dried leaves of cabbage were put on the filter paper and larvae of diamondback moth in 2nd or 3rd instar were fed on them and the Petri dishes were covered and kept in constant temperature at 28° C. with lightening. After 8 days from the treatment with the dispersion, the dead larvae were measured and the mortality rates were calculated by the following equation: ##EQU1##
Table 1______________________________________ Mortality Rate (%) (concen- tration) 200 100No. Active ingredient ppm ppm______________________________________1 N-(2-chlorobenzoyl)N'-[3-chloro-4(5-bromo-pyridyl-2-oxy)phenyl]urea 100 1002 N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-nitro-pyridyl-2-oxy)phenyl]urea 100 1003 N-(2-chlorobenzoyl)N'-[4-(3,5-dibromo-pyridyl-2-oxy)phenyl]urea 100 1004 N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dibromopyridyl-2-oxy)phenyl]urea 100 1005 N-(2-chlorobenzoyl)N'-[4-(3,5-dichloro-pyridyl-2-oxy)phenyl]urea 100 1006 N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100 1007 N-(2,6-dichlorobenzoyl)N-[4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100 1008 N-(2,6-dichlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100 1009 N-(2-chlorobenzoyl)N'-[3,5-dichloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100 8010 N-(2,6-dichlorobenzoyl)N'-[3,5-dichloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 80 6011 N-(2,6-difluorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy)phenyl]urea12 10012 N-(2,6-difluorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100 10013 N-(2-chlorobenzoyl)N'-[4-(5-bromo-pyridyl-2-oxy)phenyl]urea 100 10014 N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-chloropyridyl-2-oxy)phenyl]urea 100 10015 N-(2-chlorobenzoyl)N'-[3,5-dichloro-4-(5-chloropyridyl-2-oxy)phenyl]urea 100 6016 N-(2-chlorobenzoyl)N'-[4-(5-trifluoro-methylpyridyl-2-oxy)phenyl]urea 100 8017 N-(2,6-difluorobenzoyl)N'-[3-chloro-4-(5-chloropyridyl-2-oxy)phenyl]urea 100 100______________________________________
EXPERIMENT 2
On radish young seedlings grown in unglazed pots, adults of diamondback moth were fed and kept for 24 hours to blow ova. One day later, aqueous dispersions of the active ingredients (500 ppm) were respectively sprayed on the young seedlings to fall drops of the dispersion and dried and kept in glass greenhouse. After 10 days from the treatment with the dispersion, the dead larvae were measured and the mortality rates were calculated by the equation ##EQU2##
The results are shown in Table 2.
Table 2______________________________________ Mortality rateNO. Active ingredient (%)______________________________________1 N-(2-chlorobenzoyl)N'-[3-chloro-4-(5-nitropyridyl-2-oxy)phenyl]urea 802 N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dibromopyridyl-2-oxy)phenyl]urea 1003 N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 100______________________________________
EXPERIMENT 3
About 20 cc of germinated rice seeds were put into cups (diameter: 9 cm, height: 3 cm) to grow them. When they grew to seedlings having a height of 1 to 2 cm, the aqueous dispersions at specified concentrations were respectively sprayed at a ratio of 2 cc per 1 cup and dried, and larvae of rice stem borer (just hatched) were fed and the cups were covered. After 10 days from the treatment with the dispersion, the dead larvae were measured and the mortality rates were calculated by the equation of Experiment 1. The results are shown in Table 3.
Table 3______________________________________ Mortality rate (%) (concentration)No. Active ingredient 200 ppm 100 ppm______________________________________1 N-(2-chlorobenzoyl)N'-[3-chloro-4- (5-bromopyridyl-2-oxy) phenyl] urea 100 1002 N-(2-chlorobenzoyl)N'-[3-chloro-4- (5-nitropyridyl-2-oxy) phenyl] urea 100 1003 N-(2-chlorobenzoyl)N'-[3-chloro-4- (3,5-dibromopyridyl)-2-oxy) phenyl] urea 100 1004 N-(2-chlorobenzoyl)N'-[3-chloro-4- (3,5-dichloropyridyl-2-oxy) phenyl] urea 100 100______________________________________
EXPERIMENT 4
Young branches of persimmon tree cut in a length of 15 cm from the top, were respectively dipped into the aqueous dispersions of N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea at various concentrations for 10 seconds, and they were dried and put into wide mouth bottles and larvae of gypsy moth in 2nd or 3rd instar were fed into them. The bottles were covered with gauze and kept in a constant temperature at 28° C. with lightening. After 7 days and 15 days from the treatment with the dispersion, the dead larvae were measured and the mortality rates and the abnormal rates were calculated. The results are shown in Table 4.
Table 4______________________________________ Mortality rate (%) (concentration)Observation 400 ppm 200 ppm 100 ppm______________________________________After 7 days 100 90 (10)* 40 (30)*After 15 days 100 100 90 (10)*______________________________________ *abnormal rate
EXPERIMENT 5
N-(2-chlorobenzoyl)N'-[4-(3,5-dibromopyridyl-2-oxy)phenyl]urea was used to prepare the aqueous dispersions at specified concentrations. The effects of the dispersions to various insects were tested. The mortality rates after 10 days from the treatments were obtained in accordance with the process of Experiment 1.
The results are shown in Table 5.
Table 5______________________________________ Concent- ration MortalityInsects Treatment (ppm) rate______________________________________cabbage armyworm: cabbage leaf2nd instar larvae dipping 50 100(Lepidoptera)confused flour beetle: wheat flour2nd larval instar larvae blending 200 100(Coleoptera)1 sp. of sawfly cherry branch3rd instar larvae spraying 250 100(Hymenoptera)______________________________________
EXPERIMENT 6
200 ml of the aqueous dispersions at specified concentrations were respectively placed in glass containers with a capacity of 450 cc. 20 larvae of third instar of the mosquito (Culex pipiens pallens) were placed in each container and the containers were hold at 26°-28° C. with lightening. The mortality rates after 10 days from the treatments were obtained in accordance with the process of Experiment 1.
The results are shown in Table 6.
Table 6______________________________________ Mortality rate (%)No. Active ingredient 0.1 ppm 0.01 ppm______________________________________1 N-(2-chlorobenzoyl)N'-[4-(3,5-dibromopyridyl-2-oxy)phenyl] urea 100 1002 N-(2,6-difluorobenzoyl)N'-[4-(3,5-dichloropyridy-2-oxy)phenyl] urea 100 1003 N-(2-chlorobenzoyl)N'-[4-(5-bromo-pyridyl)-2-oxy)phenyl] urea 100 100______________________________________
COMPOSITION 1
______________________________________(a) N-(2-chlorobenzoyl)N'-[3-chloro-4-(3,5-dichloropyridyl-2-oxy)phenyl]urea 20 wt. parts(b) Dimethyl sulfoxide 70 wt. parts(c) Polyoxyethylenealkylphenyl ether 10 wt. parts______________________________________
The components were uniformly blended to dissolve the ingredient to prepare an emulsifiable concentrate.
COMPOSITION 2
______________________________________(a) N-(2-chlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy)phenyl] urea 5 wt. parts(b) Talc 92 wt. parts(c) Sodium naphthalene sulfonate formaldehyde condensate 3 wt. parts______________________________________
The mixture was pulverized to uniformly mix them to prepare dust.
COMPOSITION 3
______________________________________(a) N-(2,6-dichlorobenzoyl)N'-[4-(3,5-dichloropyridyl-2-oxy phenyl]urea 50 wt. parts(b) Jeeklite (fine divided clay) 45 wt. parts(d) Sodium ligninsulfonate 5 wt. parts______________________________________
The components were pulverized to uniformly mix them to prepare a wettable powder. | N-benzoyl N'-pyridyloxy phenyl urea having the formula ##STR1## wherein X 1 represents a halogen atom; X 2 represents hydrogen or halogen atom; X 3 and X 4 respectively represent hydrogen or chlorine atom; X 5 represents hydrogen or halogen atom; and X 6 represents a halogen atom or nitro or trifluoromethyl group are novel compounds.
The compositions containing the compound as the active ingredient are effective as the insecticide for extinction of injurious insects with high safety in agricultural, forestry and hygienic applications. | 2 |
BACKGROUND OF THE INVENTION
The present invention relates to a pneumatic separator for flowable particulate materials, e.g., chaff from grain.
Pneumatic separators for this purpose are already known. For example, German Pat. DE No. 1,131,491 discloses a pneumatic separator in which a cylindrical housing surrounds a tubular separating channel the inner wall of which forms a container that is closed at the top and open at the bottom. Beneath this container and coaxially therewith, there is arranged a distributor body having a central passage and a conical guide face. An annular gap is provided between the body and the container for entry of the material into the separating channel. A central duct terminates beneath and at a distance from the body; the material to be processed is blown via compressed air through the central passage into the container and at the same time some of the air is branched off beneath the distributor body to enter laterally into the separating channel. A tube nipple concentrically surrounds the outlet end of the duct and conically diverges towards the distributor body; its inlet end communicates with the atmosphere and its outlet end, through which additional air is supplied into the separating channel, is shielded against the entry of material leaving the channel.
An analogous separator is disclosed in German Pat. DE No. 1,507,715. Here, the container arranged in the housing is of frustoconical shape, so that the separating channel converges in the flow direction of the separating air stream. An annular step is provided on the conical guide face of the distributor body to achieve a brief retardation of the particulate material, the aim being to assure that it enters into the separating channel in a constant flow and substantially uniformly distributed over the periphery of the body.
According to a proposal in German Gebrauchsmuster DE-GM No. 6,910,093 the material is supplied via a separate duct entering the container in the housing. Housing parts contacted by the material are provided with arrangements for cleaning them via airstreams, to prevent agglomeration of the material on these parts.
Finally, separators are known in which material is admitted from above via a central supply tube and the conical distributor body arranged under the outlet end of the tube can be moved relative to the tube counter to the action of an energy-storing device, so that it opens the outlet of the tube to a greater or lesser extent in dependence upon the weight of the column of incoming material acting upon it (U.S. Pat. No. 1,987,615 and British Pat. No. 715,176).
These prior-art devices are employed in a variety of applications, for example to separate chaff from grain, dust from grain and malt, substandard (shrivelled) kernels from acceptable ones, to clean and segregate granulates by fractions, and the like. In many of these applications the prior-art devices operate satisfactorily. However, when materials are involved which are difficult to separate pneumatically, such as e.g., dehusked cereals, it has been found in practice that they will produce only very limited results. Also, these devices are at least in some instances rather complicated and therefore also expensive. Dehusked crop mixtures of grains and legumes, e.g., oats, rice, soy beans, peas and the like, are difficult to separate because the kernels (grain, beans or peas) have very different floating speeds from the husks or shells or parts thereof.
SUMMARY OF THE INVENTION
The principal object of the invention is to overcome the prior-art disadvantages.
A more particular object of the invention is to provide an improved pneumatic separator which is of simple construction and requires little maintenance and which has universal applicability.
An equally important object is to provide such an improved pneumatic separator which produces a highly effective separation of the different fractions, even when difficult-to-separate flowable (pourable) particulate materials are involved.
Pursuant to these objects, and still others which will become apparent hereafter, one aspect of the invention resides in a pneumatic separator for flowable particulate materials. Briefly stated, such a separator may comprise first means defining a first upright passage for admission of a multi-fraction particulate material and having a first open lower end; second means defining an upright annular second passage surrounding the first passage outwardly spaced therefrom and having a second open lower end downwardly spaced from said first end, the second passage having an outlet in the region of its upper end and converging in the direction towards the region; and a guide body centrally located beneath the first end and having a conical surface which directs the material towards the second end, and a shoulder extending at least substantially normal to a central axis of the annular second passage and having an edge over which material is discharged into the second channel, the second channel having at least in the region below the shoulder at least one zig-zag shaped passage portion so that, when suction is applied to the outlet and material is discharged into the passage portion, the material undergoes repeated directional changes during each of which the airstream aspirated by application of the suction travels transversely through the material.
Due to the shoulder which is inclined to the separating air stream and over which the material is discharged, components of speed counter to the flow direction of the separating (air) stream are either completely avoided or reduced to a negligible factor. The effect of this deflection of the flow of particulate material is the stronger, the heavier the particles are because the afore-mentioned speed components increase with increasing particle weight. The (in cross-section) zig-zag shaped deflecting region deflects the flow of particles repeatedly, so that the separating stream flows through it in transverse direction several times. Tests and measurements carried out under actual operating conditions have shown that the combination of these two measures results in a substantial improvement of both the quality and quantity of separation, particularly with respect to the dehusked crop mixtures which are otherwise difficult to separate because of their voluminous husk fraction. Depending upon the desired separation effect, several particle-deflecting locations may be arranged sequentially (with reference to the flow direction of the separating stream) ahead of the shoulder and one or more may also be located behind (i.e., following) the shoulder.
The novel features which are considered as characteristic for the invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a somewhat diagrammatic vertical section through a separator embodying the invention; and
FIG. 2 is a fragmentary sectional view, showing a detail of FIG. 1 on an enlarged scale.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An exemplary embodiment of a separator according to the invention is illustrated in FIGS. 1 and 2 and is particularly, but not exclusively, suited for separating dehusked crops, e.g., oats. The separator has a housing 1 composed of an upper part 2, a center part 3 and a lower part 4. At their respective adjoining ends these parts have circumferential flanges which are straddled and pulled together by respective U-section clamping rings 5 and 6. The housing parts are thus rigidly but releasably connected with one another.
The upper part 2 is basically of cylindrical shape but its top portion converges in upward direction and is terminated at the upper end by a cover 7. A supply pipe 8 extends through and is secured to the cover 7 to enter coaxially into the housing. An outlet portion 9 on part 2 is connected via a not-illustrated cyclone separator with the suction side of not-illustrated blower which produces the separating air stream. A throttle 10 in the portion 9 permits regulation of the air flow. The lower area of part 2 is provided with two e.g., diametrally opposite windows 11 through which the flow of particulate material and the separating operation can be observed.
As will be more fully explained later on, the particulate material to be separated (e.g., a mixture of oat grain and husks) enters through port 46 in the direction of arrow 48. To compensate for the effect of different portions of the material dropping into the port 46 from different heights, a tubular elbow 12 is interposed between the port 46 and the part 2, to which latter it is connected by a clamping ring 13.
The housing part 3 is also of cylindrical shape but is provided with a zig-zag shaped internal cross-sectional constriction 14. Lower housing part 4 converges downwardly and terminates in an outlet 15 for one of the separated fractions. A suction pipe 16 extends at an angle through the part 4, as shown; where it penetrates the outer wall of part 4 it is sealingly connected to this wall. The upper end of pipe 16 is angled so as to have its outlet opening coaxial with the central vertical axis of housing 1.
A double-conical hollow body 17 is coaxially mounted in the housing 1; it surrounds the pipe 8 and its upper end is sealingly connected to the same. The circumferential wall of the body 17 has an opening 20 which is located approximately at the level of the outlet opening 18 through which the incoming particulate material leaves the pipe 8. A plate or baffle 19 is mounted in the opening 20 and can be turned therein to an open and a closed position, so that direct visual observation of the stream of incoming material is possible.
A sheet-metal material-guiding body 21 of double-conical shape is mounted in part 3, slightly downwardly spaced from the body 17. It has an upwardly convergent frustoconical section 22 and immediately below that a frustoconical shape which converges very slightly in downward direction and is provided with an inner cross-sectional constriction 24. The lower end of body 21 is open and a plurality (one shown) of circumferentially distributed bolts 25 and nuts 26 secure the body to the part 3. The conical outer surface 27 of section 22 merges radially outwardly into an annular shoulder 28 which extends approximately normal to the vertical longitudinal axis of housing 1 (and from which the particulate material to be separated runs off).
As FIG. 1 shows, the body 21 is so arranged relative to the body 17 that an annular gap is formed between their proximal ends. This gap constitutes the material entry 29 for the separating channel 30 which is bounded by the walls of housing parts 2, 3 on the one hand and the walls of body 17 and of section 23 on the other hand. In direction upwardly of the shoulder 28 the channel 30 converges and in direction downwardly from the same shoulder it diverges. The volumetric capacity of channel 30 in the zig-zag shaped deflecting region 31 is greater, by the volume of the particulate material to be separated which enters the channel 30 per unit time, than the volumetric capacity which would be needed to obtain the desired separating-air flow speed without any particulate material present in the device; related to the here assumed separation of an oat husk mixture, this volumetric excess would be about 5%.
A conical guide baffle 33 is mounted on the upper end wall 32 of body 21 by means of a bolt 34 which is welded to baffle 33 and extends through a hole 37 in end wall 37 where it is secured via a washer 35 and a nut 36. The size of hole 37 is so selected (FIG. 2) that after release of nut 36 the bolt 34 can be shifted in it in all directions, which is to say that the baffle 33 itself can be correspondingly shifted relative to the outlet 18 of pipe 8. The upper end of baffle 33 is provided with a bushing 38 (FIG. 2) which slidably accommodates a rod 39 that is adjustable up or down in (i.e., lengthwise of) the housing 1 and carries a conical closure member 40 which can be moved (by movement of rod 40) between the full-line position and the broken-line position shown in FIG. 2 (or to intermediate positions). In the brokenline position it closes the outlet 18. The rod 39 itself extends through pipe 8 and elbow 12 and projets outwardly through a hole in the wall of the latter. Its outwardly projecting endportion is surrounded by two axially spaced dished springs 42, 43 (or else just spring seats) between and bearing upon which a helical spring 45 is confined. A nut 44 is threaded onto the rod 39 and compresses the spring 45 via the element 43; this compression is so selected (by advancing the nut or backing it off) that there will always be a certain minimum quantity of particulate material present in the pipe 8 (assuming a continuing supply via port 46), to assure the infeeding of a wholly or almost completely uniform "veil" of particulate material which runs over the shoulder 28 (at the entire circmference thereof) into the channel 30.
THE OPERATION
In operation the not-illustrated blower, the suction side of which is connected with the outlet 9, draws atmospheric air through the pipe 16, as indicated by the arrows 47 in FIG. 1. A stream--the separating air stream--of this air passes out of the interior of body 21 and enters past the lower edge thereof into the lower open end of channel 30. From there it travels upwardly into the housing part 2 and then via the outlet 9 to the cyclone separator and blower.
The particulate material to be separated, e.g., a mix of husks and oats, enters in free fall via the port 46 as indicated by the arrows 48 and from there passes via elbow 12 into pipe 8 in which it travels downwardly to escape from the outlet 18, or more particularly the annular gap formed between the edge bounding outlet 18 and the surface of member 40. The size--i.e., axial length --of this gap is a function of the weight of the column of material present in pipe 8 and bearing upon member 40, to thus cause member 40 and rod 39 to move downwardly to a greater or lesser extent in accordance with the prestress of spring 45.
The material issuing from the annular gap slides over the surface 27 and in uniform circumferential distribution proceeds to the shoulder 28 from which it slides off into the channel 30. Due to the orientation of the shoulder 28 the flow directon of the material is oriented to be approximately normal to the flow direction of the separating air stream which blows now through the material and upwardly entrains the loose husks or husk fragments, to remove them via outlet 9 to the cylcone separator as one fraction (see arrow 49).
Those husks and husk fragments which are not immediatlely entrained in this manner (and also fragmented grains and shrivelled grains) drop into the deflecting region 31, together with the whole oat grains. In this region the mixture undergoes repeated direction change (deflections) and after each such change the separating air flows transversely through the mixture. During this treatmemt the remaining husks and husk fragments, grain fragments, shrivelled grains and even any lighter impurities present, are entrained and removed via outlet 9. The remaining (acceptable) grains drop out of the section 31 into the part 4, from where they flow off (see arrow 50) as the second separated fraction via the outlet 15, to enter either into a container (e.g., bag or the like) or to be removed by conveyor.
An advantage of having the section 31 below shoulder 28 conical diverge counter to the airflow direction, is that this measure improves the separating effectiveness.
The volume ratio explained earlier assures that the net volumetric capacity of the channel section 31 cannot be reduced by the inflowing material and that optimum flow conditions are maintained for the separation.
The use of element 40 is particularly advantageous to permit compensation for possible tolerance variations in the manufacture. For example, by lateral shifting of the element 40 the cross-section of the annular gap through which the material to be separated issues, can be made uniform over the entire gap circumference, so as to obtain a uniform outflow of material which is one of the prerequisites for proper operation.
Having the body 21 be open downwardly and the suction pipe terminate in it, has the advantage that a preliminary resistance is formed in simple manner which is needed to assure uniform air distribution over the cross-section of channel 30 and cause a dual change in direction of airstream. In turn, this causes the stream of air to intercept and slow down the flow of particulate material and guarantees intensive separation action. By extending or shortenting the part of the suction pipe 16 which extends into the body 21, the preliminary resistance can be increased or decreased, respectively.
It is self-evident that a gas other than air could be aspirated through pipe 16, although generally air will be preferred as being most practical and/or least costly.
While the invention has been illustrated and described as embodied in a pneumatic separator for grain and legume crops, it is not intended to be limited to the details shown, since various modifications and structural changes may be made without departing in any way from the spirit of the present invention.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention. | A device for separating multi-fraction particulate materials includes a housing with an inner passage for admitting the material to be processed and an outer passage having an outlet and connected to a suction device for producing an air stream in an upward direction. A guide body with a conical surface and a shoulder having an edge are mounted in the housing. The second passage has in the region below the shoulder a zig-zag shaped passage portion. The incoming stream of mixture falls on the conical surface, then on the edge of the shoulder and then is discharged into the zig-zag shaped portion so that when suction is applied to the outlet of the outer passage the material undergoes repeated directional changes during each of which the air stream travels transversely through the material. | 1 |
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to the field of container devices for carrying small personal items. In particular, the invention relates to a patch for holding keys, cards, driver's license and the like, wherein the patch is reversibly attachable to a fabric or clothing.
BACKGROUND OF THE INVENTION
[0002] People find it desirable to participate in outdoor activities for exercise. Such activities may include beachcombing, walking, jogging, running, pet walking, sailing, biking, attending an amusement park, watching sporting events, as well as a myriad of other pursuits. These activities are characterized by a short period of time when an individual leaves the home, or a hotel room, in pursuit of the activity before returning. Typically, individuals need to carry small articles, such as keys, key cards, credit cards, cash, coins and the like, during these periods.
[0003] There are available a wide variety of devices that are intended to hold money, credit cards, keys and spare change. However, all designs employ a clip or hook for attachment of the device to the person of the individual.
[0004] The following patents disclose devices retain keys or key rings: U.S. Des. Pat. No. 382,105; U.S. Des. Pat. No. 845,743; U.S. Des. 374,765; and, U.S. Des. Pat. No. 468,090. U.S. Design Pat. No. 364,269 (Sabosky) discloses a clip to hang keys with VELCRO® closure elements. U.S. Pat. App. Pub. No. 20050035005 discloses a money clip comprising a spare key chamber.
[0005] U.S. Pat. No. 6,679,405 (Zalis-Hecker, et al.) discloses a pouch attachable to a shoe lace. Amphipod, Inc. (Seattle, Wash.) markets Micropak Rapid Access™ pouches that have a locking clip or hook designed to clamp onto standard waistbands or belts.
[0006] One disadvantage of such pouches attached by a clip or hook to a waistband, belt or shoelace is that they are Further, they are dependent on the consumer wearing certain items of clothing and would not be useable by consumers engaged in activities, such as swimming, that are not compatible with the wearing of shoes or belts. In any event, such containers are attachable only to specific articles of clothing such as laced up shoes or belts and thus restrict the options available to a user in dressing for a particular activity.
[0007] Another disadvantage of these types of carrier pouches is that they hang loosely off the user's body as the mode of attachment does not allow for a snug fit that would prevent the pouch from swaying, bouncing, sliding or otherwise causing discomfort in the user when the user is engaged in moderate to vigorous activities. Further, the user has to sacrifice comfort as they constantly feel the presence of a clip or hook on their person during their activities.
[0008] What is needed is a lightweight container device for small items that is attachable to any article of clothing at any site with a fit that is unnoticeable to the user, and which does not sway, bounce or slide from the user's person as occurs when the attachment is via loops, hooks and the like.
SUMMARY OF THE INVENTION
[0009] This invention provides a lightweight, wearable container device made of fabric or like material that is designed to attach to any part of a user's clothing and is of sufficient dimensions to securely hold small personal items, such as keys, credit cards, driver's license, and the like.
[0010] The invention relates to a container device comprising: a body comprising a flexible material defining an interior volume and an opening providing access to the interior volume; a reclosable fastening mechanism secured to the flexible material adjacent the opening and operable to releasably retain the opening of the pouch in a closed state; an attachment means on one side of the body comprising a means to reversibly attach and detach the device from a location comprising a complementary attachment means, wherein the body has dimensions suitable for securely holding one or more personal effects.
[0011] In some aspects, the dimensions of the body are sufficient for holding one or more household or car keys. In other aspects, the dimensions of the body are suitable for holding one or more of credit cards, key cards, identification cards, driver's licenses, insurance cards, medical instructions and special instructions.
[0012] In preferred embodiments the attachment means comprises a hook and loop mechanism, such as VELCRO®.
[0013] The invention also provides a method for reversibly attaching a container device comprising a body having dimensions suitable for securely holding one or more personal effects, wherein the container device comprises an attachment mechanism on one side of the body, the method comprising: positioning an attachment means at a preferred location, wherein the attachment means is complementary to an attachment means on a surface of the container device; and reversibly attaching the device to the location by contacting the complementary attachment means on the location with the attachment means on the device.
[0014] When the attachment means comprises a hook and loop mechanism, such as VELCRO®, the complementary attachment means can be positioned by heat activation.
[0015] These and other aspects will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
[0017] FIG. 1 is a perspective frontal view of a smaller embodiment of the container device suitable for holding keys and the like, with the flap for securing the contents in a closed position. The closure mechanism 140 is indicated.
[0018] FIG. 2 is a perspective rear view of a smaller embodiment of the container device suitable for holding keys and the like. The attachment mechanisms 250 and 252 are indicated.
[0019] FIG. 3 is a perspective frontal view of a larger embodiment of the container device suitable for holding cards and the like, with the flap for securing the contents in a closed position. The closure mechanism 350 is indicated.
[0020] FIG. 4 is a perspective rear view of a larger embodiment of the container device suitable for holding cards and the like, with the flap for securing the contents in a closed position. The closure mechanisms 440 and 442 are indicated.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.
[0023] The present invention is now described with reference to illustrative embodiments. For this reason, numerous modifications can be made to these embodiments and the results will still come within the scope of the invention. No limitations with respect to the specific embodiments described herein are intended or should be inferred.
[0024] The container device of the invention may be made of different lightweight and flexible materials. Suitable materials include cotton, cotton blends, nylon, polymers, plastic, reinforced paper, suede, fur, microfiber, leather, PVC, linen, silk, corduroy or any combination of natural or synthetic materials. In some embodiments, the container is fabricated from lightweight, strong, flexible and durable fabric material(s) such as cotton or cotton blends, denim, nylon, GORE-TEX® (available from W. L. Gore & Associates, Inc.), or canvas, that can withstand the daily wear.
[0025] The container device is designed to coordinate with any outfit. The container device may be fabricated in different colors, patterns, textures and designs or a combination thereof. The fabric or material may be printed, embossed, embroidered, appliqued, painted, photo transferred and/or decorated or ornamented in any other way.
[0026] To form a container device, the material is folded and/or joined to form a pouch or bag defining an interior space and a reclosable fastener is provided at the opening, for securing the contents of the pouch. The enclosure formed is roomy, wide-mouthed, and optionally cushioned and/or moisture resistant.
[0027] The container device is designed to conveniently carry a variety of small objects. While the container device can be made in any size or shape imaginable including abstract, geometric, or any combination thereof, the shape and design on the container devices are dictated by the shape and size of the items they are designed to carry as a snug fit without room for the items to move around loosely is desirable.
[0028] FIG. 1 shows a front perspective view of a container device 100 in accordance with an illustrative embodiment of the invention. The embodiment is a smaller version of the device designed primarily for holding keys, cash, coins and the like.
[0029] The container is defined by a rectangular shape typical of household or car keys with a longer dimension 110 and a shorter dimension 120 . Typically the longer dimension 110 is 2, 2.5, 3, 3.5, 4 or 5 times the length of the shorter dimension. In some embodiments the longer dimension 110 is 10, 11, 12, 13, or more cm while the shorter dimension 120 is 5, 5.2, 5.5, 6, 7, 8 or more cm.
[0030] The interior compartment has sufficient space to hold a key, coins or bank notes in a manner that is intended to prevent the contents from shifting. The contents of the inner compartment are secured by a flap 130 which can be held in place by a fastening mechanism 140 . In one embodiment the fastening mechanism comprises a hook and loop system such as VELCRO®. Other fastening mechanisms such as zippers, snaps, ties, button and/or any other form of closure can also be used. More than one form of fastening mechanism can be employed for closing the opening of the container device.
[0031] Some container devices are constructed with side or bottom gussets that expand when the container is filled.
[0032] FIG. 2 shows a rear perspective view 200 of the same container device 100 . The embodiment is a smaller version of the device designed primarily for holding keys, cash, coins and the like. The closure flap 230 and the fastening mechanism 240 are not accessible from the rear of the device.
[0033] The surface of the rear perspective of the container defined by a rectangular shape with a longer dimension 210 and a shorter dimension 220 further contains an attachment mechanism 250 . In some embodiments a second attachment mechanism 252 is employed to enhance security and stability. Preferably this is a reversible attachment mechanism. In some preferred embodiments a hook-and-loop closure sometimes sold under the mark VELCRO® is employed.
[0034] A hook and loop closure mechanism employs a reversible mating of a hook element with a loop element. In some embodiments, the hook element is present on the rear surface attachment mechanism 250 and/or 252 of the container device. In these cases, the compatible loop element can be positioned at any place on the user's clothing where attachment of the device is desired. The position for attachment on the clothing is typically determined by a location that least interferes with the intended activities of the user and is accessible with relative ease.
[0035] In other embodiments, the loop element is associated with the rear surface attachment mechanism 250 and/or 252 of the container device. In these cases, the compatible hook element is placed on the user's clothing. In a third embodiment, each of the rear surface attachment mechanisms 250 and 252 of the container device contain a different hook or loop element. This enables positioning of the container devices in a fixed orientation on the article of clothing.
[0036] The location on the article of clothing where the device can be placed is determined by the location of the complementary hook strip or loop strip. VELCRO® strips can be attached by heat activation and thus placed by simply ironing on. Other fastening mechanisms can include sewing stitching, adhesive and the like.
[0037] FIG. 3 shows a front perspective view of a container device 300 in accordance with an illustrative embodiment of the invention. The embodiment is a larger version of the device designed primarily for holding credit cards, key cards, identification, medical or special instructions, cash, coins and other like personal effects that the user may carry.
[0038] The container is defined by a rectangular shape typical of household or car keys with a longer dimension 320 and a shorter dimension 330 . Typically the longer dimension 110 is 1, 1.2, 1.4, 1.5, 1.7, 2, or 3 times the length of the shorter dimension. In some embodiments the longer dimension 320 is 9, 10, 11, 12, 13, or more cm while the shorter dimension 330 is 7, 7.5, 8, 8.5, 9, or 10 cm. In some embodiments the sealed end 310 between the longer 320 and shorter 330 dimensions forms a taper.
[0039] The interior compartment has sufficient space to hold personal effects in a manner that prevent the contents from shifting. The contents of the inner compartment are secured by a flap 340 which can be held in place by a fastening mechanism 350 .
[0040] In some embodiments the front surface of the container device further comprises a see-through window that allows viewing of identification. In some embodiments, identification includes one or more of name, address, employment, phone number, employee identification number and medical facts.
[0041] Examples of such fastening mechanisms 350 include hook-and-loop closures sometimes sold under the mark VELCRO®. Other refastenable strip-form fastening mechanism that can be used on the container devices features mating arrays of discrete, interlocking stems or fastening elements. These include the common rib-and-groove closures sometimes sold under then mark ZIP-LOC®, zippers, buttons, snaps, eyelets, grommets, and snap tape. Some container devices are constructed with side or bottom gussets that expand when the container is filled.
[0042] FIG. 4 shows a rear perspective view 400 of the larger container device 300 . The surface of the rear perspective of the container defined by a rectangular shape with a longer dimension 420 and a shorter dimension 430 further contains an attachment mechanism 440 . In some embodiments a second attachment mechanism 442 is employed to enhance security and stability. Preferably this is a reversible attachment mechanism. In some preferred embodiments a hook-and-loop closure sometimes sold under the mark VELCRO® is employed.
[0043] A hook and loop closure mechanism employs a reversible mating of a hook element with a loop element. In some embodiments, the hook element is present on the rear surface attachment mechanism 440 and/or 442 of the container device. In these cases, the compatible loop element can be positioned at any place on the user's clothing where attachment of the device is desired. The position for attachment on the clothing is typically determined by a location that least interferes with the intended activities of the user and is accessible with relative ease.
[0044] In other embodiments, the loop element is associated with the rear surface attachment mechanism 440 and/or 442 of the container device. In these cases, the compatible hook element is placed on the user's clothing. In a third embodiment, each of the rear surface attachment mechanisms 440 and 442 of the container device contain a different hook or loop element. This enables positioning of the container devices in a fixed orientation on the article of clothing. The location on the article of clothing where the device can be placed is determined by the location of the complementary hook or loop strip. VELCRO® strips can be attached by heat activation and thus placed by simply ironing on. Other fastening mechanisms can include sewing stitching, adhesive and the like.
[0045] The container devices are designed for placement on any desired location on a garment. Typical garments include shirts, T shirts, shorts, pant, skirts, jeans, swimwear, hats, caps, sweat shirts, sweatpants, shoes, socks, stockings, leggings, athletic wear, and any other article that may be on a user's person at the time the container is intended for use. The container device is also intended for easy transfer from one location to another. Thus, the container device can be positioned on a back pack, golf bag, camping gear or any other item a user may carry.
[0046] These and other design determinations may vary as trend and consumer preferences require. The preferred structure of the container device comprises a lightweight material suitable for ease of carrying on one's person and also ideal for inserting and extracting it from one location to another. Exterior fabrications of the container device may vary in pattern, color, texture or other design preferences so that it can match aesthetic preferences. However, a preferred exterior fabrication of the container device would lend itself to a smooth transition from one outer covering to another.
[0047] It is understood that outer coverings may be constructed in a variety of configurations and forms with a multitude of pockets, hardware, design elements, fabrications and functions according to a variety of fashion and usage considerations. Examples may be, but are not limited to, an embodiment constructed of canvas, nylon, microfiber, leather, PVC, linen, silk, corduroy or any combination of natural or synthetic materials. A plurality of colors, materials, print themes, designs or textures may be used so as to coincide with fashion trends, holidays, special occasions, other fashion accessories or utilitarian considerations.
[0048] The disclosed lightweight container device can be used for shopping trips, walks, sporting events, as well as various other indoor and outdoor activities. It can be used for both for day to day activities, vacations, or for special events. For example, the present invention can be used to carry various accessories during swimming, diving, snorkeling, dog/pet walking, sporting events, camping, hiking, yard duty, life guarding, gardening, fishing, coaching, grocery/window shopping, walking, recreational bike riding, school, work, beach/outdoor activities/festivities, roller blading, cleaning the house, skate boarding, hunting/fishing, golfing, running, jogging and the like.
[0049] All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
[0050] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claim. | A lightweight, wearable container device made of fabric or like material that is designed to attach to any part of a user's clothing and is of sufficient dimensions to securely hold small personal effects, is provided. The device can be fabricated in different sizes suitable for holding household keys, car keys, credit cards, key cards, identification cards, employment cards, driver's licenses, insurance cards, medical instructions or special instructions. The reversibly attachable device is suitable for positioning at any desired location on a user's garment. Attachment means utilizing hook and loop mechanisms are provided. | 0 |
FIELD OF THE INVENTION
The invention relates to methods of inhibiting the corrosion of copper-bearing alloys in contact with aqueous media.
BACKGROUND OF THE INVENTION
In many industrial processes, undesirable excess heat is removed by the use of heat exchangers in which water is used as the heat exchange fluid. Copper and copper-bearing alloys are often used in the fabrication of such heat exchangers, as well as in other parts in contact with the cooling water, such as pump impellers, stator and valve parts. The cooling fluid is often corrosive towards these metal parts by virtue of containing aggressive ions and by the intentional introduction of oxidizing substances for biological control. The consequences of such corrosion are the loss of metal from the equipment, leading to failure or requiring expensive maintenance, creation of insoluble corrosion product films on the heat exchange surfaces, leading to decreased heat transfer and subsequent loss of productivity, and discharge of copper ions which can then "plate out" on less noble metal surfaces and cause severe galvanic corrosion, a particularly insidious form of corrosion.
Accordingly, it is common practice to introduce corrosion inhibitors into the cooling water. These materials interact with the metal to directly produce a film which is resistant to corrosion, or to indirectly promote formation of protective films by activating the metal surface so as to form stable oxides or other insoluble salts. However, such protective films are not completely stable, but rather are constantly degrading under the influence of aggressive conditions in the cooling water. Under very aggressive aqueous environments, such as those defined as brackish, those containing salt or brine or those containing sulfides, the maintenance of protective films is particularly difficult. The common copper corrosion inhibitors, such as benzotriazole, tolytriazole or mercaptobenzotriazole cannot establish a passive film on the metallic surface under these conditions. This is true even for the exceptional copper corrosion inhibitor, n-butyl benzotriazole. It appears that the copper ions produced at a high rate under these conditions complex with and deactivate the inhibitors. However, if excess inhibitor is used, the result is the undesirable formation of a film consisting of the insoluble copper-inhibitor complex. It is an object of this invention to provide an effective corrosion inhibitor for copper or copper containing surfaces in contact with a very aggressive aqueous environment.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 2,618,606, Schaffer, discloses a composition useful in preventing the discoloration of metal surfaces, including copper, in contact with aggressive aqueous environments. The patentee teaches using azoles, such as benzotriazole, along with either select salts or phosphates.
The combination of azoles with phosphates is further taught in U.S. Pat. No. 4,101,411, Hwa et al. The patentees disclose a composition and method for controlling corrosion in aqueous systems comprising an azole, a water soluble phosphate and a water soluble organophosphonic acid. In addition, Japanese Patent 56-142872 describes similar technology. In this patent, benzotriazole is combined with organophosphoric acid to produce an effective metal corrosion inhibitor.
U.S. Pat. No. 4,406,811, Christensen et al., discloses a composition and method for inhibiting corrosion in aqueous systems using triazoles in combination with carboxylic acids.
A 1971 publication authored by Weisstuch et al., teaches that chelating agents, such as ethylenediaminetetraacetic acid, are useful as metal corrosion inhibitors in aqueous systems. These compounds achieve this result by being "chemisorbed" on the metal surface to form a metal-chelant complex layer. Similarly, Japanese Patent 57-152476 discloses the formation of a metal ligand layer comprising use of a composition consisting of benzotriazole and N-cyclic amines.
GENERAL DESCRIPTION OF THE INVENTION
The corrosion inhibitor of the present invention is intended to function in aggressive aqueous systems in contact with copper bearing metallurgies. Systems which are high corrosive to copper include brackish or salt water. Additionally, sulfides or what are commonly referred to as brines may be present.
Conventional copper corrosion inhibitors, such as azole compounds, are combined with certain chelants to form an inhibitor especially effective in the aggressively corrosive environments defined above. What is surprising is that these chelants, when used alone, are corrosive to copper metallurgy. Furthermore, the azoles alone are very ineffective under aggressive aqueous conditions. It is believed that these inhibitors are prevented from forming their usual passive film on the metallic surface because the copper ions which are produced at such a high rate under these aggressive circumstances complex with and deactivate the inhibitors. If excess inhibitor is used as undesireable insoluble copper/inhibitor complex forms which may lead to underdeposit corrosion.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered that in accordance with the method of the present invention a chelant which forms a stable, water soluble complex with copper, used in conjunction with a copper corrosion inhibitor will promote the formation of passive film to inhibit corrosion in aggressive aqueous systems.
This invention comprises combining azoles with certain select chelants. The azoles utilized according to the present invention generally include benzotriazole, benzimidazole, and mercaptobenzothiazole. The benzotriazole compound also encompasses its C 1 to C 6 alkyl derivatives, hydroxybenzotriazole and its C 1 to C 6 alkyl derivatives and carboxybenzotriazole and its C 1 to C 6 alkyl derivatives. These compounds have the formula: ##STR1## where X is H, OH, CO 2 H, or CnH 2 n+1, n=1 to 6, and Y is H, OH, CO 2 H, and Y≠X unless Y=H.
The benzimidazole compound also encompasses its C 1 to C 6 alkyl derivatives, hydroxybenzimidazole and its C 1 to C 6 alkyl derivatives and caroboxybenzimidazole and its C 1 to C 6 alkyl derivatives. These compounds have the formula: ##STR2## where X is H, OH, CO 2 H or CnH 2 n+1, n=1 to 6, and Y is H, OH, CO 2 H, and Y≠X unless Y=H.
the mercaptobenzothiazole compound also encompasses its C 1 to C 6 alkyl derivatives, hydroxymercaptobenzothiazole and its C 1 to C 6 alkyl derivatives, and carboxymercaptobenzothiazole and its C 1 to C 6 alkyl derivatives. These compounds have the formula; ##STR3## where X is H, OH, CO 2 H, or CnH 2 n+1, n=1 to 6, and Y is H, OH, CO 2 H, and Y≠X unless Y=H.
The chelants according to the present invention include ethylenediaminetetraacetic acid (EDTA), the mono-or triesters of EDTA, nitrilotriacetic acid or monoesters thereof, ethylenediamine mono or tricarboxylic acid, citric acid, its salts and derivatives thereof, tartaric acid, its salts and derivatives thereof, and dialkyldithiocarbomates.
The corrosion inhibitor may be added to the aqueous system to be treated as a preblended composition by combining the azole and chelant components beforehand, or each component may be added separately. The concentration of the two components may vary in response to different aqueous environments. Generally, however the azole compound may be added in an amount to maintain a concentration of from about 0.1 ppm to about 1000 ppm and the chelant may also be added in an amount to maintain a concentration of from about 0.1 ppm to about 1000 ppm, in excess of any competing demand by hardness ions present in the environment.
Beaker Tests
The following test results show the synergistic corrosion inhibition properties exhibited by combining an azole with a chelant. The tests were conducted at room temperature in 2 liter beakers. Water composition was as follows: (per liter) 25.22 g NaCl (15,300 ppm Cl), 16.82 g Na 2 SO 4 , 0.166 g NaHCO 3 and having a pH adusted to 8.15 with NaOH and H 2 SO 4 . No hardness ion was included so as not to interfere with the demand for chelant by the copper ion. Cupronickel (90/10) coupons were cleaned and weighed prior to immersion. The coupons were then exposed for 24 hours to one of the 9 test solutions identified below. They were then cleaned and reweighed. The results are as follows:
______________________________________butyl- tetra-sodiumbenzo- ethylenediamine Corrosion CopperTest triazole tetraacetic acid Rate ConcentrationNo. (ppm) (ppm) (MPY) (PPM)______________________________________1 5 0 13.1 0.372 5 1 12.8 0.523 5 5 16.3 0.614 50 5 4.2 <0.055 50 25 3.1 <0.056 0 100 21.6 11.87 0 0 16.3 0.138 100 0 1.1 <0.5*9 100 100 1.0 <0.5**______________________________________ *coupon had green tarnish on surface **coupon was clean and shiny
Tests 1-3 show that low concentrations of butyl-benzotriazole with or without the chelant do not inhibit corrosion of the copper alloy. Tests 6 and 7 indicate that the chelant alone is more aggressive than no chelant at all. Tests 8 and 9 show that even though very high levels of inhibitor can passivate the metal without chelant, an undesirable green tarnish develops in the absence of the chelant.
Recirculator Tests
In the tests, a hardness ion was included so as to stimulate sea water conditions. Accordingly, the Na 4 EDTA concentration was adjusted to take into account demand by the hardness ion. On this basis, 3.74 ppm of Na 4 EDTA was used for every 1.0 ppm of hardness ion, expressed as CaCO 3 equivalent.
Water conditions were as follows: (per liter) 11.831 g MgSO 4 .7H 2 O (4800 ppm as CaCO 3 ), 1.544 g CaCl 2 .2H 2 O (1050 ppm as CaCO 3 ), 23.997 g NaCl (15,300 ppm total Cl), 16.2 g Na 2 SO 4 and 0.166 g NaHCO 3 at 123° F. Total hardness was measured to be 5200 ppm as CaCO 3 .
To the water was added 19,800 ppm of Na 4 EDTA (3.74×5200+100) and 100 ppm of butyl-benzotriazole. The large concentration of Na 4 EDTA was required because the specific hardness ion used herein would complex with the chelant and thereby prevent it from interacting with the metal ion. Other hardness ions may not place such a demand, if any, on the chelant, therefore not requiring the loading of so much of the chelant into the system. Under conditions where there is no competing demand, the chelant concentration need not exceed 1,000 ppm. Six samples of cupronickel (90/10) coupons preweighed, immersed and weighed again as shown above. The coupons exhibited corrosion rates of between 0.02 and 0.07 mpy with no tarnishing of the metallurgy being evident.
While this invention has been described with respect to particular embodiments thereof, it is apparent that numerous other forms and modifications of this invention will be obvious to those skilled in the art. The appended claims and this invention generally should be construed to cover all such obvious forms and modifications which are within the true spirit and scope of the present invention. | A method for inhibiting the corrosion of copper or copper-bearing metals in contact with an aggressive aqueous environment by combining a copper corrosion inhibitor with a chelant. Azoles are employed as the corrosion inhibitor. Characteristic chelants include ethylenediamine tetracetic acid nitrilotriacetic acid, citric acid, tartaric acid and dialkyldithiocarbamates. | 2 |
FIELD OF THE INVENTION
[0001] This invention pertains to vehicle signalization accessories, and more particularly it pertains to an after market vehicle signalization system in the form of an universal retrofit kit.
BACKGROUND OF THE INVENTION
[0002] Conventional signalization for vehicles is generally limited to the brake lights at the rear end of a vehicle and the turn signal lights at both the front end and the rear end of the vehicle. It has been stated by numerous inventors in the past, that it would be safer to operate a motor vehicle if a driver could better predict the intentions of other drivers in nearby vehicles. Numerous proposals were made in that regard to add signalization on the outside of a vehicle in order to reduce the number of accidents involving motor vehicles.
[0003] Prior inventors have proposed in the 1960's or before, as a safety feature, an additional brake light in a highly visible location on the rear end of a vehicle, well above the regular brake lights. This courtesy brake light became standard on all automobiles and pickup trucks since the 1970's, and is now considered essential to safe driving. Similarly, prior inventors have proposed in the 1930's or before, a signalization system including an amber light to signal a deceleration by compression of the engine, a green light to signal an acceleration or a steady speed, and of course, a red light in the front as well as in the back of the vehicle to indicate a braking condition. However, these additional light circuits require the installation of switches to detect the movements of the arms of the brake and the accelerator pedals, additional light modules to be affixed to the outside of the vehicle and additional wiring. The cost of these accessories would have been passed on the purchaser of the vehicle or taken out from the manufacturer's profit. It is believed that it is for that reason, basically, that only the brake light in the back, and the turn signal lights were considered essential and were kept in the standard design. Consequently, the amber and the green light proposals never enjoyed a commercial success.
[0004] Examples of the signalization systems proposed by prior inventors are listed below:
U.S. Pat. No. 2,096,069 issued to E. J. Seiden on Oct. 19, 1937; U.S. Pat. No. 2,128,769 issued to L. O. Finnell on Aug. 30, 1938; U.S. Pat. No. 2,250,133 issued to E. S. Pearce et al. on Jul. 22, 1941. U.S. Pat. No. 2,463,088 issued to R. S. Coombs on Mar. 1, 1949; U.S. Pat. No. 2,513,712 issued to R. S. Coombs on Jul. 4, 1950; U.S. Pat. No. RE. 23,719 issued to R. S. Coombs on Oct. 6, 1953; U.S. Pat. No. 3,109,158 issued to R. S. Coombs on Oct. 29, 1963; U.S. Pat. No. 3,115,559 issued to L. G. Cass et al. on Dec. 24, 1963; U.S. Pat. No 3,395,388 issued to J. R. Hendrickson on Jul. 30, 1968; U.S. Pat. No 3,497,871 issued to A. S. Damico on Feb. 24, 1970; U.S. Pat. No 4,491,824 issued to N. M. Chiou on Jan. 1, 1985; U.S. Pat. No 4,933,666 issued to H. G. Maple on Jun. 12, 1990; U.S. Pat. No. 4,891,625 issued to B. C. VanRiper et al. on Jan. 2, 1990; U.S. Pat. No. 5,164,701 issued to C. Nan-Mu et al. on Nov. 17, 1992; U.S. Pat. No 5,663,707 issued to G. M. Bartilucci on Sep. 2, 1997; U.S. Publ. US2002/0171543 of D. C. Abbe et al. dated Nov. 21, 2002; U.S. Publ. US2003/0234724 of C. P. Chiu dated Dec. 25, 2003; CA Appl. 2,007,060 of R. Dugas et al. published on Jul. 03, 1991; CA Appl. 2,015,418 of N. M. Chiou, published on Oct. 25, 1991.
[0024] Although the devices and apparatus of the prior art deserve undeniable merits, is believed that these prior art systems can only be installed at the factory during the construction of the vehicle, or in the dealers' garages by technicians specialized in the electrical systems of motor vehicles. It is believed that the installation of any of the signalization systems of the prior art would have been relatively costly, and therefore, these systems did not appeal to a majority of vehicle owners.
[0025] Therefore, it is believed that a market demand still exists for better signalization on the outside of a motor vehicle, and especially for a better and easier method of installing the additional signalization without having to tap into the existing wiring system of the vehicle or to attach switches to hard-to-reach places under the dashboard of the vehicle.
SUMMARY OF THE INVENTION
[0026] The vehicle signalization system according to the present invention, comprises a limit switch assembly wherein the limit switches are pre-wired with a colour coded wiring system and connectors, and are adjustably affixed to a post that is easily mountable by bonding to the firewall of the vehicle, between the brake pedal and the accelerator pedal. The wiring system has a connection to the battery of the vehicle such that no interference with the wiring system or the fuse box of the vehicle is required. The vehicle signalization retrofit kit according to the present invention is mountable in various makes and models of vehicles without drilling, tapping, or modifying in any way the structure or the electrical system of the vehicle.
[0027] In a broad aspect of the present invention, there is provided a vehicle signalization retrofit kit, comprising a pair of light modules each having coloured lights of red, amber and green colours. A colour-coded wiring system is provided for supplying power directly from the battery of the vehicle to the light modules. The colour codes on the wiring correspond to the colours of the coloured lights. A first and second limit switches are also provided and are connected to the wiring system for controlling the lighting up of the coloured lights according to various conditions of the switches. There is also provided a switch post to which the limit switches are adjustably mounted. This switch post has a base that is attachable by bonding to the firewall of a vehicle.
[0028] This vehicle signalization retrofit kit is by its configuration easily installed in a vehicle without special tools or special knowledge of the electrical system of that vehicle.
[0029] In another aspect of the present invention, the wiring system and the limit switches are connected in such a way as to energize only the red lights, only the amber lights, or only the green lights at the same time. The limit switches and the wiring system are also connected in such a way that the amber and green lights are positively de-energized when the red lights are lit up such that the red lights have priority over the other ones.
[0030] In yet another aspect of the present invention, the wiring system comprises several series of single-wire connectors, such that portions of the wiring system can be threaded, one connector at the time, through relatively small openings out of the passenger compartment of a vehicle.
[0031] In yet another aspect of the present invention, each light module has mounting tabs hinged to the housing thereof for easy mounting of the light module to various portions of a vehicle. Furthermore, the housing of each light module is made of a malleable material so that it can be shaped to accommodate the curvature of the portion of the vehicle on which it is mounted. It is believed that the light modules included in the retrofit kit according to the present invention do not lessen the visual appeal of any modem vehicle on which they are mounted.
[0032] This brief summary has been provided so that the nature of the invention may be understood quickly. A more complete understanding of the invention can be obtained by reference to the following detailed description of the preferred embodiment thereof in connection with the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] One embodiment of the present invention is illustrated in the accompanying drawings, in which like numerals denote like parts throughout the several views, and in which:
[0034] FIG. 1 is a perspective view of the vehicle signalization retrofit kit according to the preferred embodiment of the present invention;
[0035] FIG. 2 is a perspective cutaway view through the dashboard of a vehicle showing the mounting of the switch post of the preferred vehicle signalization retrofit kit to the firewall of the vehicle;
[0036] FIG. 3 is a perspective front and top view of a vehicle having a pair of the signalization light modules as described herein, mounted thereto;
[0037] FIG. 4 is a top view of the switch post in an installed position;
[0038] FIG. 5 is rear view of the switch post in an installed position;
[0039] FIG. 6 is an enlarged top view of the base of the switch post and of its mounting to the firewall of a vehicle;
[0040] FIG. 7 is schematic diagram of the wiring system in the vehicle signalization retrofit kit according to the preferred embodiment.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0041] While this invention is susceptible of embodiment in many different forms, there is shown in the drawings and will be described in details herein one specific embodiment, with the understanding that the present disclosure is to be considered as an example of the principles of the invention and is not intended to limit the invention to the embodiment illustrated and described.
[0042] Referring firstly to FIG. 1 , the basic components of the preferred universal retrofit kit 20 are illustrated therein. The preferred retrofit kit comprises a pair of limit switches 24 , 26 mounted to a switch post 28 . A wiring system is provided and is generally labelled as 30 . A pair of light modules 32 are provided for attachment to the front end and to the rear end of a vehicle. Illuminated monitoring switches 34 are optional. These switches 34 are optionally provided for mounting inside the vehicle for monitoring the operation of the light modules 32 .
[0043] The switch post 28 has an enlarged base 36 for bonding to the firewall of a vehicle, as it will be explained later. The limit switches 24 , 26 are mounted to the switch post 28 by means of tube clamps 38 . The clamps 38 are mounted to the switch post 28 with a sliding fit tolerance or tension, such that the limit switches 24 , 26 can be adjusted along and around the switch post 28 by a force of approximately 5 lbs.
[0044] The wiring system 30 comprises several series of single-wire connectors 40 such that portions of this wiring system can be threaded, one connector at the time, into a relatively small hole through the firewall of the vehicle, or alongside existing conduits or cables extending outside the passenger compartment of the vehicle.
[0045] Each light module 32 is made of coloured light emitting diodes (LEDs) 50 mounted side by side in a sealed housing 52 . These diodes 50 are arranged in sets of three, aligned behind a clear lens 54 . Each set of diodes 50 , contains a red diode, an amber diode and a green diode. For convenience, the word diodes and lights are used interchangeably herein to refer to the light emitting diodes 50 .
[0046] It will be understood from the following description, that the red light indicates a braking condition, the amber light indicates a coasting condition, where the operator of the vehicle does not apply pressure on neither the brake pedal nor the accelerator pedal, and the green light indicates an accelerating or constant speed condition, where the accelerator pedal is depressed at least a small amount.
[0047] There are also provided on the housing 52 of each light module 32 , a series of tabs 56 affixed to the housing 52 by means of respective hinges 58 . Each tab 56 preferably has on its surface, an adhesive tape, a mounting hole, or other means of attachment of the tab to a vehicle. The hinges 58 are adjustable to mount each light module 32 to any of several preferred locations on a vehicle. The hinges 58 have a tight fit tolerance in their moving parts so as to retain an initial adjustment thereof on a vehicle under normal driving conditions.
[0048] The housing 52 of each light module preferably has a length of about 6-10 inches, a thickness of about 3/8 to 3/4 inch, and a depth of 3/4 to 1½ inches. It preferably has a sleek design and a moderate bow shape with the ends pointing toward the rear side thereof, as illustrated in FIG. 1 . Each housing 52 is preferably made of a plastic material that is somewhat malleable and that has shape-retention memory, such that it can be bent to some degrees lengthwise and crosswise to match various curvatures on the vehicle on which it is mounted.
[0049] Referring now to FIGS. 2 and 3 , the switch post 28 is preferably affixed to the firewall 60 of a vehicle, between the brake pedal 62 and the accelerator pedal 64 , under or immediately below the dashboard 66 of the vehicle.
[0050] One of the light modules 32 is preferably mounted at any convenient location on the front end of a vehicle 70 such that it can be easily seen by approaching traffic and pedestrians. The other light module 32 is preferably affixed to another highly visible location on the rear end of the vehicle. One advantage of having the signalling light module 32 on the front end of a vehicle is that it indicates to pedestrians at an intersection for example, the running condition of an approaching vehicle. These pedestrians can readily detect the intentions of the driver in that vehicle, and decide whether or not they should walk in the front of it. One advantage of the rear light module 32 is to provide a driver in a following vehicle with the ability to predict a deceleration by compression of the engine, and an eventual braking of the vehicle ahead of him.
[0051] Referring now to FIGS. 4, 5 and 6 , the mounting of the limit switches 24 , 26 and of the switch post 28 will be explained in greater details. The limit switches are of the type having a normally open contact, a normally closed contact and a respective wand 72 extending at least about 3½ to 4 inches from the axis of the switch post 28 . One example of such limit switches is a Model Z, General Purpose Basic Switch, available from Omron™ Canada Inc. a Company having its head offices in Scarborough, Ontario, Canada.
[0052] The switch post 28 with the limit switches 24 , 26 mounted thereto is held between the brake pedal and the accelerator pedal of the vehicle at a location that is high enough so not to interfere with the foot movement of the driver, and where the wands 72 of the limit switches 24 , 26 are respectively in contact with the arm 62 of the brake pedal and with arm 64 of the accelerator pedal. The location of the base 36 of the switch post 28 is then marked on the firewall 60 of the vehicle.
[0053] Then, the carpet 74 of the firewall 60 is cut out and the metal of the firewall 60 is exposed over an area 76 corresponding to the location of the base 36 of the switch post. Using a resinous bonding compound 78 , often referred to as plastic metal or plumber putty, the base 36 of the switch post is bonded to the bare metal of the firewall 76 . A typical shear strength of the preferred bonding compound is 3,000 psi. An example of such a bonding compound 78 is marketed under the name Cold Weld™, by Permatex™, Inc., a company having its head offices in Solon, Ohio, USA. A sufficient amount of an appropriate bonding compound 78 is preferably included in the preferred vehicle signalling retrofit kit, such that it is readily available to the purchaser of the preferred retrofit kit.
[0054] In order to ensure a strong bond between the base 36 of the switch post and the firewall, the base 36 has a hollow shape and several radial holes 80 near the rim of the base. A sufficient amount of bonding compound 78 should be used to partly fill the hollow shape of the base 36 and to flow out through these holes 80 . The switch post 28 is then held in place for a few minutes until the bonding compound starts to take hold.
[0055] A preferred material of construction for the switch post 28 is a nominal 1/2 inch copper tubing and the preferred material of construction for the base 36 is a tubing reducer coupling having a nominal size of 1/2 inch to 3/4 inch. It will be appreciated that the switch post 28 , and the base 36 can be manufactured from materials other than copper, depending upon the preference of the manufacturer.
[0056] When the bonding compound has set or hardened to hold the switch post 28 in place, such as after a period of 15-30 minutes or so, the limit switches 24 , 26 can be adjusted to their final positions. The adjustment of both switches is done by moving them along the switch post 28 until their wands 72 touch the arms 62 , 64 of the brake and accelerator pedals respectively, and the normally open contact in each switch is closed. The switches are further moved slightly toward the arms 62 , 64 of the pedals such that a pre-travel of approximately 1/16 to 1/8 of an inch is required in each pedal to change the state of the switches.
[0057] It will be appreciated that the stress on the switch post 28 is maximum at the initial position of the switches 24 , 26 as described above. The force on the wands 72 of the switches is a fraction of one pound. Therefore, the force required to hold the limit switches in place along the switch post 28 and the overall stress on the switch post 28 is negligible as compared to the holding strength of the bonding compound specified above. The sturdiness of this installation is believe to be sufficient to last the life of the vehicle.
[0058] In order to further simplify the work required to install the preferred retrofit kit, the wiring of the switches 24 , 26 is preferably done before bonding the switch post in place and adjusting the position of the switches. In fact, the connection of the wiring system 30 to the limit switches 24 , 26 is preferably effected at the factory before the packaging of the retrofit kit and its distribution to retail outlets. These connections have been omitted in FIGS. 1, 2 , 4 and 5 to maintain the clarity of these drawings.
[0059] The wiring of the switches 24 , 26 and of the light modules 32 is illustrated in FIG. 7 . The wiring system 30 is preferably connected directly to the battery 90 of the vehicle. The wiring system 30 preferably comprises a fuse 92 and an on-off switch 94 . The power is firstly supplied to the common terminal of the brake pedal switch 24 . The initial pre-tensioning of the wand 72 of the brake pedal switch 24 as described before, closes the normally open contact of that switch 24 to transmit power to the common terminal of the accelerator pedal switch 26 . When the wand 72 of the brake pedal switch 24 is released from its tensioned position, the power is cut off to the accelerator pedal switch 26 and is applied to the normally closed terminal of the brake pedal switch 24 , thereby energizing the red diodes, labelled as “R” on the diagram of FIG. 7 . It will be appreciated from the above description that the red diodes have precedence over the other lights.
[0060] During all non-braking conditions, power is available to the accelerator switch 26 , to light up either the amber “A” or the green “G” diodes, of which the respective wiring is labelled by the same letters, or coded with the same colours.
[0061] When the accelerator pedal is at rest, the normally open contact of the accelerator pedal switch 26 is closed, thereby energizing the amber “A” diodes in the light modules 32 . When the accelerator pedal is depressed, the green “G” diodes are lit up.
[0062] The wiring system 30 comprises several series of single-wire connectors 40 to facilitate the threading of the wiring through relatively small openings out of the passenger compartment of the vehicle. One series of connectors 96 is preferably provided for connection to the illuminated monitoring switches 34 . Another series of connectors 98 is preferably provided for connection to a third light module mounted on a trailer towed behind the vehicle for example. One or more extensions 100 are provided for connection of the light modules 32 to the switches 24 , 26 . The connectors in each series 40 are preferably coloured or colour coded according to the colours of the diodes energized therefrom, with the ground connectors 102 left unmarked or coloured white.
[0063] The coloured diodes 50 in each light module 32 are typically 3 volt LEDs. Each diode 50 is connected to the wiring system in series with a 470 ohm resistor 104 .
[0064] The vehicle signalization retrofit kit described above does not tap into the existing wiring system of an automobile and is easily adjusted to various configurations of brake pedals, accelerator pedals and various vehicle interiors.
[0065] Furthermore, the vehicle signalization retrofit kit according to the present invention operates equally well when the vehicle is travelling in a cruise controlled mode. In the cruise controlled mode, the accelerator pedal still moves as if it was operated by the foot of the driver. This movement is detected by the accelerator limit switch 26 to operate the light modules accordingly.
[0066] As to other manner of usage and operation of the retrofit kit of present invention, the same should be apparent from the above description and accompanying drawings, and accordingly further discussion relative to the manner of usage and operation of the invention would be considered repetitious and is not provided.
[0067] While one embodiment of the present invention has been illustrated and described herein above, it will be appreciated by those skilled in the art that various modifications, alternate constructions and equivalents may be employed without departing from the true spirit and scope of the invention. Therefore, the above description and the illustrations should not be construed as limiting the scope of the invention which is defined by the appended claims. | The vehicle signalization retrofit kit according to the present invention comprises a limit switch assembly wherein a pair of limit switches are pre-wired with a colour coded wiring system and connectors, and are adjustably affixed to a post that is easily mountable by bonding to the firewall of a vehicle, between the brake pedal and the accelerator pedal. The wiring system has a connection to the battery of the vehicle such that no interference with the wiring system or the fuse box of the vehicle is required. The retrofit kit also has a pair of light modules each having coloured lights of red, amber and green colours. One light module is mountable to the front end of the vehicle and the other is mountable to the rear end of the vehicle for communicating to nearby drivers and pedestrians various operating conditions of the vehicle, such as braking, decelerating and accelerating. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to automated decoration of cakes, cookies, pastries or other foodstuffs based on an existing photograph, drawing or other art work. More specifically, the invention provides an integrated system employing a scanner for inputting the desired art work, an operator interface incorporating a display and control entry system, a high accuracy, high definition imaging head having a colorant dispensing cartridge and two axis motion and positioning for the colorant dispensing cartridge.
2. Prior Art
Decorated cakes and foodstuffs have long been a popular commercial item for bakeries. Birthday parties, anniversaries, special holiday occasions and weddings are typically occasions celebrated with highly decorated cakes or pastries. Until recently, the majority of cake decorating has been accomplished by hand application of colored frostings by skilled bakery artisans. This process is time consuming and labor intensive. Further, only trained personnel can accomplish the cake decorating tasks.
Recently, automated systems for cake decoration have appeared on the market which allow basic lettering and crude shape decorating on an automated basis. These systems provide some cost savings for bakeries and their patrons, however, detailed decorating is not provided by these systems. More sophisticated systems, such as those disclosed in U.S. Pat. No. 4,910,661 to Barth et al., provide greater flexibility in decoration. However, these systems are complex, require significant bulky and expensive componentry for operation such as video cameras, computer systems and video terminals and typically require operator training to employ the full capabilities of the system.
Automated application of colorant to the surface of a cake or other pastry requires special system considerations due to the uneven surfaces and textures present on the majority of these food articles. Application of high definition coloring simulating photographs or other art work has not previously been achievable.
It is therefore desirable for a cake decorating system to provide ease of use by patrons of a bakery directly or bakery personnel without significant training and employing a system which is compact and eliminates extraneous bulky and complex componentry. It is further desirable that such a system provide high definition imaging transfer to the surface of the foodstuff being decorated. The present invention overcomes the shortcomings of the prior art in providing a cake decorating system meeting these requirements.
SUMMARY OF THE INVENTION
The present invention provides a self contained cake decorating system employing a horizontal work surface with an integrated flatbed scanner disposed in a first portion of the work surface, an operator interface incorporating a menu display and selection system integrally disposed in a second portion of the work surface and a cake decorating station employing alignment guides for positioning the cake to be decorated on the work surface. A color cartridge employing multicolor edible dyes expelled on command through multiple orifices in a nozzle plate is carried by a multi-axis positioning system having a travelling arm extending over the work surface.
An integrated control system provides menu outputs to the operator display and receives operator input for command selection on cake size, scanned image size, and enlargement/reduction of the scanned image size for application to the cake surface. The control system controls and retrieves the scanned image and controls motion of the cartridge positioning system and ejection of colorant by the cartridge to reproduce the scanned image on the cake surface.
The integrated work surface with scanner, operator interface and the colorant application system including the cartridge and positioning mechanism is carried on a wheel mounted support frame for easy positioning and portability.
BRIEF DESCRIPTION OF THE DRAWINGS
The details of the present invention are more clearly understood with reference to the following drawings and detailed description.
FIG. 1 is a top view of the cake decorating system showing the work surface with integrated scanner, operator interface, cake alignment guides and cartridge support arm.
FIG. 2 is a side view of the cake decorating system showing the cartridge carrying travelling arm and motion system arrangement.
FIG. 3 is a front view of the cake decorating system showing relative positioning of the color cartridge and travelling arm with the work surface.
FIG. 4 is a front view of the colorant cartridge demonstrating relative positioning to the cake being decorated.
FIG. 5 is a bottom view of the nozzle plate of the colorant cartridge.
FIG. 6 is a detailed pictorial view of the colorant cartridge travelling arm and motion system.
FIG. 7 is a block diagram of the control system and its relationship to the other components of the cake decorating system.
FIG. 8 is a flow chart describing operation of the control system.
FIG. 9A-C are exemplary menu displays employed on the operator interface.
DETAILED DESCRIPTION
The basic elements of the cake decorating system are shown in FIG. 1. The cake decorating system 10 incorporates a work surface 12. A flatbed scanner 14 is incorporated into the work surface. An operator interface 16 employing a display and entry keys, to be explained in greater detail subsequently, is also incorporated into the work surface.
The scanner in the present embodiment comprises a flatbed color image scanner which is incorporated in a flush mount into the work surface. As shown in FIG. 1, a first portion of the work surface is dedicated to the scanner at an opposite corner of the work surface from the guides available for positioning the cake or other workpiece. This arrangement allows placement of a photograph or other art work in the scanner and a cake to be decorated to be located on the guides for contemporaneous scanning and printing of the image.
The operator station incorporating the display and keypad is incorporated in a portion of the work surface displaced from the scanner and guides whereby menus presented on the display may be read with the photograph on the scanner and cake in place on the work surface if desired.
Perpendicular guides 18 are inscribed on or attached to the work surface to provide a reference for positioning the cake, pastry, cookie, or other food article to be decorated on the work surface.
As best seen in FIG. 2, a colorant cartridge 20 is carried over the work surface by a motion system 22 having a travelling arm 24 to support the color cartridge over the work surface and provide one axis of motion for the color cartridge and a vertical stanchion 26 supporting the travelling arm. The vertical stanchion is carried on a bearing block riding on a slide attached to the structure of the cake decorating system for motion in the second axis as will be described in greater detail subsequently. In the embodiment shown, the travelling arm position on the vertical stanchion is adjustable for positioning of the color cartridge height over the work surface for a third axis of motion.
In the embodiment shown in the drawings, the work surface is surrounded on three sides by raised bumper elements 28 which provide some protection for the work surface and the components incorporated therein and precludes inadvertently pushing a cake or other item to be decorated off the back or sides of the work surface as best seen in FIG. 3. The embodiment shown in the drawings incorporates a support structure having side legs 30 with casters or wheels 32 for easy mobility of the unit. The body 34 of the unit provides a closed case for the control system and components of the scanner and operator station extending below the work surface.
The color cartridge employed in the present embodiment of the invention is shown schematically in FIG. 4. A drop-on-demand colorant expulsion system 36 employs food coloring reservoirs 38 for three colors (red, blue and yellow) which are ejected through a nozzle plate 40 onto the cake 44. Details of the nozzle plate are shown in FIG. 5.
The nozzle plate comprises three groups of orifices 42, each group containing 16 orifices for expulsion of colorant. The orifices in each group are contained in two columns of eight separated by approximately 0.025 inch and spaced over a 0.050 inch lateral extent. The orifices in each column are offset by one half the orifice spacing to allow more complete colorant coverage. The drop-on-demand expulsion system employed in the present embodiment incorporates components common with the Hewlett Packard 500C Desk Jet Color Printer. As shown in FIG. 4, the color cartridge is positioned between 0.005 inches to 0.75 inches above the surface of the article being decorated.
The drop on demand colorant expulsion system as described allows one pass, three color printing on the article being decorated. Resolution of 0.006 to 0.008 inches is available with this system. Employing a dithering pattern centerline of the colorant drops can approach 0.003 inch separation.
An alternative embodiment of the present invention employs piezo electric expulsion tubes for providing colorant.
As best seen in FIG. 6, the arm supporting the color cartridge incorporates two parallel guideway slides 46 on which a first bearing block 48 rides. The bearing block in turn supports the color cartridge. The parallel guides produce rigid orientation of the color cartridge transverse to the "Y" axis of travel provided by the dual slides. A first drive motor 50 is employed for positioning the color cartridge in the "Y" axis. In the embodiment shown in the drawings, a cog belt 52 riding on a drive pulley 54 on the motor and idler pulley 56 distal the motor on the support arm, is attached to the slide block by connector 58. Forward and reverse drive of the first drive motor allows positioning of the color cartridge at any desired location on the slide bars.
The support arm is carried by the vertical support stanchion 26. In the embodiment shown in the drawings, the support arm is movably positionable on the vertical support stanchion to allow adjustment of the color cartridge height over the cake or other item being decorated. The vertical support stanchion is in turn carried by a bearing block 60 which rides on a precision slide assembly 62 for motion along an "X" axis relative to the work surface. A second drive motor with cog belt and pulley system, or precision direct drive stepper motor attached to the bearing block and engaging a gear rack on the precision slide (not shown) is employed for positioning of the bearing block in the "X" axis. The precision slide assembly is mounted to the structure of the decorating unit adjacent the work surface as best shown in FIG. 2.
In the present embodiment, control of vertical positioning of the support arm incorporates a motor system (not shown) similar to that described for the "X" and "Y" axis positioning of the color cartridge. A proximity sensing means is employed to enable automatic height adjustment to maintain optimum imaging head to target surface standoff for work piece heights from 0 to 15 centimeters (0 to 6 inches). The "Z" axis servo system is capable of maintaining standoff spacing within 1 millimeter tolerance over target surface slopes up to 15 degrees at maximum slew rates for the X/Y motion of the positioning system for the color cartridge.
The control system of the present invention is shown in block diagram form in FIG. 7. Process control is provided by a central processor 64 which in the present embodiment comprises an Intel 80486 microprocessor. Data storage in the form of a random access memory 66 and storage disk 68 are connected to the central processor. Software for the system, generally designated 70, will be described in greater detail subsequently. The central processor provides menu prompts for operation of the system on the user menu display 70 which comprises a portion of the operator interface 16 previously discussed with regard to FIG. 1. User input keys 72 provide input to the central processor based on the operations desired by the user in response to the menu displays. The scanner 14 provides data of the image to be produced to the central processor which stores the image in memory or on disk as a monochrome or polychrome pixel map.
Production of the image by the decorating system on the cake or other work piece, is accomplished through control of the central processor of a motor controller 76 and imaging head drivers 78. The motor controller provides servo control for positioning of the color cartridge over the work surface. In the embodiment of the present invention, the motor controller provides incremental step pitch of no greater than 0.1 millimeters (0.004 inches). Feedback control in the servo system allows absolute positioning accuracy with respect to the pixel map.
The motor controller provides position and rate signals to the "X," "Y" and "Z" axis motors (generally designated 50 in FIG. 7).
In addition, the central processor controls colorant expulsion through imaging head drivers 78 which in turn control the color cartridge 20 previously described. Control of positioning and colorant expulsion creates the output image on the surface of the cake or other work piece.
Operation of the software in the system is generally shown in FIG. 8. Upon initiation of the system in block 80, the central processor causes a welcome message to be printed to the display in block 82. An exemplary form of the welcome message is shown in FIG. 9A which provides a representation of the operator interface display screen and input key pad. In the present embodiment of the invention, the display comprises an LCD multiline display and the input key pad incorporates five capacitive switches activated by operator contact with a finger. Alternative embodiments of the invention employ a "touch screen" system incorporating the "key pad" within the LCD display itself.
The controller awaits contact with any key by the operator in block 84. Upon key contact, a "select cake size" display is provided, block 86, which is represented in FIG. 9B. A question is provided on the LCD display to the operator "what size cake would you like to decorate" and options, including "4×4 inches," "6×8 inches," "8×10 inches" and "other" are provided adjacent the key pad switches. Selection of the desired size by the operator is input to the central processor. In the embodiment shown, selection of the "other" key by the operator prompts a secondary menu with additional sizes for the cake or workpiece for example, "16×24 inches," "3 inch cupcake," "8 inch round" and "other." Those skilled in the art will recognize that nesting of additional options based on the "other" key may be provided to any desired level.
An escape key is provided to allow return to the prior menu at any time. Operation of the escape key is represented in blocks 88. Operator contact with a cake size key results in storage of the size selection by the central processor. The central processor then provides a prompt on the display screen for selection of size of the input picture, block 90, which will be placed by the operator on the scanner. Selection of picture size is accomplished through a plurality of menus as previously described for selection of cake size. Upon selection of picture size, the central processor then provides a menu for the operator to select a "zoom option," block 92, for enlargement or reduction of the scanned picture size to the cake size. Selections for percentage enlargement or percentage reduction of 25%, 50%, 100%, 200% as exemplary values are provided to the operator for selection.
Upon completion of the selection, the controller will provide a menu instruction to the operator verifying selection of the cake size, input picture size and zoom reduction and instructions to place the picture in the scanner and the cake or work piece on the work surface aligned with the guides, block 94, followed by instructions to select "start" or "cancel" on designated input keys. Upon selection by the operator of the cancel or start key, block 96, the central processor will return to cake size selection (based on selection of cancel by the operator) or begin the scanning and printing process, block 98. The central processor controls the printing of the image on the cake or other work piece as previously described and monitors for completion of the printing process, block 100. Upon completion of the printing process, a message to the operator is printed on the display, block 102, designating a completed process and offering the option of printing another cake. Selection of the additional print option, block 104, returns the process to block 94 for printing of an additional cake using the processes previously described.
The present embodiment of the system senses key presses during the printing process and upon sensing a key press, block 106, determines if the cancel key has been pressed during the printing process. If the cancel key has in fact been pressed, block 108, the system resets the scanner and printer, block 110, and returns to the select cake size selection of block 86.
Having now described the invention in detail as required by the patent statutes, those skilled in the art will recognize modifications and substitutions to the elements of the invention as disclosed to accommodate specific applications or embodiments. Such modifications and substitutions are within the scope and intent of the invention as defined by the following claims. | A cake decoration system employing an integrated work surface having integral cake positioning guides in a first portion of the surface, a flat bed image scanner in a second portion of the surface, and an operator interface with display and entry keys incorporated in a third portion of the work surface provides an efficient self-contained cake decorating station. A motion control system using a traveling arm extending over the work surface to carry a colorant cartridge with a drop on demand colorant expulsion system all under the control of a central processor allows transfer of images obtained on the scanner to the surface of a cake to be decorated by use of a pixel map. Use of a multiple orifice drop on demand colorant expulsion system allows one pass three color printing on the article being decorated. | 0 |
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 61/506,366, filed Jul. 11, 2011, the disclosure of which is hereby incorporated in its entirety herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel polycyclic pyrrolidine-2,5-dione derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide receptor like-1 (FPRL-1) receptor. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with the N-formyl peptide receptor like-1 (FPRL-1) receptor modulation.
BACKGROUND OF THE INVENTION
[0003] The N-formyl peptide receptor like-1 (FPRL-1) receptor is a G protein-coupled receptor that is expressed on inflammatory cells such as monocytes and neutrophils, as well as T cells and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology. FPRL-1 is an exceptionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including Serum amyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocorticoid-modulated protein annexin A1. FPRL-1 transduces anti-inflammatory effects of LXA4 in many systems, but it also can mediate the pro-inflammatory signaling cascade of peptides such as SAA. The ability of the receptor to mediate two opposite effects is proposed to be a result of different receptor domains used by different agonists. Parmentier, Marc et al. Cytokine & Growth Factor Reviews 17 (2006) 501-519.
[0004] Activation of FPRL-1 by LXA4 or its analogs and by Annexin I protein has been shown to result in anti-inflammatory activity by promoting active resolution of inflammation which involves inhibition of polymorphonuclear neutrophil (PMN) and eosinophils migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner. In addition, FPRL-1 has been shown to inhibit natural killer (NK) cell cytotoxicity and promote activation of T cells which further contributes to down regulation of tissue damaging inflammatory signals. FPRL-1/LXA4 interaction has been shown to be beneficial in experimental models of ischemia reperfusion, angiogenesis, dermal inflammation, chemotherapy-induced alopecia (Peptides 27, 2006, 820-826), ocular inflammation such as endotoxin-induced uveitis, corneal wound healing, re-epithelialization etc. FPRL-1 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in diseases with excessive inflammatory responses.
SUMMARY OF THE INVENTION
[0005] We have now discovered a group of novel polycyclic pyrrolidine-2,5-dione derivatives which are potent and selective FPRL-1 modulators. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of FPRL-1 receptor. The term “modulator” as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
[0006] This invention describes compounds of Formula I, which have FPRL-1 receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by FPRL-1 modulation.
[0007] In one aspect, the invention provides a compound having Formula I or the geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
[0000]
[0000] wherein:
X is O or S; R 1 is substituted or unsubstituted —C 1-6 alkyl, substituted or unsubstituted —C 2-6 alkenyl, substituted or unsubstituted —C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted aryl; R 2 is H, halogen, substituted or unsubstituted —C 1-6 alkyl, substituted or unsubstituted —C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted aryl; R 3 is H, substituted or unsubstituted —C 1-6 alkyl, substituted or unsubstituted —C 2-6 alkenyl, or substituted or unsubstituted —C 2-6 alkynyl; and R 4 is H, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 cycloalkenyl, substituted or unsubstituted heterocycle or substituted or unsubstituted aryl.
[0013] In another aspect, the invention provides a compound having Formula I wherein:
X is O.
[0015] In another aspect, the invention provides a compound having Formula I wherein:
X is O;
[0017] R 1 is substituted or unsubstituted heterocycle or substituted or unsubstituted aryl;
R 2 is H; R 3 is H or substituted or unsubstituted —C 1-6 alkyl; and R 4 is H.
[0021] In another aspect, the invention provides a compound having Formula I wherein:
X is O; R 1 is substituted or unsubstituted pyridyl or substituted or unsubstituted phenyl; R 2 is H; R 3 is H or substituted or unsubstituted —C 1-6 alkyl; and R 4 is H.
[0027] In another aspect, the invention provides a compound having Formula I wherein:
X is O; R 1 is 4-bromophenyl, 4-(methylthio)phenyl, 4-chlorophenyl, 4-(methylsulfonyl)phenyl, 4-iodophenyl, 4-ethylphenyl, 4-acetylphenyl, 6-chloropyridin-3-yl, 4-fluorophenyl or 4-methoxyphenyl; R 2 is H; R 3 is H or methyl; and R 4 is H.
[0034] In another aspect, the invention provides a compound having Formula I wherein:
X is O; R 1 is 4-bromophenyl, 4-(methylthio)phenyl, or 4-methoxyphenyl; R 2 is H; R 3 is H; and R 4 is H.
[0040] The term “alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 6 carbon atoms. One methylene (—CH 2 —) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, NH, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amido, sulfonamido, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkyl groups can be independently substituted by halogen, hydroxyl, cycloalkyl, amino, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamides groups, aldehyde, ketone or ester groups.
[0041] The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen, hydroxyl, cycloalkyl, amino, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamides groups, aldehyde, ketone or ester groups.
[0042] The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by halogen, hydroxyl, cycloalkyl, amino, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamide groups, aldehyde, ketone or ester groups.
[0043] The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.
[0044] The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by C 1-8 alkyl, as defined above, or by halogen.
[0045] The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. Alkynyl groups can be substituted by C 1-8 alkyl, as defined above, or by halogen.
[0046] The term “heterocycle” as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C═O; the S and N heteroatoms can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen, hydroxyl, cycloalkyl, amino, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamides groups, aldehyde, ketone or ester groups.
[0047] The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can be substituted by halogen, hydroxyl, cycloalkyl, amino, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, sulfonamides groups, aldehyde, ketone or ester groups. Usually aryl is phenyl. Preferred substitution site on aryl are the meta and the para positions. Most preferred substitution sites on aryl are the para positions.
[0048] The term “hydroxyl” as used herein, represents a group of formula “—OH”.
[0049] The term “carbonyl” as used herein, represents a group of formula “—C(O)—”.
[0050] The term “carboxyl” as used herein, represents a group of formula “—C(O)O—”.
[0051] The term “sulfonyl” as used herein, represents a group of formula “—SO 2 —”.
[0052] The term “sulfate” as used herein, represents a group of formula “—O—S(O) 2 —O—”.
[0053] The term “sulfonate” as used herein, represents a group of the formula “—S(O) 2 —O—”.
[0054] The term “amino” as used herein, represents a group of formula NR x R y ,” wherein R x and R y can be independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
[0055] The term “ketone” as used herein, represents a group of formula —C(O)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
[0056] The term “carboxylic acid” as used herein, represents a group of formula “—C(O)ON”.
[0057] The term “ester” as used herein, represents a group of formula —C(O)OR x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
[0058] The term “nitro” as used herein, represents a group of formula “—NO 2 ”.
[0059] The term “cyano” as used herein, represents a group of formula “—CN”.
[0060] The term “amide” as used herein, represents a group of formula “—C(O)NR x R y ,” wherein R x and R y can be independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
[0061] The term “amido” as used herein, represents a group of formula “—C(O)NR x —,” wherein R x can be H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
[0062] The term “sulfonamide” as used herein, represents a group of formula “—S(O) 2 NR x R y ” wherein R x and R y can independently be H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
[0063] The term “sulfonamido” as used herein, represents a group of formula “—S(O) 2 NR x —” wherein R x can be H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.
[0064] The term “sulfoxide” as used herein, represents a group of formula “—S(O)—”.
[0065] The term “phosphonic acid” as used herein, represents a group of formula “—P(O)(OH) 2 ”.
[0066] The term “phosphoric acid” as used herein, represents a group of formula “—OP(O)(OH) 2 ”.
[0067] The term “sulphonic acid” as used herein, represents a group of formula “—S(O) 2 OH”.
[0068] The term “aldehyde” as used herein, represents a group of formula “—C(O)H”.
[0069] The formula “H”, as used herein, represents a hydrogen atom.
[0070] The formula “O”, as used herein, represents an oxygen atom.
[0071] The formula “N”, as used herein, represents a nitrogen atom.
[0072] The formula “S”, as used herein, represents a sulfur atom.
[0073] Preferred compounds of the invention are:
N-(4-bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-[4-(methylthio)phenyl]acetamide; N-(4-chlorophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-[4-(methylsulfonyl)phenyl]acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-(4-iodophenyl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-(4-ethylphenyl)acetamide; N-(4-acetylphenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide; N-(6-chloropyridin-3-yl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-(4-fluorophenyl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-(4-methoxyphenyl)acetamide; N-(4-bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)propanamide; N-(4-bromophenyl)-2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide.
[0086] Most Preferred compounds of the invention are:
N-(4-bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-[4-(methylthio)phenyl]acetamide; 2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)-N-(4-methoxyphenyl)acetamide.
[0090] Compounds N-(4-bromophenyl)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindole-2-acetamide (CAS 444337-41-1) and N-(4-bromophenyl)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-2H-isoindole-2-acetamide, (CAS 697238-09-8) are disclosed in chemical libraries.
[0000]
[0091] Some compounds of Formula I and some of their intermediates have at least one asymmetric center in their structure. This asymmetric center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
[0092] The compounds of Formula I can exist in the endo or exo configuration.
[0093] The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I are able to form.
[0094] The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).
[0095] Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
[0096] With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
[0097] Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
[0098] The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the N-formyl peptide receptor like-1 receptor.
[0099] In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.
[0100] In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of the N-formyl peptide receptor like-1 receptor.
[0101] Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.
[0102] Therapeutic utilities of the N-formyl peptide receptor like-1 receptor modulators are ocular inflammatory diseases including, but not limited to, wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, uveitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, cystoids macular edema, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, post surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus, eczema, psoriasis, CNS disorders such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, post-surgical corneal inflammation, blepharitis, MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts, photoaging rheumatoid arthritis and related inflammatory disorders, alopecia, glaucoma, branch vein occlusion, Best's vitelliform macular degenartion, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE (Perretti, Mauro et al. Pharmacology & Therapeutics 127 (2010) 175-188.)
[0103] These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by the N-formyl peptide receptor like-1 receptor modulation: including, but not limited to the treatment of wet and dry age-related macular degeneration (ARMD), diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), diabetic macular edema, uveitis, retinal vein occlusion, cystoids macular edema, glaucoma, branch vein occlusion, Best's vitelliform macular degenartion, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE.
[0104] In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of the FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof.
[0105] The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of, including but not limited to, ocular inflammatory diseases wet and dry age-related macular degeneration (ARMD), uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, uveitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, cystoids macular edema, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, post surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus, eczema, psoriasis, CNS disorders such as Alzheimer's disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, post-surgical corneal inflammation, blepharitis, MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratoses, viral warts, photoaging rheumatoid arthritis and related inflammatory disorders, alopecia, glaucoma, branch vein occlusion, Best's vitelliform macular degenartion, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE.
[0106] The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
[0107] The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
[0108] In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0109] Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
[0110] Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
[0111] In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
[0112] The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
[0113] The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
[0114] Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.
[0115] The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of the N-formyl peptide receptor like-1 (FPRL-1) receptor. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of the N-formyl peptide receptor like-1 (FPRL-1) receptor. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.
[0116] The present invention concerns also processes for preparing the compounds of Formula I. The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. Synthetic Scheme 1 set forth below, illustrates how the compounds according to the invention can be made.
[0000]
[0117] Known compound 3a′,4′,7′,7a′-tetrahydrospiro[cyclopropane-1,8′-[2]oxa[4,7]methano[2]benzofuran]-1′,3′-dione (CAS 56587-29-2) was reduced to intermediate 1 in the presence of Hydrogen (H 2 ) and Palladium on Carbon (Pd—C) in ethyl acetate. Glycine or a substituted derivative reacted with intermediate 1 in refluxing pyridine (Py) and toluene. The product obtained, intermediate 2, was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) 4-dimethylaminopyridine (DMAP) in N,N-dimethylformamide (DMF) and the amine derivative to give after workup and purification the desired compound of general Formula I. Compounds within the scope of the invention may be prepared as depicted in Scheme 1. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. Details of certain specific chemical transformations are provided in the examples.
[0118] Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0119] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
[0120] It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
[0121] The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of hydrogen 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
[0122] The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
[0123] As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
[0124] Compound names were generated with ACD version 11.0; and Intermediates and reagent names used in the examples were generated with softwares such as Chem Bio Draw Ultra version 12.0, ACD version 11.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.
[0125] In general, characterization of the compounds is performed according to the following methods:
[0126] NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. The optical rotation was recorded on Perkin Elmer Polarimeter 341, 589 nm at 20° C., Na/Hal lamp.
[0127] All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
[0128] Usually the compounds of the invention were purified by column chromatography (Auto-column) on an Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise.
[0000] The following abbreviations are used in the examples:
CH 2 Cl 2 dichloromethane EtOAc ethyl acetate K 2 CO 3 potassium carbonate CDCl 3 deuterated chloroform Pd—C palladium(0) on carbon THF tetrahydrofuran CD 3 OD deuterated methanol CD 3 COCD 3 deuterated acetone RT room temperature CHCl 3 chloroform Me 2 SO 4 dimethylsulfate MgSO 4 magnesium sulfate CD 3 CN deuterated acetonitrile CD 3 OD deuterated methanol
[0143] The following synthetic schemes illustrate how compounds according to the invention can be made. Those skilled in the art will be routinely able to modify and/or adapt the following schemes to synthesize any compound of the invention covered by Formula I.
EXAMPLE 1
Intermediate 1
Hexahydrospiro[cyclopropane-1,8′-[2]oxa[4,7]methano[2]benzofuran]-1′,3′-dione
[0144]
[0145] A mixture of compound 3a′,4′,7′,7a′-tetrahydrospiro[cyclopropane-1,8′-[2]oxa[4,7]methano[2]benzofuran]-1′,3′-dione (CAS 56587-29-2) (4 g, 21.5 mmol), EtOAc (50 mL) and 10% Pd—C (100 mg) was stirred at RT under hydrogen atmosphere using a hydrogen filled balloon for 4 h. The solid was filtered off, and the solvent was removed under reduced pressure. Intermediate 1 was isolated as a white solid.
[0146] 1 HNMR (CDCl 3 ): δ 0.65 (s, 4H), 1.57 (q, J=6.9 Hz, 2H), 1.90-1.99 (m, 2H), 2.01 (br s, 2H), 3.65-3.70 (m, 2H).
EXAMPLE 2
Intermediate 2
(1,3-Dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetic Acid
[0147]
[0148] A mixture of Intermediate 1 (490 mg, 2.55 mmol), glycine (750 mg, 10 mmol), pyridine (4 mL) and toluene (100 mL) was refluxed for 48 h using a Dean-Stark apparatus. The hot solution was filtered to remove the unreacted starting material. The filtrate was collected and the solvent was removed under reduced pressure. Intermediate 2 was isolated as a white solid.
[0149] 1 HNMR (CDCl 3 ): δ 0.60-0.70 (m, 4H), 1.53 (d, J=8.1 Hz, 2H), 1.75-1.85 (m, 2H), 2.01 (br s, 2H), 3.35-3.40 (m, 2H), 4.29 (s, 2H).
EXAMPLE 3
Compound 1
N-(4-Bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide
[0150]
[0151] To a mixture of Intermediate 2 (62 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, CAS 25952-53-8) (96 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP) (30 mg, 0.25 mmol), and N,N-dimethylformamide (DMF) (5 mL) was added 4-bromoaniline (CAS 106-40-1) (53 mg, 0.31 mmol) and the solution was stirred at RT for 3h. The reaction mixture was diluted with dichloromethane (50 mL), then washed with water (3×20 mL) and brine (20 mL). The dichloromethane layer was dried with MgSO 4 , the solid was filtered off, and the solvent was removed under reduced pressure from the filtrate. The crude product was purified by silicagel chromatography (EtOAc:hexane, 1:4) to give Compound 1 as a white solid.
[0152] 1 HNMR (CDCl 3 ): δ 0.58-0.70 (m, 4H), 1.58 (q, J=8.4 Hz, 2H), 1.84 (d, J=9.0 Hz, 2H), 2.02 (br s, 2H), 3.39 (s, 2H), 4.29 (s, 2H), 7.33 (d J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).
[0153] Compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 were prepared from the corresponding starting materials and in a similar manner to the procedure described in Example 3 for Compound 1. The reagents, reactants used and the results are described below in Table 1.
[0000]
TABLE 1
Comp.
1 H NMR δ (ppm) for
number
IUPAC name
Reactant
Compound
2
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-[4- (methylthio)phenyl] acetamide
4-methylthio- benzamine (CAS 104-96-1)
1 HNMR (CD 3 COCD 3 ): δ 0.56- 0.70 (m, 4H), 1.65-1.80 (m, 4H), 1.93 (br s, 2H), 2.45 (s, 3H), 3.38 (t, J = 1.2 Hz, 2H), 4.27 (s, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H).
3
N-(4-chlorophenyl)- 2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)acetamide
4-Chloro- benzamine (CAS 106-47-8)
1 HNMR (CDCl 3 ): δ 0.60-0.70 (m, 4H), 1.59 (q, J = 7.8 Hz, 2H), 1.84 (d, J = 9.6 Hz, 2H), 2.03 (br s, 2H), 3.38 (s, 2H), 4.29 (s, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H).
4
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-[4- (methylsulfonyl) phenyl]acetamide
4-(methylsulfonyl)- benzamine (CAS 5470-49-5)
1 HNMR (CD 3 CN): δ 0.55- 0.70 (m, 4H), 1.60 (q, J = 7.8 Hz, 2H), 1.84 (d, J = 9.6 Hz, 2H), 2.15 (s, 2H), 3.05 (s, 3H), 3.40 (s, 2H), 4.27 (s, 2H), 7.78 (d, J = 9.0 Hz, 2H), 7.88 (d, J = 9.0 Hz, 2H).
5
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-(4- iodophenyl) acetamide
4-iodo-benzamine (CAS 540-37-4)
1 HNMR (CD 3 OD): δ 0.58- 0.70 (m, 4H), 1.62 (q, J = 7.8 Hz, 2H), 1.80 (d, J = 9.6 Hz, 2H), 1.95 (s, 2H), 3.42 (s, 2H), 4.28 (s, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.63 (d, J = 9.0 Hz, 2H).
6
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-(4- ethylphenyl) acetamide
4-ethyl-benzamine (CAS 589-16-2)
1 HNMR (CDCl 3 ): δ 0.56-0.70 (m, 4H), 1.19 (t, J = 7.8 Hz, 3H), 1.61 (q, J = 7.8 Hz, 2H), 1.80 (d, J = 9.0 Hz, 2H), 1.99 (s, 2H), 2.57 (q, J = 7.8 Hz, 2H), 3.34 (s, 2H), 4.29 (s, 2H), 7.08 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H).
7
N-(4-acetylphenyl)-2- (1,3-dioxooctahydro- 2H-spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)acetamide
1-(4-aminophenyl)- ethanone (CAS 99-92-3)
1 HNMR (CDCl 3 ): δ 0.60-0.71 (m, 4H), 1.59 (q, J = 7.8 Hz, 2H), 1.84 (d, J = 9.0 Hz, 2H), 2.04 (s, 2H), 2.56 (s, 3H), 3.31 (s, 2H), 4.34 (s, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H).
8
N-(6-chloropyridin-3- yl)-2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)acetamide
6-chloro-3- pyridinamine (CAS 5350-93-6)
1 HNMR (CDCl 3 ): δ 0.60-0.70 (m, 4H), 1.58 (q, J = 8.4 Hz, 2H), 1.85 (d, J = 9.0 Hz, 2H), 2.03 (s, 2H), 3.41 (s, 2H), 4.34 (s, 2H), 7.22 (d, J = 8.4 Hz, 1H), 8.08 (dd, J = 8.4, 3.0 Hz, 1H), 8.25 (d, J = 3.0 Hz, 1H).
9
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-(4- fluorophenyl) acetamide
4-fluoro- benzamine (CAS 371-40-4)
1 HNMR (CDCl 3 ): δ 0.58-0.68 (m, 4H), 1.60 (q, J = 8.4 Hz, 2H), 1.83 (d, J = 9.0 Hz, 2H), 2.01 (s, 2H), 3.38 (s, 2H), 4.30 (s, 2H), 6.94 (d, J = 4.9 Hz, 2H), 7.38 (d, J = 4.9 Hz, 2H).
10
2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)-N-(4- methoxyphenyl) acetamide
4-methoxy- benzamine (CAS 104-94-9)
1 HNMR (CDCl 3 ): δ 0.55-0.68 (m, 4H), 1.60 (q, J = 8.4 Hz, 2H), 1.81 (d, J = 9.0 Hz, 2H), 2.00 (s, 2H), 3.36 (s, 2H), 3.76 (s, 3H), 4.28 (s, 2H), 6.80 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H).
11
N-(4-bromophenyl)- 2-(1,3- dioxooctahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)propanamide
4-bromoaniline (CAS 106-40-1)
1 HNMR (CDCl 3 ): δ 0.55-0.68 (m, 4H), 1.40-1.50 (m, 2H), 1.70 (d, J = 7.2 Hz, 3H), 1.81 (s, 2H), 2.00 (s, 2H), 3.36 (s, 2H), 4.91 (q, J = 7.2 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H).
12
N-(4-bromophenyl)- 2-(1,3-dioxo- 1,3,3a,4,7,7a- hexahydro-2H- spiro[2-aza-4,7- methanoisoindole- 8,1′-cyclopropan]-2- yl)acetamide
3a′,4′,7′,7a′- tetrahydrospiro [cyclopropane-1,8′- [2]oxa[4,7]methano [2]benzofuran]- 1′,3′-dione (CAS 56587-29-2) 4-bromoaniline (CAS 106-40-1)
1 HNMR (CD 3 OD): δ 0.57 (s, 4H), 2.74 (s, 2H), 3.58 (s, 2H), 4.14 (s, 2H), 6.19 (t, J = 2.1 Hz, 2H), 7.45 (s, 4H).
Biological Data
[0154] Biological activity of compounds according to Formula 1 is set forth in Table 2 below. CHO-Ga16 cells stably expressing FPRL1 were cultured in (F12, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin) and HEK-Gqi5 cells stable expressing FPR1 were cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin). In general, the day before the experiment, 18,000 cells/well were plated in a 384-well clear bottom poly-d-lysine coated plate. The following day the screening compound-induced calcium activity was assayed on the FLIPR Tetra . The drug plates were prepared in 384-well microplates using the EP3 and the MultiPROBE robotic liquid handling systems. Compounds were tested at concentrations ranging from 0.61 to 10,000 nM. Results are expressed as EC 50 (nM) and efficacy values.
[0000]
TABLE 2
FPRL1
EC 50 [nM]
Compound IUPAC name
(rel. eff.)
N-(4-bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-
118
4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide
(0.9)
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
336
8,1′-cyclopropan]-2-yl)-N-[4-(methylthio)phenyl]acetamide
(1.0)
N-(4-chlorophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-
2054
4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide
(1.0)
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
3459
8,1′-cyclopropan]-2-yl)-N-[4(methylsulfonyl)phenyl]
(0.72)
acetamide
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
2648
8,1′-cyclopropan]-2-yl)-N-(4-iodophenyl)acetamide
(0.86)
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
1153
8,1′-cyclopropan]-2-yl)-N-(4-ethylphenyl)acetamide
(0.91)
N-(4-acetylphenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-
7829
4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide
(0.63)
N-(6-chloropyridin-3-yl)-2-(1,3-dioxooctahydro-2H-spiro[2-
2508
aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)acetamide
(0.86)
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
2322
8,1′-cyclopropan]-2-yl)-N-(4-fluorophenyl)acetamide
(0.9)
2-(1,3-dioxooctahydro-2H-spiro[2-aza-4,7-methanoisoindole-
267
8,1′-cyclopropan]-2-yl)-N-(4-methoxyphenyl)acetamide
(1.0)
N-(4-bromophenyl)-2-(1,3-dioxooctahydro-2H-spiro[2-aza-
>5K
4,7-methanoisoindole-8,1′-cyclopropan]-2-yl)propanamide
(0.93)
N-(4-bromophenyl)-2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-
812
2H-spiro[2-aza-4,7-methanoisoindole-8,1′-cyclopropan]-2-
(0.91)
yl)acetamide
N-(4-bromophenyl)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-
575
methano-2H-isoindole-2-acetamide (CAS 444337-41-1)
(0.90)
N-(4-bromophenyl)-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-2H-
395
isoindole-2-acetamide, (CAS 697238-09-8)
(0.98) | The present invention relates to novel polycyclic pyrrolidine-2,5-dione derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the N-formyl peptide receptor like-1 (FPRL-1) receptor. | 2 |
BACKGROUND OF THE INVENTION
This invention relates to metallic surgical implants, i.e., to metallic surgical construction elements which are intended to remain either permanently (endoprosthesis) or only temporarily in human or animal bodies.
Implants of this type have been made completely ("Contimet" Titan-Information, Ed. Hannover 1973) or partially (German Pat. No. 923,383) from metal. The drawback of these is the inadequate corrosion and stress-cracking resistance of the metals against the fluids and secretions of the living body as well as the insufficient abrasion resistance which results when parts of the implant slide relative to each other. The danger involved in metallic abrasion is that the abraded particles are carried into the surrounding tissues and become deposited therein. This may give rise to irritation and to the build up of connecting tissue which causes stiff joints. Also, this abrasion reduces the life expectancy of the implant, so that repeated operations may be required, particularly with younger patients. Several metallic implants in the body or foreign bodies with different electrochemical potential may lead, via the body fluids and secretions, to the formation of electrochemical circuits in the body.
Metallic implants may be anchored to the bones by means of bone cements based on methyl methacrylate. This cement has a tendency to polymerize and to shrink, whereby the rigid seating of the implant becomes lost. Furthermore, over long periods, monomers are spread within the body and may produce toxicity and circulatory difficulties.
Implants made from solid oxide ceramic without (British Pat. No. 1,083,769) or with (German Pat. No. 583,589) a glossy transparent mineral glaze are also known. The implants are given the glaze to produce a glossy surface when they are used as anatomical or panoptical models, but not when they are used for surgical purposes. The drawback of oxide ceramic implants is their relatively great brittleness and low fracture elongation, which means that they must be relatively large. Accordingly, their application is excluded where insufficient space is available. Also, the notch sensitivity of these material and the weight of implants manufactured therefrom are relatively high.
SUMMARY OF THE INVENTION
An object of this invention is to provide biocompatible and toxically satisfactory implants while insuring adequate strength, toughness and durability, and increasing the wear and corrosion resistance. Simultaneously, an enhanced construction freedom in the configuration of implants is achieved.
According to the invention, the implant comprises a metallic substrate at least partially coated with enamel. As used herein, the term enamel means a porcelain enamel, i.e., a vitreous or partially devitrified inorganic coating bonded to metal by fusion at a temperature above 800° F. The enamel can be a single layer or applied in a plurality of layers, e.g., with a ground coat next to the metallic substrate and one or more cover coats of enamel over the ground coat. The enamel can be applied over a variety of metals, such as high alloy steel or highly alloyed non-ferrous metals. The substrate metal can be adapted very exactly and reliably to special location circumstances, both as regards its configuration and as to its mechanical and physical properties. At the same time, the enamel can be selected with regard to optimum chemical stability, resistance to wear, tissue compatibility, progressive ingrowth (i.e., increasing incorporation or growing in of the implant with time) and electrical insulating properties. The enamel also forms a very firm bond with the base metal, which makes the implant safe for the patient.
Generally it is preferred to use a metal having relatively good chemical durability. This insures that the effects of bodyily contact with the metallic substrate will be slight if a pore in the enamel is penetrated or if a portion of the enamel is worn away after long mechanical stressing.
It is also preferable to use a metal having a low linear coefficient of expansion, e.g., 110-140 × 10 - 7 /° C between 20° and 400° C. Implants are frequently relatively small articles with numerous and often very small radii. Typical examples are connecting and self-tapping screws, which are normally not enamelled. Sharp edges or corners can thus occur which cannot be taken off for constructional or operational reasons. Enamel coatings are normally applied so that they are under compressive stress. Over convex, very small curvatures, this leads to forces in the enamel layer perpendicular to the surface which can cause spalling of the enamel. This risk is minimized by matching the coefficient of expansion of the base metal to that of the enamel, so that the compressive stresses in the enamel can be reduced. The smaller the curvatures occuring in the implants, the lower the coefficients of expansion should be for the metallic substrate. Two examples of metals which substantially define the preferred range of linear coefficients of expansion are the materials known as Numbers 1.4762 and 2.4631 according to DIN 17007. These are the materials X 10 Cr Al 24 and Ni Cr 20 Ti Al according to DIN 17006.
In some embodiments of this invention the enamel may be partially devitrified or crystallized. Enamels of this type, some of which are disclosed in German Published Specification No. 1,291,597 and U.S. Pat. No. 3,368,712, have outstanding mechanical and physical characteristics. These crystallized enamels can be applied in several layers and, if desired, can be applied only to a portion of the metallic substrate.
With multi-layer applications the enamel can have a partially crystallized enamel ground coat on the base metal. These partially crystallized ground coats produce a firm adhesion between the base metal and enamel. With multi-layer application, the implant can also have a vitreous cover coat of enamel. In this way, with frictionally stressed implant parts, a better sliding behaviour can be obtained. The microscopic roughness which may be present on the surface of the partially crystallized enamel under the cover enamel can thus be avoided by a relatively thin vitreous enamel covering layer which, by its flame polishing and relatively low modulus of elasticity, insures the best break-in conditions for frictionally stressed implant parts.
The enamel surface may be profiled locally, e.g. by mechanical or chemical roughening or by the cutting of grooves or recesses. In this way, ingrowth or growing in of the implant into the body can be promoted and facilitated. The ground or cut recesses can have a diameter of 1 mm, for example, and, in relatively thick enamel layers, can be 1 mm deep. The centers of adjacent recesses can be about 4-5 mm apart.
While in many applications a partial enameling of the metallic substrate is sufficient, the enameling of the entire surface of the implant is preferred. This excludes any contact between the body and metallic substrate and thus excludes the formation of electrochemical circuits. Also, a relative common base metal can be used, as long as those requirements are fully taken into account which the metal is to fulfill in the metal-enamel composite article. Thus, implants of relatively low cost can be made.
Another object of this invention is to provide a method for manufacturing a surgical implant wholly coated with enamel. The metallic substrate is partially coated with a partially crystallize enamel, the substrate is positioned on a firing support with the partially crystallized enamel in contact with the support, and the remaining non-enameled surface of the substrate is coated with enamel. For this remaining surface, either a partially crystallized enamel or a stable vitreous enamel can be used. If required, the remaining surface may also be provided with an enamel ground coat and one or more enamel cover coats. With this method, the otherwise customary firing supports or firing projections on the article to be enameled can be eliminated because the increase in the viscosity of the partially crystallize enamel is made use of following its crystallization. This increase in viscosity is such that the implant can be laid directly on the firing support, with the surface coated with the partially crystallized enamel in contact with the support, without the contact surface suffering damage in the subsequent enameling of the remaining surface of the implant.
A typical embodiment of the invention, namely a dorsal vertebra endoprosthesis, comprises two mutually connectible parts interconnectible with each other substantially along the main longitudinal plane of the prosthesis. Each part has two connecting portions attachable to two adjacent vertebrae and a connecting limb between the two connecting portions. Like all other implants according to the invention, the vertebra endoprosthesis can be manufactured either by welding or by casting construction methods. The implant can be made relatively easily and may be comparatively lightweight yet strong, particularly by welded construction. In the operation, or installation of the implant, the mounting and firm anchoring of the two implant parts to the adjacent vertebrae is carried out rapidly and safely.
According to a further embodiment of the invention, the two connecting limbs are mutually engageable by means of an enamelled screw which is arranged with a guide shaft on the head side in a through bore in one of the limbs and is screwed with a threaded part into a threaded bore in the other limb. This implant consists of relatively few parts. The screw can have rounded threads, in order to facilitate the enamelling, and can be secured in the threaded bore by bone cement, e.g., a methyl methacrylate composition. The two parts of the implant can be fixed relative to each other by at least one securing pin and can thus be secured against relative rotation.
According to a further embodiment of the invention, each connecting portion includes at least one aperture or recess for the reception of a bone screw screwed into the adjacent vertebra. Thus, a rigid connection and firm seating between the connecting portion and the vertebra is ensured. The bone screw can be provided with self-tapping threads, so that it itself cuts the internal thread in the bone in a boring of predetermined diameter previously made in the bone.
According to a further embodiment of the invention, one wall of the recess is made at least partially spherically concave and a head of the bone screw is made complementarily spherically convex. Thus, the surface pressure between the screw head and the wall of the recess remains within predeterminable limits even if there is an angle between the axes of the screw and of the recess. Thus, the risk of damage to the enamel is reduced.
According to another embodiment of the invention, each connecting portion has a platform facing the end of the adjacent vertebra and at least one projection on the platform for cooperating with a side surface of the vertebra. This solution is technically simple and thus very functionally reliable. It also serves to save weight. The platform and the projections can also define together an acute angle. This ensures that the projections engage the side surfaces of the vertebra. This gives a positive, very firm and safe connection between the implant and the vertebra. To facilitate mounting of the implant during the operation, at least one holding aperture for a holding tool is provided in at least one of the connecting limbs. The holding tool can be a relatively long probe or rod, e.g., of titanium or stainless steel, which the surgeon inserts into the holding aperture. In this way, the surgeon can exert holding forces upon the implant part first inserted into the body and thus prevent any undesirable movement of this implant part during the operation. Also, the probes or rods facilitate parallel engagement of the two implant parts.
In another embodiment of the invention, namely a hip joint endoprosthesis, with a shank and a ball connectible with this shank and cooperating with a socket, the shank is divided into an anchoring part and a transition part connectible therewith and the ball is connectible with the transition part.
It is known to secure hip joint endoprostheses with bone cement in the femur, or upper thigh bone. As already mentioned, there is always the risk of separation of the cement and thus release of the prosthesis. Thus, complications and pathological tissue reactions can occur. This disadvantage is avoided by the invention, in that the anchoring part is provided with an external thread which taps itself into the femur. Preferably, in order to facilitate enamelling, this thread is made as a rounded thread. The transition part is coupled with the anchoring part which is thus connected in a closely fitting and durably rigid way with the bone, by making optimum use of the internal space of the femur and producing for the ball a very stiff support construction having due regard to all likely requirements.
According to another aspect of the invention, the anchoring part has a guide pin that fits into a recess in the transition part, and the latter can be stressed against the anchoring part by a securing screw screwed into the guide pin. Thus, the transition part can be installed at any desired rotational angle with reference to the anchoring part and fixed in the desired position by the securing screw, which can be secured by bone cement.
According to another embodiment of the invention, the ball can be screwed onto the free end of the transition part. This provides for axial adjustment of the ball relative to the transition part. Securement of the thread can again be provided by means of bone cement.
According to a further embodiment of the invention, a supporting member can be located between the ball and the femur. The supporting member can engage circumferentially around the transition part and can be supported with its abutment surface, which faces away from the ball, upon a seating surface on the femur, which has previously been prepared by the surgeon and adapted to the shape of the supporting member. Thus, force transfer between the femur and the supporting member takes place over the largest possible surface area for the best possible imitation of the natural conditions of the head of the hip joint.
DRAWINGS
FIG. 1 is a partially sectioned view of a bone screw according to this invention.
FIG. 2 illustrates a stamped sheet metal part for the production of one portion of a dorsal vertebra endoprosthesis.
FIG. 3 is a sectional view through the vertebra endoprosthesis along lines III--III in FIG. 4.
FIG. 4 shows a part of this vertebra endoprosthesis in side elevation view.
FIG. 5 is a plan view of the prosthesis along line V-V in FIG. 3, with the vertebra partly omitted.
FIG. 6 shows a holding tool in side view.
FIG. 7 shows a bone screw according to FIG. 1 in the mounted state;
FIG. 8 is a diagrammatic view of a multi-layer enamel construction.
FIG. 9 is a longitudinal section through a hip joint prosthesis in finished mounted condition.
DETAILED DESCRIPTION
In FIG. 1 a bone screw 20 is shown with a cylindrical shank 21 and a forward cutting part 23 narrowing to a rounded tip. The bone screw 20 has a rounded screw thread 25 and a head 27 which is made spherically convex on the side adjacent the shank 21 and, on the other side, is provided with a slot 29 for the reception of a screwdriver.
The entire surface of the bone screw 20 is coated with enamel 30. For simplicity, this and other enamel coats are represented in the drawings by dotted lines. These enamel coats can be formed in the way previously mentioned either as single layers or as multiple layers.
FIG. 2 shows a stamped sheet metal element 31 which is slit through along the dotted line 32. This provides two platforms 36 and 37. Spaced projections 39, 40 and 41, 42 extend from each of the platforms 36 and 37.
The projections 39-42 can be bent either downwardly or upwardly from the flat position shown in FIG. 2. This produces connecting members 43-46 of the two parts 47 and 48 of a dorsal vertebral endoprosthesis 50.
A connecting limb 51 is welded to the platforms 37 of the part 48. The limb contains two holding apertures 53 and 54, two openings 56 and 57 and a threaded bore 59, best seen in FIG. 4. A securing pin 60 is firmly pressed into the aperture 57.
In a similar way, a connecting limb 63 is welded to the two platforms 36 of the part 47. Limb 63 is provided with holding apertures (not shown) corresponding to the apertures 53 and 54 of FIG. 4 and also with openings 65 and 66 and a through bore 67. A securing pin 69 is fixed in the opening 65.
Apertures 70, the shape of which is described in detail below in connection with FIG. 7, are provided in the projections 39-42. The apertures 70 are intended to receive bone screws 20 of the kind shown on an enlarged scale in FIG. 1.
The two parts 47 and 48 of the vertebra endoprosthesis 50 are coated over their entire surfaces with enamel 72 and 73, which can be applied either as a single layer or in multiple layers and also with locally differing thicknesses. The parts 47 and 48 are held in the mounted state, as shown in FIG. 3, by a screw 75, which is located with its guide shank 77 in the through bore 67 and screwed into threaded bore 59. Screw 75 is also coated over its entire surface with enamel 78.
As FIG. 4 shows, the platforms 37 of each part, e.g., 48, are not parallel or are not entirely parallel to one another, but if required are inclined to one another locally so as to correspond to the natural relative inclination of the adjacent vertebrae 79 and 80 (FIG. 3).
In FIG. 5, that part of the vertebra 79 is omitted which is connected with the connecting members 43 and 45. FIG. 5 also shows how the upper ends of the projections 39-42 are inclined inwardly and positively engage around and firmly hold the vertebra 79 in the clamped state (FIG. 3). This anchoring is further improved by bone screw 20.
In FIG. 6 a longitudinally extending rod-shaped holding tool 83 of stainless steel or titanium is shown, which slidably fits into the holding openings, e.g., 53 and 54.
In FIG. 7 an aperture 70 is shown in the projection 39, The wall 87 of aperture 70 is constructed at 89 so as to be spherically complementarily concave to the head 27 of the screw 20. The axis 88 of the screw 20 and the axis 90 of the aperture 70 can thus define between them an angle 91 without forming any edge or point contact between the screw 20 and the projection 39 with the risk of local damage of the enamel 30 or 72.
The operation preferably takes place with the patient in the lateral position. First, after preparation of the abutment surfaces of the adjacent vertebrae 79 and 80, the part 48 of the vertebra endoprosthesis 50 is inserted downwardly. Then the surgeon inserts one or two of the holding tools 83 (FIG. 6) with their ends into the holding apertures 53 and 54 and thus can prevent displacement of the part 48 from its desired position. Then the second part 47, with its holding apertures aligned with the openings 53, 54, is slid on the holding tools 83, guided along parallel to the first part 48 and then butted up to the first part 48, so that the securing pin 60 is inserted into opening 66 and the securing pin 69 into opening 56. Thus, parts 47 and 48 are fixed with respect to one another. The holding tools 83 are then removed and the screw 75 can be inserted by means of a screwdriver. Prior to this, some bone cement is applied in the threaded bore 59, which after insertion of the screw 75 hardens and thus secures the screw 75 against undesirable loosening or falling out. Finally, borings are made into the vertebrae 79 and/or 80 through the apertures 70 in one or more of the projections 40 and 41. Self-tapping bone screws 20 are screwed into these borings at an angle to the adjacent platform 36 or 37. The adjacent vertebrae 79 and 80 are thereby drawn firmly up to the associated platforms 36 and 37. For further securement, bone screws 20 can be inserted through the apertures 70 located in the projections 39 and 42, namely perpendicularly into the vertebrae 79 and 80. In this way, a positively firm and very rigid connection with the vertebrae 79 and 80 is given.
PREPARATIVE EXAMPLE
The parts 47, 48, made from the material identified by the number 2.4631 and are prepared in the usual way by pickling or sand blasting for the enamelling process. A crystallizable enamel composition according to Table I is melted, fritted, ground, applied, fired and finally subjected to controlled heat treatment so as to induce partial crystallization, in the way described in German Published Specification No. 1,291,597 and U.S. Pat. No. 3,368,712.
TABLE I______________________________________ Weight percent of the total coatingOxide composition______________________________________SiO.sub.2 56.02Na.sub.2 O 6.50Li.sub.2 O 10.38Al.sub.2 O.sub.3 5.46TiO.sub.2 16.60B.sub.2 O.sub.3 4.50SrO 1.50______________________________________
The frit, prepared as slip, is preferably applied by spraying On the flat surfaces, particularly the platforms 36 and 37, more enamel is preferably applied then on the sides and edges. The enamel thickness on the supporting surfaces for the vertebrae 79 and 80 preferably amounts to 1 to 2 mm and over the edges is 0.2 to 0.3 mm, which is achieved after 2 to 3 firings. In the foregoing steps, enamel is not applied to the surfaces required for supporting or suspending the implant parts in the enamelling oven. After the enamel has been applied controlled crystallization is carried out. With the above-mentioned material, it is unnecessary to apply a ground coat under the crystallizable enamel, however, if such a ground coat is desired, it can have the composition corresponding to Table II below.
TABLE II______________________________________Oxide Weight Percent______________________________________SiO.sub.2 48.5Na.sub.2 O 14.7K.sub.2 O 4.4Al.sub.2 O.sub.3 6.4MnO.sub.2 1.7B.sub.2 O.sub.3 16.0______________________________________
The article enamelled and partially crystallized except on the support surfaces is then tested for contact points with the metal substrate by means of a high potential (3 to 10 kV) or by the current measuring method after immersion in an electrolyte. If no fractures are found, the fired region is mechanically cleaned and then treated with an enamel slip, e.g., according to Table I. In the then-repeated firing and crystallization processes, the article is supported with the already partially crystallized enamel coat upon a non-oxidizing support.
The screw 75 can be made of high-alloy steel with the material number 1.4762 and can be enamelled over its entire surface according to the above-described method.
In the case of the parts 47 and 48, the enamelling can also be carried out according to a known method in which the parts are suspended and enamelled upon an extension of the securing pins 60 and 69 which are no longer present as these are shown in FIG. 3. The extensions are then removed and the free ends of the securing pins 69 and 60 are likewise enamelled by local heating and melting in a tube furnace.
In FIG. 8, a multilayer construction is illustrated by way of example. An enamel ground coat 96, two intermediate enamel coats 97 and 98 of partially crystallized enamel and a vitreous enamel cover coat 99 are located in that order on a metal substrate 95. Depressions or recesses 100 are ground or otherwise cut or made in the enamel at mutually spaced locations which improve growing in of the implant into the body.
As the enamel cover coat 99, the four known highly acidresistant enamels shown in Table III below can be used.
TABLE III______________________________________ 1 2 3 4______________________________________SiO.sub.2 65.1 66.9 51.1 65.3Al.sub.2 O.sub.3 3.5 3.0 2.6 3.1B.sub.2 O.sub.3 2.0 -- 9.4 --K.sub.2 O 2.6 1.3 1.5 18.7Na.sub.2 O 19.1 17.3 18.1CaO 7.7 7.3 6.5 6.9MgO -- -- -- 5.1ZnO -- 1.1 11.8 --Li.sub.2 O -- 3.0 -- --______________________________________
FIG. 9 shows a hip joint endoprosthesis 110. An anchoring part 113 with a self-tapping external rounded screw thread 114 is screwed into a femur or upper thigh bone 111. At the top, the anchoring part 113 carries a boss or guide pin 115 of essentially annular cross-section. At its upper end only, the guide pin 115 has two diametrically opposite flat lateral surfaces 116 which a tool, e.g., a box spanner, can engage for inserting and, if required, removing the anchoring part 113. A central threaded blind hole 118 is also provided in the guide pin 115.
Above the guide pin 115, a transition part 125 with a downward recess 120 is located, which sits with its lower edge upon a shoulder 127 formed on the anchoring part 113. A securing screw or bolt 129 has two diametrically opposite flats 130 on its otherwise cylindrical head, by means of which a tool can be applied for inserting and removing the securing screw 129.
The free end 132 of the transition part 125 is made hollow to save weight and is also provided with an external rounded thread 133 on which a ball 135 with an internal rounded thread 137 can be screwed. Between the ball 135 and the femur 111, a supporting member 140 is held and bears with its lower surface 143 over the largest possible area of a corresondingly prepared counter-surface made on the femur 111.
As the dotted external contours show, all the individual parts of the hip joint endoprosthesis 110 described are coated over their entire surfaces with enamel, so that the base metal is not exposed anywhere.
The securing screw 129 and the ball 135 are secured to their complementary screw threads by means of a small amount of bone cement.
Thus, it may be seen that this invention provides implants that are biocompatible, toxically satisfactory, strong, tough, durable, easily manufactured, and possessing increased wear and corrosion resistance. Furthermore, these implants can easily be tailored to the requirements of specific problems. Of course, the implants described above are but two of many possible embodiments falling within the scope of this invention, which is defined by the following claims. | A surgical implant is produced by coating a metallic substrate with enamel. The metallic substrate provides structural strength and the enamel provides chemical stability, resistance to wear, tissue compatibility, progressive ingrowth and electrical insulating properties. The implant may be produced by coating a portion of the metallic substrate with a partially crystallized enamel, and then positioning the implant on a firing support with the partially crystallized enamel in contact with the support and coating the remaining non-enamelled surface. | 0 |
BACKGROUND OF THE INVENTION
The present invention pertains to a pipe bending apparatus for use in bending large diameter pipes which have either a thin or thick walled construction. More specifically, the invention is directed to a pivotable rolling mill type pipe bending mechanism wherein a pipe may be received between a bending shoe having an arcuate surface and a follower shoe and bent to assume the shape of the bending shoe by pivotal movement of the bending shoe.
SUMMARY OF THE INVENTION
The present invention provides an improved pipe bending apparatus which is capable of bending either a thin or thick walled pipe having a relatively large cross-sectional diameter. The apparatus is constructed to be generally portable and relatively compact yet to function in the manner of a rolling mill device wherein it is possible to maintain external pressure around the circumference of the pipe during the bending operation thereby preventing kinks or undue distortion even in very thin walled pipe during the bending process.
The invention comprises the combination of a bending shoe which is pivotably supported by a frame, a hydraulic motor which is operable to cause pivotal movement of the bending shoe and a means for forcing the pipe to assume the shape of the arcuate surface of the bending shoe upon actuation of the hydraulic motor. The frame comprises a pair of flat horizontally disposed elongated arms which rigidly support the fluid motor between them at one end and which pivotably support one end of the bending shoe at their other end. The bending shoe is generally semi-circular in configuration and has an arcuate outer surface which includes a groove for receiving a pipe therein.
The shoe is pivotably connected to the frame by a pivot pin located adjacent to the arcuate surface of the shoe and at one end thereof such that the pivot point of the shoe is off-set from the center of the arc defined by the surface of the shoe. The bending shoe is generally designed for use with an elongated straight follower shoe which includes a groove complementary to that in the arcuate surface of the bending shoe such that a pipe can be received therebetween in clamped engagement. The clamping means generally comprise a plurality of rollers which clampingly engage the follower shoe and the bending shoe and force them against the pipe received therebetween to compress the pipe. One roller is disposed within an arcuate slot in the bending shoe and another roller is disposed to abut the rear surface of the follower shoe. The rollers are secured against movement with respect to each other by a pair of linking plates which support the shafts of the rollers.
In operation, when the fluid motor is actuated, the roller assembly connected to the end of the fluid motor piston places a torque on the bending shoe causing the bending shoe to pivot. As the bending shoe pivots, the rollers of the securing means, which are spaced on opposite sides of the respective shoes, cause the shoes to place a compressive force on the pipe disposed therebetween. In a typical rolling mill action, the follower shoe will thus cause the pipe to be bent to conform to the arcuate shape of the bending shoe. Since pressure is maintained on the entire periphery of the pipe at the place where it is being bent, undue distortion or crimping of the pipe is avoided and a smooth bend is created.
The pipe bending apparatus of the invention thus functions to prevent undue distortion or kinks in even very thin walled pipe during the bending operation. Though the invention facilitates rolling mill type bending, the apparatus of the invention is relatively portable and compact. Furthermore, the roller disposed in the arcuate slot of the bending shoe is mounted on an eccentric cam which permits the distances between the rollers to be adjusted thereby providing means for adjusting the pressure applied to the pipes and facilitating use of the apparatus with pipes having varied wall thickness. Since the pressure applied to the pipe, using the apparatus of the invention, does not depend directly on the hydraulic pressure of the hydraulic motor, but rather on the compressive forces exerted by the opposed rollers, it is possible to use less powerful hydraulic motors than are permissible with prior art apparatus and thus conserve energy. The arrangement of the position of the pivot point of the bending shoe with respect to the hydraulic motor and the frame also permit even very large pipes to be bent in a complete 90° arc in a single bending cycle whereas prior art apparatus allow for only a 45° bend of larger pipes thus requiring two bending operations to achieve a 90° bend. The frame assembly of the present invention also facilitates the use of any of a variety of sizes of fluid motors and permits the use of fluid motors which have relatively short stroke pistons.
The arrangement of the rollers with respect to the follower shoe and the bending shoe have the advantage that they function to maintain consistent pressure upon the pipe throughout the bending cycle and do not vary with respect to the stage of operation. Furthermore, the present invention is a distinct advantage over the prior art bending apparatus wherein compression of the pipe was maintained by use of hydraulic pressure generated by the hydraulic motor in that, in the present invention, compression is maintained on the pipe solely by the clamping action of the rollers. The hydraulic motor functions to create torque on the bending shoe to cause it to pivot and to cause the pipe to be bent but does not control the compressive force on the pipe.
The invention has the additional advantage that it can be readily disassembled to permit, for example, substitution of alternative bending shoes etc., to facilitate bending of pipes having varied cross-sectional diameters.
As an alternative to the previously described operation of the invention, in the event that the pipe being bent has a sufficient inherent strength to be satisfactorily bent without compressive force being applied to its external surface, the follower shoe can be deleted and a pressure roller having a shape conforming to that of the pipe can be used instead.
Further advantages of the present invention will become readily apparent with reference to the drawings and the following description of the preferred embodiment. The invention illustrated in the drawings should not be viewed as a limitation of the present invention but merely depicts a single embodiment thereof. For example, though the invention is shown disposed in a generally horizontal plane, it should be readily apparent that the invention would function equally well in a vertical orientation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of the pipe bending apparatus of the present invention at the commencement of a pipe bending operation.
FIG. 2 is an enlarged partial view of the connection of the clamping assembly to the hydraulic motor.
FIG. 3 is a cross-sectional view taken along the line 3--3 in FIG. 1.
FIG. 4 is a cross-sectional view taken generally along the line 4--4 in FIG. 1.
FIG. 5 is a view similar to that shown in FIG. 1 but showing the pipe bending assembly in an intermediate stage of its operation.
FIG. 6 is a view similar to FIGS. 1 and 5 but showing the pipe bending assembly at the completion of a pipe bending operation.
FIG. 7 is a view taken generally along the line 7--7 in FIG. 5.
FIG. 8 is an exploded isometric view of portions of the frame assembly and the hydraulic motor.
FIG. 9 is an exploded isometric view of the bending shoe and the follower shoe.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Generally the pipe bending apparatus of the present invention, shown in a plan view in FIG. 1, is comprised of a horizontally extending frame 10, a bending shoe 30 which is pivotably mounted to the frame 10 for horizontal pivoting movement and means for bending a pipe P to conform to the configuration of the arcuate surface 32 of the bending shoe 30. A hydraulic motor 26 is rigidly secured to the frame 10 and includes a piston 64 operably connected to a clamping assembly 40 which functions to force a follower shoe 50 into engagement with the bending shoe 30 to cause the pipe P to conform to the configuration of the bending shoe.
The frame 10 is comprised of a pair of parallel vertically separated frame arms 12 and 13 which are spaced to receive therebetween the bending shoe 30, the pipe P, the follower shoe 50 and the hydraulic motor 26. The frame arms 12 and 13 each include a central axially extending elongated slot 14 for receiving the ends of a vertically extending pin 16 for slideable movement therein. The frame arms 12 and 13 are provided with aligned bores 18 at one end for receiving a bending shoe pivot pin 20 which pivotably supports the bending shoe 30 with respect to the frame 10. The frame arms 12 and 13 include at their other end a pair of aligned bores 22 which receive fluid motor supporting pins 24.
FIG. 3 illustrates in greater detail the manner in which the bending shoe 30 is pivotably mounted with respect to the frame 10. The figure illustrates a cross-sectional view showing the removable pivot pin 20 extending through the aligned bores 18 in the upper and lower arms 12 and 13 and extending through a bore 31 in the bending shoe 30. A sleeve 33 is provided within the bore 31 for receiving the pivot pin 20 and for facilitating relatively free pivotal movement of the bending shoe with respect to the frame 10. The pivot pin 20 is freely slideable within the sleeve 33 and can be readily withdrawn to permit disassembly of the frame 10 in order to facilitate substitution of various bending shoes 30 depending upon the type and cross-sectional diameter of the pipe to be bent.
The supporting pins 24 which secure the fluid motor 26 between the frame arms 12 and 13 are also freely removable as best shown in FIG. 8. A fluid motor 26 is shown therein as including a cylinder head 28 received between the frame arms 12 and 13 and including a pair of bores 27 which are aligned with complementary bores 22 in the arms 12 and 13 to receive the supporting pins 24. The cylinder head 28 also includes keys 21 and 23 bolted to opposite surfaces. The keys 21 and 23 have a generally oval shape and are slideably receivable within the slots 14 in the arms 12 and 13. The keys 21 and 23 function to permit axial sliding movement of the hydraulic motor 26 in the slots 14 of the arms 12 and 13. A catch member 29 having a shape the same as that of the keys 21 and 23, is also screwed into the cylinder head 28 adjacent to the key 23 and is pivotable with respect to that key such that it can be positioned transverse to the axially extending slot 14, to hold the arm 12 in clamped engagement with respect to the cylinder head 28. However, the catch 29 can also be pivotably aligned with the key 23 such that, when the supporting pins 24 have also been removed, the arm 12 can be readily removed from the cylinder head 28. A catch pad 29a is also secured to the cylinder head 28 over the key 21 to slideably secure the arm 13 to the cylinder head 28. It should be noted that the frame arms 12 and 13 include additional spaced aligned bores 22 along their length such that the fluid motor 26 can be secured in alternative positions along the length of the frame 10 to permit the use of fluid motors having variable piston lengths and also to permit the bending of pipes having various diameters in a manner which will be described hereafter.
As previously stated, the bending shoe 30, which is secured to the frame 10 by the pivot pin 20 extending through the bores 18, is pivotable around the pivot pin 20 in a horizontal plane. The bending shoe has a configuration which includes an arcuate surface 32 having a groove 34 therein for receiving a pipe P. The groove 34 is generally semi-circular when taken in cross-section and the diameter of the groove is substantially the same as the outside diameter of the pipe to be bent. The bending shoe 30 also includes a central arcuate slot 36 which includes an arcuate surface 38 generally concentric with the arcuate surface 32. The arcuate surface 38 is generally flat and is designed to receive a roller 54 of the clamping assembly 40 during the pipe bending process as will be described. It should be noted that the bending shoe 30 is pivotable about a pivot point which is off-set from the center of an arc defined by the arcuate surfaces 32 and 38 since the pivot pin 20 is located adjacent to one end of the arc 32. Adjacent the opposite end of the arcuate surface 32 is a bore 42 designed to receive a pin 44 for securing a saddle 46 to the bending shoe 30. The saddle 46 generally comprises a U-shaped bracket which can be received around the end of a pipe to secure that end of the pipe to the bending shoe 30 during the bending process.
The follower shoe 50, which functions in conjunction with the bending shoe 30 to cause bending of the pipe P, is comprised of a generally elongated straight member with a groove 52 extending along its length. The groove 52 has a semi-circular cross-sectional configuration substantially equal to the groove 34 such that, when a pipe is received between the follower shoe 50 and the bending shoe 30, the pipe is surrounded by the grooves 34 and 52 and the respective shoes will cause a compressive force around the circumference of the pipe P.
Such compressive force is generated by a clamping means 40 which comprises a plurality of rollers 54, 56, 58 and 59 rotatably supported and spaced with respect to each other by a pair of linking plates 60 and 62. As shown in FIGS. 1 and 4-6, the plates 60 and 62 are received between and adjacent to the frame arms 12 and 13 and are slideable with respect to the frame arms 12 and 13 during bending of the pipe P. The rollers 58 and 59 are mounted vertically with respect to each other and are rotatably mounted on the pin 16 which extends through a vertically extending bore in the end 65 of the piston rod 64. More specifically, as shown in FIG. 4, the pin 16 is secured within the piston end 65 by a set screw 63. The linking plates 60 and 62 each include opposed inwardly extending bushings 67 and 69 which receive opposite ends of the pin 16. The rollers 58 and 59 and the roller 56 which is rotatably supported by a pin 68, are engageable with the surface 66 of the follower shoe 50 and function to force the follower shoe 50 into engagement with the pipe P and toward the bending shoe 30. The plates 60 and 62 also function to support the bending shoe 30, and the follower shoe in horizontal alignment with each other. The plates include projecting portions 63 which provide additional support for the shoes to ensure their alignment and to prevent binding during the bending operation.
The other roller 54 of the clamping means 40 is received against the arcuate surface 38 of the bending shoe such that the pipe P, the follower shoe 50 and the bending shoe 30 are, in effect, held in clamping engagement between the rollers of the clamping assembly 40. The roller 54 is rigidly but rotatably supported by an eccentric shaft 70 which is secured at its ends in the plates 60 and 62. The shaft is also supported by a bushing 71 welded to the inner surface of the plate 60 and by a bushing 72 welded to the inner surface of the plate 62. The bushing 72 includes a pair of flats 73 on its inner bore 74 for receiving complementary flats on the sides of the eccentric shaft 70. When the eccentric shaft 70 is positioned with the complementary flats of the shaft and the bushing 72 disposed as shown in FIG. 4, the roller 54 will be positioned in relatively closely spaced relationship with respect to the roller 56 such that the rollers support the bending shoe 30 in clamping engagement with the pipe P and the follower shoe 50. Due to the eccentricity of the shaft 70, however, it is also possible, by rotating the shaft 180°, to increase the gap between the roller 54 and the rollers 56, 58 and 59 thereby decreasing the pressure applied by the bending shoe 30. The ecentric shaft mechanism illustrated as the means to support the roller 54 and to adjust the spacing between the rollers of the clamping means 40 is only one of several possible alternatives, and it should be clear that any of a plurality of similar adjustment means are within the scope of the invention.
Operation
The successive steps of a pipe bending operation using the apparatus of the present invention are best shown in FIGS. 1, 5 and 6. With the bending shoe 30 positioned as shown in FIG. 1, a pipe P may be positioned between the frame arms 12 and 13 within the groove 34 in the bending shoe 30. The saddle 46 is then placed over the end of the pipe P and secured in place with the saddle pin 44 as shown in FIG. 7. The follower shoe 50, which is freely removable from the apparatus, is then inserted between the pipe P and the rollers 56, 58 and 59. It should be noted that the follower shoe 50 includes an inclined surface 51 on its forward end so that it is easily insertable between the pipe P and the rollers.
With the elements of the bending apparatus in the position as shown in FIG. 1, the fluid motor 26 is actuated to cause the piston 64 to extend and to cause the clamping assembly 40, connected to the end of the piston, to create torque on the bending shoe 30 thereby causing initial horizontal pivotal movement of the bending shoe 30 around the pivot pin 20. When the fluid motor 26 is actuated, the rollers 56, 58 and 59 are forced against the follower shoe 50, and the follower shoe 50 in turn places a compressive force on the pipe P. The pipe P exerts a force on the surface of the bending shoe 30 generally acting in a direction normal to the surface where it contacts the arcuate surface 32 thus creating a torque on the bending shoe 30 about the pivot pin 20. This torque results in rotation of the bending shoe 30 around the pivot pin 20. It should be readily apparent, however, that the fluid motor 26 does not function directly to apply a compressive force on the pipe P but merely functions to cause pivotal movement of the bending shoe 30. The compressive force is generated by the compression of the rollers 54, 56, 58 and 59 on the respective shoes 30 and 50 in the manner previously described. As the bending shoe continues to rotate in the manner shown in FIGS. 5 and 6, the rollers will maintain clamping engagement between the follower shoe 50 and the bending shoe 30 and will cause the pipe P to conform to the surface configuration of the arcuate surface 32 thus creating a bend in the pipe. During this operation, the roller 54 will traverse the arc defined by the arcuate surface 38 and the rollers 56, 58 and 59 will traverse the length of the follower shoe surface 66.
In the event that the hydraulic motor 26 does not have a piston 64 of sufficient length to form a complete bend in the pipe, after a first stroke is completed and a partial bend formed, the pins 24 may be removed and the hydraulic motor may be slideably moved toward the pipe until bores 27 are aligned with a closer set of bores 22 in the arm 12 and 13. The pins may then be reinserted and the motor 26 actuated again to complete the bend.
The apparatus of the present invention is also equally adaptable to be used to bend pipe which is of sufficient wall thickness that it is not subjected to undesirable deformations of thin walled pipe. In such cases, it is generally unnecessary to use the follower shoe 50. Instead, the rollers 56 and 58 can be provided with external surfaces which conform to the shape of the pipe being bent or as an alternative, they can be fitted with elastomeric sleeves wherein they can be used to exert pressure directly onto the pipe during the bending operation.
The apparatus of the present invention is also readily adapted for use in bending pipes which have varying diameters including pipes having diameters of up to 6 inches. In order to bend pipes having different diameters, it is necessary to use bending shoes 30 and follower shoes 50 which have grooves equal to the diameters of the pipe to be bent. When it is desired to substitute a different bending shoe for that being used, the frame of the apparatus can be readily disassembled by removal of the pivot pin 20 and the two pivot pins 24 which thus permit removal of the upper frame arm 12. A bending shoe having a groove of the desired cross-sectional diameter can then be substituted and the arm 12 replaced. In the event that the replacement bending shoe is, for example, substantially shorter than the previously used bending shoe, the hydraulic motor 26 can be slideably moved in the slots 14 until the bores 27 in cylinder head 28 are aligned with a closer pair of the spaced bores 22 and pins 24 can be reinserted to secure the motor 26 in place with respect to the arms 12 and 13.
Resume
The pipe bending apparatus of the present invention thus provides a means for bending thin or thick walled pipe, and is readily adaptable for use in bending pipes having various diameters. The apparatus has the advantage that pressure can be maintained on and around the entire periphery of the pipe where it is being bent during the bending process to preclude kinks or any other type of undesirable distortion of the pipe even though the pipe is constructed from relatively soft material or has thin walls. The invention also has the advantage that it can be readily converted for use with pipes having different diameters or for use with pipes which have sufficient wall thickness that they are self-supporting. The invention also includes a means for applying compressive forces against the pipe bending shoes which ensures consistent pressure throughout the length of the bend and which requires a relatively small hydraulic motor when compared to those used in the prior art. The apparatus is also capable of forming a continuous 90° bend even in large diameter thin walled pipes. | A pipe bending apparatus for bending large diameter pipe of either thin or thick walled construction. The pipe bending apparatus includes a bending shoe which is pivotably mounted to a frame member and a follower shoe which is operable with the bending shoe to receive a pipe therebetween for bending. The apparatus also includes a fluid motor which is operable to cause pivotal movement of the bending shoe and a clamping assembly comprising a plurality of rollers which are secured together to clampingly engage the follower shoe and the bending shoe to force them together such that the pipe is forced to conform to the arcuate configuration of the bending shoe as the bending shoe pivots. During such pivotal movement, the rollers of the clamping assembly traverse the arcuate surface of the bending shoe and the rear surface of the follower shoe clamping the pipe between the bending and follower shoe and causing the pipe to assume the configuration of the bending shoe in a rolling mill type operation. | 1 |
BACKGROUND OF THE INVENTION
This invention relates to a method of forming the core of a ball.
The conventional method of forming the core of a ball is disadvantageous in that the core loses its shape when it is taken out of the metallic mold because of the fact that the fibers are merely fixed by compression. Accordingly, the operation of fastening a thread to the core is difficult. Moreover, another disadvantage is that the core having the fastened thread cannot be formed into a perfectly round ball.
SUMMARY OF THE INVENTION
The present invention has been proposed to solve the afore-mentioned problems, and its main object is to carry out shape retention and forming at the same time.
A further object of the present invention is to improve the shape-retaining property of the core following the formation thereof; thereby facilitating the thread fastening operation.
A still further object of the present invention is to provide a method of forming the core of a ball which has a perfectly round shape.
Further objects and features of this invention will be apparent from the following detailed description taken in conjunction with the accompanying drawings in which like reference characters designate the same or similar parts throughout the figures thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-sectional view of wool soaked in an alkaline solution;
FIG. 2 is a general view of the apparatus for forming the core;
FIG. 3 is a block diagram of the vibrating means; and
FIG. 4 is a general view of the keyed mold.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Wool is immersed in an alkaline solution comprising 0.1 percent by weight of soda carbonate and 0.0005 percent by weight of caustic soda. In FIG. 1, wool is indicated at reference number 1, and the alkaline solution at numeral 2. An alternative to immersing the wool in the alkaline solution 2 is to spray the wool with the alkaline solution.
The core 7 of a ball is formed by packing a guide tube 3 with the wool 1 treated as described above, and by forcibly pressing a half mold 5 forcibly against another half mold 6 by means of a cylinder 4 which vibrates as it descends. (FIG. 2)
The cylinder 4, as shown in FIG. 3, adds an intertwining action to the compressing motion by vibrating means. This motion is achieved by actuating a pressure supply 10, and at the same time by supplying the cylinder 4 with compressed air alternately through lines 13 and 14 when a signal generator 11 delivers a signal to the solenoid of a switch valve 12. As a result, the core 7 is subjected to a mechanical action owing to the motion of the cylinder 4 as it repeatedly pushes against and separates from the mold 5.
The molds 5 and 6 formed in this way are heated to temperature of from 100° C. to 120° C. for a period from 20 to 25 minutes while they are maintained in the joined condition by keys 20, 20. The result is that shrinking of the wool 1 is further hastened and that the wool 1 changes into felt having a spherical shape. More particularly, the wool fiber is considered to turn into felt due to shrinkage when it is soaked in water (especially an alkaline aqueous solution) and heated, and because of intertwining owing to the crimping property of the wool fiber. The wool fiber therefore keeps its spherical shape even after taking the core out of the mold. Therefore, the operation of fastening the thread to the core and of covering the core with rubber can be easily carried out.
In the above description, the wool is soaked in the alkaline solution, but a neutral aqueous solution may be employed instead. Though the above description relates to an example where the ball 7 is formed integrally, this is not a strict requirement. Two cores may be joined with a rubber adhesives after each has been formed in the shape of a hemisphere.
As many apparently widely different embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that the invention is not limited to the specific embodiments thereof except as defined in the appended claims. | Wool fiber is moistened and compressed, and the moistened wool fiber is heated in a metallic mold. Said wool fiber is intertwined in the mold and forms a core of a ball. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Patent Application No. 61/614,794 filed Mar. 23, 2012 and U.S. Provisional Patent Application No. 61/495,100 on Jun. 9, 2011, the entireties of which applications are hereby incorporated by reference into this application.
BACKGROUND OF THE INVENTION
Conventional supports provide a polyester filled or foam boot for support of a lower leg. Other conventional supports include an ankle foot orthotic (AFO) or foot wrap. Another conventional support includes an air chamber in a boot configuration. The air chamber supports a leg and heel above a surface of a bed patient when lying in a supine and side lying position, such as in a hospital bed.
The conventional supports have the disadvantage that pressure is applied to the heel or leg for maintaining the heel above the surface of the bed. In addition, the leg can be raised too high such that joints can lock, nerves can be potentially entrapped and the circulation to the leg can be compromised. In addition, the intraluminal pressure of conventional supports minimizes its ability to contour to the object applying the force.
Sequential or intermittent compression devices have been described which include inflatable sleeves. The sleeve is placed over the leg or foot. Pressure modulation is used in order to reduce risk of clot formation in the leg or foot.
It is desirable to provide a sequential or intermittent compression device in combination with a lower leg protection system for supporting the leg and heel when a patient is recumbent while maintaining neutral leg alignment without lifting the leg and heel from the resting surface.
SUMMARY OF THE INVENTION
The present invention relates to a support for a body part including a compression device in combination with a lower leg protection system. The compression device can be inflated sequentially or intermittently. The compression device can be inlaid into a support boot and attached to the boot with a flexible material. A valve is combined with the compression device for increasing and reducing pressure within the compression device in a sequential or intermittent manner. It is optimal to barely elevate the heel from the surface of the bed. This helps to minimize leg rotation and locking of the knee.
In one embodiment, the compression device is combined with a fluidized lower protection system including an inner positioner and an outer support. The inner positioner includes a bladder, preferably filled with a fluidized particulate material, to provide three-dimensional contouring to the lower leg and heel. The inner positioner has low pressure and is not sufficient alone to support the leg. The inner positioner has little or no flow characteristics unless an outside force is applied other than gravity. The inner positioner can displace and contour three-dimensionally as though it was fluid to the sides and top of the leg while not having flow characteristics that would result in migration of the medium under the force of gravity. The inner positioner can provide three-dimensional contouring to the Achilles tendon. The inner positioner can include a temperature regulating material for keeping the leg in an optimal range of skin temperature to keep the leg comfortable longer. The inner positioner can be shaped as a pad to mold to the underside portion of the lower leg and heel. Alternatively, the inner positioner can include various shapes to support the lower leg and heel. In one embodiment, the inner positioner also includes a portion which extends over a top portion of the leg, such as the shin.
The outer support is received over the inner positioner. The outer support can be in the shape of an open boot. In one embodiment, the compression device can be integral with the outer support at a position received over the lower leg. One or more valves can extend from a compression bladder for attachment to a pneumatic device. Inflation of the compression bladder positioner adjacent the lower leg also displaces air in the outer support toward the foot which causes simultaneous massaging of the foot. The pneumatic device can be adjusted to provide either sequential or intermittent therapies.
The outer support can include an ultra low pressure plenum. The ultra low pressure plenum is filled at a predetermined low pressure for distributing pressure along the length of the outer support, but not providing significant elevation of the lower leg and heel by itself. In this embodiment, the inner positioner is partially filled with the fluidized particulate material so it cannot support a leg on its own. For example, the inner positioner can be filled up to ⅔ of its capacity. The outer portion of the inner positioner contours to the inner portion of the ultra low pressure plenum for providing more air displacement of the outer support than if the inner positioner was not present.
In one embodiment the system is strapless. In an alternate embodiment, the system includes a strap for attachment of the outer support to the leg. The strap can be sufficiently wide and cushioned to protect the skin. In one embodiment, the strap is air bearing. In one embodiment, a rear end of the outer support includes a gate, which can be opened to allow access to the foot and heel from the rear of the boot.
The inner positioner or outer support can include a fluidized thermal regulating medium. In one embodiment, a phase change material can be used for adjusting the temperature of the system.
The system of the present invention can be a one size fits all and adapts to the size and shape of a patient's leg. The system maintains neutral alignment and helps prevent foot drop. The system gently but securely wraps the leg, helping to maintain constant heel position. The system promotes proper dorsiflexion without causing undue pressure on the lower limb.
The combination of the inner positioner including a fluidized medium along with the outer support including a ultra low pressure plenum creates sufficient support of the lower leg while responding to normal patient movement. The combination of the inner positioner and the outer support provides three-dimensional contouring to the lower leg and heel for micro adjustment while the outer support or boot is closed for minimizing friction and shear. This is not possible in conventional devices where the inner chamber is not free to communicate with the leg without negatively affecting the functionality of the outer chamber. In general, the custom fitting protection can be used in such a way as to elevate the foot without “locking out the knee” due to three-dimensional molding and provide comfort to the skin. The natural contour of the leg can be maintained while eliminating harmful pressure to the heel, ankle, Achilles and foot. The system of the present invention can respond to the twisting of the leg without causing movement of the outer support. The system of the present invention can minimize shear forces that would be associated with a non-fluidized medium.
The invention will be more fully described by reference to the following drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a side schematic diagram of an embodiment of a compression device in combination with a fluidized lower leg protection and support system including an outer support.
FIG. 1B is a rear schematic diagram of the compression device in combination with a fluidized lower leg protection and support system including an outer support, as shown in FIG. 1A .
FIG. 2 is a schematic diagram of the embodiment of the compression device in combination with a fluidized lower leg protection and support system shown in FIG. 1A from an opposite side.
FIG. 3 is a schematic diagram of the embodiment of the compression device in combination with a fluidized lower leg protection and support system shown in FIG. 1A from a rear side.
FIG. 4 is a schematic diagram of the embodiment of the compression device in combination with a fluidized lower leg protection and support system shown in FIG. 1A from a rear side in an open position.
FIG. 5 is a schematic plan view of the embodiment of the compression device in combination with a fluidized lower leg protection and support system shown in FIG. 1A .
FIG. 6 is a schematic diagram of an alternate embodiment of the compression device in combination with a fluidized lower leg protection and support system including an outer support and support strap.
FIG. 7 is a schematic diagram of an alternate embodiment of the compression device in combination with a fluidized lower leg protection and support system including an outer support, support strap and ankle strap.
FIG. 8 is a schematic diagram of the embodiment of the compression device in combination with a fluidized lower leg protection and support system shown in FIG. 7 from an opposite side.
FIG. 9 is a schematic diagram of an alternate embodiment of the compression device in combination with a fluidized lower leg protection and support system including an opening between side portions of the outer support.
FIG. 10A is a top perspective view of an alternate embodiment of the compression device in combination with a fluidized lower leg protection and support system in a fully open position.
FIG. 10B is a bottom perspective view of the embodiment shown in FIG. 10A .
FIG. 11 is a top perspective view of the embodiment of FIG. 10A including an inner positioner.
FIG. 12 is a top perspective view of the embodiment of FIG. 11 in which the rear end of the compression device in combination with a fluidized lower leg protection and support system is closed.
FIG. 13 is a top perspective view of the embodiment of FIG. 12 in which a lower leg is placed adjacent the rear end of the compression device in combination with a fluidized lower leg protection and support system.
FIG. 14 is a top perspective view of the embodiment of FIG. 13 in which a flap of the compression device in combination with a fluidized lower leg protection and support system is closed over the received lower leg.
FIG. 15 is a top plan view of a valve extending through the compression device in combination with a fluidized lower leg protection and support system for attachment to the compression device.
FIG. 16 is a schematic diagram of the compression device including a plenum providing low air loss.
DETAILED DESCRIPTION
Reference will now be made in greater detail to a preferred embodiment of the invention, an example of which is illustrated in the accompanying drawings. Wherever possible, the same reference numerals will be used throughout the drawings and the description to refer to the same or like parts.
FIGS. 1-5 illustrate an embodiment of a compression device in combination with a lower leg protection and support system 30 .
Compression system 40 is combined with fluidized lower leg support system 50 . In one embodiment, compression system 40 can be inlaid into lower leg protection and support system 50 and attached thereto with coupling member 42 . Lower leg protection and support system 50 can be a conventional support boot. In one embodiment, lower leg protection and support system 50 includes outer support 52 and inner positioner 14 . Compression system 40 can include bladder 44 attached with coupling member 42 to outer support 52 . Valve 46 can be associated with compression system 40 for inflating and deflating compression system 40 in a sequential or intermittent manner.
Outer support 52 can include a plurality of rows of parallel ultra low pressure plenums 53 . For example, ultra low pressure plenums 53 can be positioned within outer support 52 along the length L 1 of outer support 52 . Flap 54 can extend over front of lower leg 16 . Flap 54 can include ultra low pressure air plenums 55 , which protect lower leg 16 from strap 56 . Flap 54 can also provide anti-rotation of fluidized lower leg protection and support system 50 . Strap 56 can be adjustable for closing flap 54 for different sizes of legs. Strap 54 can include a coupling portion 57 at one end thereof for attaching to attachment section 58 . Strap 56 can include a cushioning material. In one embodiment, strap 56 is air bearing. Coupling portion 57 can be formed of a hook and loop material. Attachment section 58 can be formed of a hook and loop material. Attachment section 58 can be positioned along length L 1 of outer support 52 . Outer support 52 can be received under U-shaped base 59 , as shown in FIG. 3 . U-shaped base 59 provides anti-rotation of outer support 52 . Air pressure within ultra low pressure plenum 53 is reduced sufficiently to provide reduced pressure for conforming outer support 52 to the shape of lower leg 16 and optionally heel 17 for distributing pressure along the length of outer support 52 , but is not providing support of lower leg 16 and heel 17 .
Inner positioner 14 is formed of bladder 13 including fluidized material 15 therein which can retain its shape after sculpting. Fluidized material 15 can be a particulate material including interstitial spaces between the particles. A lubricant can be present in the interstitial spaces. For example, the lubricant can be a particulate material having a lower coefficient of friction, such as a powder. The volume of the particulate material can be controlled for controlling the interstitial air within the fluidized medium.
Bladder 13 is filled with fluidized material 15 which can retain its shape after sculpting. The flowability or lubricity of fluidized material 15 can be increased by adding a lubricant or by the removal of air from the interstitial spaces or both. The preferred medium of fluidized material 15 is a particulate material that has been modified in such a way that it acts like a fluid Fluidized material 15 refers to a compound or composition which can be sculpted and retain its shape and has no memory or substantially no memory. The no memory or substantially no memory feature enables bladder 13 to increase in height and maintain support of a body part. Fluidized material 15 is made of a viscosity that will allow it to contour but not collapse under the weight of the body part.
At sea level, the normal interstitial air pressure would exceed about 760 millibars of mercury. This increases or decreases marginally as altitude varies. Depending on the nature of the particulate fluidized material 15 , the pressure can be lowered below about 500 millibars, preferably, about 350 millibars to about 5 millibars, while still maintaining the necessary flow characteristics of the product. The amount the pressure is lowered is dependent on the interstitial spaces needed to provide desired flow characteristics of the product.
Fluidized material 15 can include beads, such as polyethylene or polystyrene (PS) beads, expanded polyethylene (PE), crosslinked expanded polyethylene (PE), polypropylene (PP) pellets, closed cell foams, microspheres, encapsulated phase changing materials (PCM). The beads can be hard shelled or flexible. In one embodiment, the beads are flexible and air can be evacuated from the beads. In one embodiment, hard beads can be mixed with flexible beads in which air can be evacuated from the flexible beads. In an alternative embodiment, fluidized material 15 can a porous foam substance including pockets of interstitial air. In one embodiment, fluidized material 15 can be a polyurethane foam. The polyurethane foam can be open or closed cell and cut into small shapes such as spheres or blocks. For example, a sphere of polyurethane foam can have a size of 2 inches in diameter. For example, a block of polyurethane foam can be a 1×1×1 inch block.
Suitable examples of fluidized material 15 can be formed of a mixture of microspheres and lubricant. The microspheres can include hollow or gas-filled structural bubbles (typically of glass or plastic) with an average diameter of less than 200 microns. The composition flows and stresses in response to a deforming pressure exerted on it and the composition ceases to flow and stresses when the deforming pressure is terminated. For example, fluidized material 15 can be formed of a product referenced to as Floam™. A flowable compound comprising lubricated microspheres, including the compound itself, formulations for making the compound, methods for making the compound, products made from the compound and methods for making products from the compound as defined by U.S. Pat. Nos. 5,421,874, 5,549,743, 5,626,657, 6,020,055, 6,197,099, and 8,171,585, each of which is hereby incorporated by reference into this application. Bladder 13 provides micro-contouring because fluidized material 15 can respond three-dimensionally.
For example, bladder 13 can be formed of a flexible plastic, such as urethane. Upon removal of residual air from fluidized material 15 bladder 13 flows concurrent with the flow of fluidized material 15 such that bladder 13 moves with movement of fluidized material 15 . Bladder 13 can have a size and shape to support lower leg 16 and heel 17 of a user. Bladder 13 can include portion 18 which extends over top portion 19 of lower leg 16 . Optionally, air can communicate throughout the whole bladder 13 for allowing maximum contouring and functional displacement of both the air and the fluidized chamber thereby providing maximum contouring to a desired body part.
Inner positioner 14 or outer support 52 can include thermo-regulating medium. Thermo-regulating medium can be a phase change material for adjusting the temperature to adapt support system 10 to temperature changes of a body part of a user. Thermo-regulating material can be associated with fluidized material 15 or cover (not shown) placed over inner positioner 14 . An example material for thermo-regulating material is manufactured by Outlast Technologies as fibers, fabrics, and foams comprising micro-encapsulated phase changing materials referred to as Thermocules, which store and release heat as further described in U.S. Pat. Nos. 7,790,283, 7,666,502 and 7,579,078, hereby incorporated by reference into this application.
For example, the pressure in ultra low pressure plenum 53 can be below 20 mm of water. It will be appreciated that all equivalents such as mm Hg and PSI can be used for measuring the pressure within ultra low pressure plenum 53 .
The pressure within ultra low pressure plenum 53 can be below about 20 mm of water if no inner positioner is used or if an area of less than about 30% of outer support 52 is covered by inner positioner 14 . The pressure within ultra low pressure plenum 54 can be below about 10 mm of water if an area of between about 30% to about 60% of outer support 52 is covered by inner positioner 14 . The pressure within ultra low pressure plenum 53 can be below about 5 mm of water if an area of greater than about 60% of outer support 52 is covered by inner positioner 14 .
Rear end 60 of outer support 52 can include overlapping flap members 62 and 63 for forming a gate to allow access to foot 19 including heel 17 , as shown in FIGS. 3A-3B . Flap members 62 and 63 can include respective coupling portions 64 and 65 for attaching flap members 62 and 63 to one another. For example, coupling portions 64 and 65 can be formed of a hook and loop material. Flap members 62 and 63 can be opened to allow access to foot 19 , as shown in FIG. 4 .
FIG. 6 illustrates an alternate embodiment of a fluidized lower leg protection support system 70 , including support strap 72 . Support strap 72 can extend around rear end 60 for providing support, for example, in supporting a patient with foot drop. Support strap 72 can include coupling portion 77 at one end thereof. Coupling portion 77 can be formed of a hook and loop material. Coupling portion 77 can attach to attachment section 58 .
FIGS. 7 and 8 illustrate an alternate embodiment of a fluidized lower leg protection and support system 80 . Support strap 82 can include coupling portion 87 at one end thereof. Coupling portion 87 can be formed of a hook and loop material. Coupling portion 87 can attach to attachment section 88 . Attachment section 88 can be positioned circumferentially around top portion 89 . Coupling portion 87 can be coupled at various locations on attachment section 88 . Ankle strap 92 can attach to attachment section 94 . Ankle strap 92 can include coupling portion 93 at one end thereof. Coupling portion 93 can be formed of a hook and loop material. Attachment section 94 can be formed of a hook and loop material. Ankle strap 92 can be positioned above ankle 95 . Attachment section 94 can be positioned adjacent or below ankle 95 .
FIG. 9 illustrates an alternate embodiment of a fluidized lower leg protection and support system 100 which includes opening 102 between side portions 103 and 104 for allowing air to contact lower leg 16 and allowing cooling of lower leg 16 while providing support. Straps 105 and 106 can attach to respective attachment sections 107 and 108 . Straps 105 and 106 can include coupling portion 109 at one end thereof. Coupling portion 109 can be formed of a hook and loop material. Attachment section 107 and 108 can be formed of a hook and loop material.
Inner positioner 14 described above can be used with each of the fluidized lower leg protection and support systems 50 , 70 , 80 and 100 . In one embodiment, inner positioner 14 is positioned horizontally at ankle 19 and wraps around the Achilles to protect the ankle.
FIGS. 10-15 illustrate leg protection and support system having compression 200 . Outer support 202 includes one or more of parallel rows of ultra low pressure plenums 203 forming outer support bladder 201 . For example, ultra low pressure plenums 203 can be positioned within outer support 202 along the length L 1 of outer support 202 . Flap 204 can include ultra low pressure air plenums 205 .
Compression bladder 214 can be positioned on inner surface 215 of outer support 202 , as shown in FIG. 10A . Compression bladder 214 can be integral with outer support 202 in which compression bladder is joined at edges 216 of outer support bladder 201 . Support bladder 214 can extend into flap 204 .
Valve 210 extends through outer support 202 to provide access to end 211 of valve 210 , as shown in FIG. 10B and FIG. 11 . End 212 of valve 210 extends into compression bladder 214 . Valve 220 extends through flap 204 of outer support 202 to provide access to end 221 of valve 220 . End 222 of valve 220 extends into flap 204 .
Rear end 230 of outer support 202 can include flap members 232 and 233 , as shown in FIGS. 10A-10B . Flap members 232 and 233 can include respective coupling portions 234 and 235 for attaching flap members 232 and 233 to one another. In one embodiment, coupling portion 234 is attached to inner surface 237 of flap member 232 and coupling portion 235 is attached to outer surface 238 of flap member 233 , as shown in FIG. 12 . For example, coupling portions 234 and 235 can be formed of a hook and loop material.
During use, inner positioner 14 can be placed over outer support 202 , as shown in FIG. 12 . Flap members 232 and 233 are attached to one another for closing leg protection and support system having compression 200 and forming foot and heel support portion 240 of outer support 202 , as shown in FIG. 13 . Lower leg 16 is received in leg protection and support system having compression 200 adjacent to heel support 240 , as shown in FIG. 14 . Inner positioner 14 provides three dimensional contouring to the received lower leg 16 and heel 17 . Flap 204 can be closed over lower leg 16 , as shown in FIG. 15 . Strap 206 can be adjusted for closing flap 204 . End 221 of valve 220 can be connected to compression device 250 . Compression device 250 can provide pneumatic pressure for inflating and deflating compression bladder 214 in a sequential or intermittent manner.
FIG. 16 illustrates an alternate embodiment of compression device in combination with lower leg support system 1000 . Outer support 1001 of system 1000 has a three layer construction. Top layer 1020 , intermediate layer 1030 and bottom layer 1040 are sealed to one another along outside edge 1050 . For example, top layer 1020 , intermediate layer 1030 and bottom layer 1040 can be formed of urethane.
Plenum 1100 formed between top layer 1020 and intermediate layer 1030 can include dynamic air. Air 1150 is pumped into plenum 1100 through valve 1110 by pump 1120 . Air 1150 is pumped beneath top layer 1020 . Top layer 1020 is perforated with apertures 1180 . Plenum 1100 provides a dynamic amount of air to system 1000 for adjusting the amount of air in plenum 1140 and providing low air loss.
Plenum 1140 formed between bottom layer 1040 and intermediate layer 1030 can include a fixed amount of static air. In one embodiment, plenum 1140 is filled with an ultra low pressure of a pressure of about 500 millibars through about 10 millibars or in some cases even lower pressures can be used. Valve 1160 can be used to adjust the pressure in plenum 1140 .
It is to be understood that the above-described embodiments are illustrative of only a few of the many possible specific embodiments, which can represent applications of the principles of the invention. Numerous and varied other arrangements can be readily devised in accordance with these principles by those skilled in the art without departing from the spirit and scope of the invention. | The present invention relates to a support for a body part including a compression device in combination with a lower leg protection system. The compression device can be integral with the outer support at a position received over the lower leg. One or more valves can extend from a compression bladder for attachment to a pneumatic device. Inflation of the compression bladder positioner adjacent the lower leg also displaces air in the outer support toward the foot which causes simultaneous massaging of the foot. The pneumatic device can be adjusted to provide either sequential or intermittent therapies. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. patent application Ser. No. 10/780,827 filed Feb. 18, 2004; which is a continuation in part of co-pending U.S. patent application Ser. No. 09/941,247 filed Aug. 28, 2001; and claims the benefit of U.S. provisional patent application Ser. No. 60/448,573 filed Feb. 19, 2003, which applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to an improved system for generating electrical power using a fuel cell. More particularly, the invention pertains to a system for generating hydrogen gas by reacting water vapor with a substantially non-fluid substance in a regulated manner, and transporting the generated hydrogen gas to the fuel cell which in turn generates electrical power. The invention also relates to a pneumatic valve for use in a hydrogen gas generating apparatus.
[0004] 2. Description of the Related Art
[0005] Similar to batteries, fuel cells function to produce electric power through chemical reactions. Rather than storing reactants as batteries do, fuel cells are operated by continuously supplying reactants to the cell. Proton exchange membrane (PEM) fuel cells operating with H 2 from hydrocarbon liquids have emerged as leading candidates to replace batteries in portable electronic devices, power cleaners, more fuel efficient vehicles and for powering microelectromechanical systems (MEMS) devices such as MEMS electrical power generators. In a typical fuel cell, hydrogen gas acts as one reactant and oxygen as the other, with the two reacting at electrodes to form water molecules and releasing energy in the form of direct current electricity. This direct current electricity may then be converted into an alternating current. The system may produce electricity continuously as long as hydrogen and oxygen are provided. While oxygen is typically provided from the air, it is generally necessary to generate hydrogen gas from other compounds through controlled chemical reactions rather than storing hydrogen, because storing of hydrogen gas requires that it either be compressed or cryogenically cooled. As fuel cell technology evolves, so do the means by which hydrogen gas is generated for application with fuel cells.
[0006] Currently, there are various methods which are known and employed for generating hydrogen gas. The predominant method is by a process known as reformation in which fossil fuels are broken down into their hydrogen and carbon products. However, this system is undesirable in the long term because it is dependent upon a non-renewable resource. Another method is electrolysis, in which hydrogen is split from water molecules. However, this method is not well suited for large scale applications, such as use in automobiles. Another means of generating hydrogen gas is by reversibly adsorbing and releasing hydrogen gas from metal hydrides or alloys through heating. While this method is useful, it is not preferred because the metal hydrides are typically very heavy, expensive and only release small quantities of hydrogen. Yet another means by which hydrogen gas is generated is through reactive chemical hydrides. This process involves chemically generating hydrogen gas from dry, highly reactive solids by reacting them with liquid water or acids. Chemicals especially suitable for this process are lithium hydride, calcium hydride, B 10 H 14 , lithium aluminum hydride and sodium borohydride, each of which are capable of releasing plentiful quantities of hydrogen. The disadvantages associated with this method is that reaction products from the chemical and liquid water typically form a cake or pasty substance which interferes with further reaction of the reactive chemical with the liquid water or acid.
[0007] It is of great interest in the art to provide a means by which hydrogen gas may be generated in a regulated manner for use in fuel cells, without relying on non-renewable resources and without the disadvantages of each of the aforementioned methods. The present invention provides a solution to this problem. The invention provides an electrical power generator and a process for controllably generating hydrogen gas at the rate that a fuel cell requires it. The electrical power generator comprises a water vapor generator at least partially filled with water vapor, at least one hydrogen gas generator connected to the water vapor generator, a regulating valve and a fuel cell connected to the hydrogen gas generator, the hydrogen generation chamber being at least partially filled with a substantially non-fluid substance which reacts with water vapor to generate hydrogen gas. The hydrogen gas generated may then be used as a “fuel” which allows the fuel cell to generate electrical power. The present invention improves upon the related art by reacting a water vapor with a substantially non-fluid substance to controllably generate hydrogen gas, rather than liquid water. By reacting a water vapor with the aforementioned non-fluid chemical substance, it has been found that the typical problems associated with reactive chemical hydrides are avoided, resulting in a more efficient system than those of the prior art.
[0008] The invention also provides a non-electrically actuated valve suitable for use in hydrogen generating apparatuses. The valve of the invention is actuated by hydrogen overpressure to regulate the diffusion of water vapor into a powdered chemical fuel. Since the valve is non-electrically actuated, the need for a control voltage, a controller and a control voltage generator is eliminated, and the problem of electrical discharge in valves operating in humid conditions is avoided.
SUMMARY OF THE INVENTION
[0009] The invention provides an electrical power generator comprising:
[0000] a) a water vapor generator;
b) a hydrogen gas generator attached to the water vapor generator, said hydrogen generator containing a substantially non-fluid substance which reacts with water vapor to generate hydrogen gas; said hydrogen generator optionally being attached to said water vapor generator via at least one conduit; and
c) a fuel cell attached to the hydrogen gas generator; said fuel cell optionally being attached to said hydrogen gas generator via at least one conduit.
[0010] The invention also provides a process for generating hydrogen gas for fueling a fuel cell comprising:
[0000] a) directing water vapor from a water vapor generator to a hydrogen generator, said hydrogen generator being at least partially filled with a substantially non-fluid substance which reacts with water vapor to generate hydrogen gas; and
b) directing said hydrogen gas and any residual water vapor to a fuel cell.
[0011] The invention further provides an improved process for generating electrical energy wherein water and hydrogen gas are directed from a water containing chamber to a fuel cell; and water and any residual hydrogen gas are directed from the fuel cell back to the water containing chamber; and water and hydrogen gas are directed through a hydrogen gas generator, which hydrogen gas generator is connected to each of the fuel cell and water containing chamber and which hydrogen gas generator is at least partially filled with a substance which reacts with water to generate hydrogen gas, wherein the improvement comprises contacting water in the form of water vapor with a substantially non-fluid substance which reacts with water vapor to generate hydrogen gas.
[0012] The invention still further comprises a hydrogen gas generating apparatus, the apparatus comprising a housing which encloses:
[0000] a) a water vapor generator;
b) a hydrogen gas generator, comprising a substantially non-fluid substance that reacts with water vapor to generate hydrogen gas;
c) at least one conduit connecting the water vapor generator and the hydrogen gas generator, the conduit allowing for the flow of water vapor from the water vapor generator to the hydrogen gas generator; and
d) a valve positioned through said conduit for alternately opening and closing the conduit, said valve comprising:
i) a flexible diaphragm having a periphery that is fixed to said housing; ii) a valve disc positioned opposite the diaphragm and mating with the conduit for alternately opening and closing the conduit; iii) a rod connector having opposite ends, the rod extending through a portion of the conduit and attached at one of its ends to the diaphragm and attached at its opposite end to the valve disc; and iv) a seal attached around a periphery of the conduit and positioned for mating with the valve disc when the valve disk is positioned to close the conduit.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a schematic representation of an electrical power generator having a conduit and a separate return line.
[0018] FIG. 2 is a schematic representation of an electrical power generator having neither a conduit nor a return line.
[0019] FIG. 3 is a schematic representation of an electrical power generator having a conduit connecting each of the water vapor generator, the hydrogen gas generator and the fuel cell, and also having a pump, a tensile membrane within the water vapor generator and a thermal insulator around the fuel cell.
[0020] FIG. 4 illustrates the components for the electronic control system and the overall interconnection scheme of the electrical power generator.
[0021] FIG. 5 is a perspective view of the electrical power generator formed within a polymeric block.
[0022] FIG. 6 illustrates a perspective view of an electrical power generator and its component parts, in the form of a thin molded card.
[0023] FIG. 7 is a graph of voltage current measurement of the electrical power generator.
[0024] FIG. 8 illustrates a schematic representation of a mesovalve.
[0025] FIG. 9 illustrates a perspective view of a mesovalve.
[0026] FIGS. 10A-10I illustrate the process steps for forming a MEMS fuel cell.
[0027] FIG. 11 is a cross-sectional side-view of a hydrogen gas generating apparatus of the invention having a non-electrically actuated valve.
[0028] FIG. 12 is a top-view of a hydrogen gas generating apparatus of the invention regulated by a non-electrically actuated valve.
[0029] FIG. 13 is a cross-sectional side view of a hydrogen gas generating apparatus of the invention having a non-electrically actuated valve.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0030] An electrical power generator is provided which generates hydrogen gas through controlled reactions of water vapor with a substantially non-fluid substance, which hydrogen gas is then used to fuel a fuel cell. The electrical energy generated may be used to power miniature devices such as wireless sensors, cellular phones or other hand held electronic devices.
[0031] A seen in FIGS. 1-3 , the electrical power generator 10 broadly comprises at least one water vapor generator 12 , at least one hydrogen gas generator 14 attached to the water vapor generator 12 and a fuel cell 16 attached to the hydrogen gas generator 14 . The water vapor generator 12 is preferably a chamber that is at least partially filled with water in the form of either water vapor, liquid water or ice. The quantity of either liquid water or ice may vary and generally depends on the size of the water vapor generating chamber 12 and the application for which the power generator 10 is used. If a liquid is used, the liquid may comprise a mixture of water and alcohol, in any proportion, to prevent the liquid water from freezing until very low temperatures. In this case, the water vapor generator may generate both water and alcohol vapors. Both vapors may then enter the hydrogen generator and induce the generation of hydrogen. The preferred embodiment is to use pure water.
[0032] Should a liquid water be present within the water vapor generator 12 , the liquid water may be prevented from seeping out of the water vapor generator 12 by either porous plugs 24 or by a valve 26 . Porous plugs 24 comprise a porous material such as cotton or a polymeric fabric, which acts as a barrier to liquid water while allowing the passage of water vapor into and out of the water vapor generator 12 .
[0033] Alternately, valve 26 , may regulate the passage of water vapor out of the water vapor generator 12 and prevent the seeping out of any liquid water. This embodiment is shown in FIG. 2 . The valve 26 may be either a manually or pneumatically or electrically controlled valve. The preferred embodiment is a pneumatically controlled valve. If the valve is controlled electrically, the initial power necessary to open the valve, causing an initial flow of water vapor from the water vapor generator 12 to the hydrogen gas generator 14 , is preferably supplied by power stored in a device 30 . The valve 26 may be directly electrically connected to the device 30 or to the fuel cell 16 , with the fuel cell then being electrically connected to the device 30 . The device 30 may alternately be attached to either the water vapor generator 12 , the hydrogen gas generator 14 or another element of the power generator 10 . Once the valve 26 is initially opened to allow water vapor out of the water vapor generator 12 , the power generated from the fuel cell 16 is then preferably used to supply the power for controlling the valve 26 . In the preferred embodiment of the invention using an electrically controlled valve, the device 30 comprises a battery. The opening and closing of the valve 26 is preferably controlled pneumatically depending on when it is desired to generate hydrogen gas and fuel the fuel cell. Electrically controlled valves of several types exist. Preferably the electrically controlled valve is a mesovalve. Structures for useful mesovalves are shown in FIGS. 8 and 9 . Mesovalves are also described in U.S. Pat. No. 5,836,750, which is incorporated herein by reference. A series of mesovalves forms a mesopump. Such ultra-light compact, water-vapor diffusive-flow regulator mesovalves, use an electrostatically actuated moving polymer membrane. Control of the mesovalve actively regulates the internal pressure of the generator since it controls water vapor access to the powder fuel chamber.
[0034] While valve 26 is only depicted in FIG. 2 , it is intended that any embodiment of the present invention may include at least one valve 26 . Further, several different arrangements of interconnecting the fuel cell, hydrogen generator, water vapor generator, valves and pumps are available as is evident to persons familiar with gas and vapor interconnections. It should be understood that when elements herein are described as being attached or connected together that they may be either directly or indirectly attached, unless a direct attachment is specified. Also, when the flow of water vapor and/or hydrogen gas is described herein, it should be understood that the gases may flow directly or indirectly from one element to another, unless particularly specified. For example, hydrogen gas may flow from the hydrogen gas generator to a fuel cell indirectly by the hydrogen gas first passing through the water vapor generator.
[0035] In the preferred embodiment, the power generator 10 is initially loaded with hydrogen gas within at least one of said water vapor generator 12 , hydrogen gas generator 14 , fuel cell 16 and said optional conduits 18 or return line 20 . This initial loading of hydrogen gas will travel to the fuel cell 16 , causing a reaction within the fuel cell, and generating electricity. This electricity is then used to power the valve 26 . In the preferred embodiment of the invention, the power generator is always filled with hydrogen during operation. Furthermore, the fuel cell may be fed with hydrogen of lower or higher humidity, according to its exact attachment, so that the hydration of the fuel cell may be adjusted. The humidity of the hydrogen is higher in the water vapor generator, and lower in the hydrogen generator.
[0036] The dimensions of the water vapor generator 12 are preferably very small in scale, but may also vary with respect to the use of the power generator 10 . In preferred small scale embodiments, the water vapor generator 12 is preferably from about 0.1 cm to about 1.0 cm in height, from about 0.1 cm to about 1.0 cm in width and from about 0.1 cm to about 1.0 cm in length. As seen in FIG. 3 , optionally within the water vapor generator is a tensile membrane 32 . The tensile membrane 32 acts to exert pressure on water vapor within the water vapor generator 12 forcing the water vapor out of the water vapor generator 12 and toward the hydrogen gas generator 14 . The pressure within the water vapor generator 12 is preferably maintained at a pressure of slightly more than atmospheric pressure.
[0037] Attached to the water vapor generator 12 is a hydrogen gas generator 14 . The hydrogen gas generator 14 is preferably in the form of a chamber and is at least partially filled with a substantially non-fluid substance which reacts with water vapor to generate hydrogen gas. Alternately, the hydrogen gas generator 14 may be a volume adjacent to the water vapor generator 12 suitable for retaining the non-fluid substance. Similar to the water vapor generator 12 , the dimensions of the hydrogen gas generator 14 will vary depending on the proposed use of the power generator 10 . When the hydrogen gas generator 14 comprises a chamber in a small scale application, it is preferably from about 0.1 cm to about 1.0 cm in height, from about 0.1 cm to about 1.0 cm in width and from about 0.1 cm to about 1.0 cm in length.
[0038] The substantially non-fluid substance within the hydrogen gas generator 14 preferably comprises a material in powder, granule or pellet form and is preferably an alkali metal, calcium hydride, lithium hydride, lithium aluminum hydride, B 10 H 14 , sodium borohydride, lithium borohydride, and combinations thereof. Suitable alkali metals non-exclusively include lithium, sodium and potassium. The preferred materials for the non-fluid substance are sodium borohydride, lithium borohydride and lithium aluminum hydride. The non-fluid substance is also preferably combined with a hydrogen generation catalyst to catalyze the reaction of the water vapor and the non-fluid substance. Suitable catalysts include non-exclusively include cobalt, nickel, ruthenium, magnesium and alloys and combinations thereof.
[0039] Attached to the hydrogen gas generator 14 is a fuel cell 16 . Hydrogen powered fuel cells are well known in the art. The dimensions of the fuel cell 16 also depend on the intended use of the power generator 10 . In small scale applications, the fuel cell is preferably from about 0.1 cm to about 0.2 cm in height, from about 0.1 cm to about 1.0 cm in width and from about 0.1 cm to about 1.0 cm in length. As seen in FIG. 3 , it is preferred that the fuel cell 16 is at least partially surrounded by a thermal insulator 28 . The thermal insulator 28 may comprise anything suitable to maintain the fuel cell above the freezing temperature of water. Suitable thermal insulators non-exclusively include insulators comprising a plastic foam. In addition to the thermal insulator, a heater 34 may be placed adjacent to or attached to the fuel cell 16 to maintain the temperature of the fuel cell and power generator 10 above the freezing temperature of water. In the preferred embodiment of the invention, the power generator 10 will be maintained at a temperature of from about −20° C. to about 50° C., more preferably from about 0° C. to about 50° C. and most preferably from about 20° C. to about 50° C. while in use.
[0040] As seen in FIGS. 1 and 3 , the water vapor generator 12 is preferably connected to the hydrogen generator 14 via at least one conduit 18 containing a valve, and the hydrogen generator 14 is preferably connected to the fuel cell 16 via at least one conduit 18 . The conduits 18 may also connect to the water vapor generator so that more humid hydrogen is passed to the fuel cell. The conduits 18 may comprise anything sufficient to facilitate the transport of water vapor from the water vapor generator 12 to the hydrogen generator 14 and hydrogen gas from the hydrogen generator 14 to the fuel cell 16 . As seen in FIG. 1 , in the preferred embodiment of the invention, the power generator 10 also includes a return line 20 that directs any residual water vapor and hydrogen gas from the fuel cell 16 back to the water vapor generator 12 . The return line 20 is preferably substantially identical to conduits 18 . As shown in FIG. 2 , neither the conduits 18 nor the return line 20 are necessary elements for the efficient performance of the invention. In this embodiment, the water vapor generator 12 may be directly attached to the hydrogen gas generator 14 and the fuel cell 16 directly attached to the hydrogen gas generator 14 .
[0041] It is further preferred that at least one pump 22 is coupled with the power generator 10 to pump hydrogen gas and water vapor between the water vapor generator 12 and the hydrogen gas generator 14 . The pump 22 is preferably electrically connected to and powered by the fuel cell 16 , with the pump optionally being powered initially by power stored in device 30 . In a preferred embodiment, the pump is a mesoscopic pump, or mesopump. One preferred mesopump is described in U.S. Pat. No. 5,836,750, which is incorporated herein by reference. It is also preferred that an inert gas is initially present within the water vapor generator 12 , hydrogen gas generator 14 , fuel cell 16 and in the optional conduits 18 and optional return line 20 . The inert gas assists in transporting water vapor and hydrogen gas to the fuel cell 16 and is preferably a gas selected from the group consisting of nitrogen, argon, combinations thereof and the like.
[0042] In use, the water vapor generator 12 may generate water vapor in a variety of ways, such as by evaporation of liquid water from the water vapor generator 12 , by diffusion of water molecules into the air, by bubbling gas through the water, or by passing gas over the surface of the liquid water or the ice if present or over surfaces wetted by the water, or by pumping water so as to induce a higher vapor generation rate. Once the water vapor is generated it is directed from the water vapor generator 12 toward the hydrogen gas generator 16 either via diffusion, via pressure exerted by tensile membrane 32 , via a force generated by pump 22 , by a flow induced as water vapor is consumed in the hydrogen generator, or by flow induced as hydrogen is consumed by the fuel cell. The water vapor then passes through either the porous plugs 24 or open valve 26 , preferably into conduit 18 and then to the hydrogen gas generator 14 which is at least partially filled with the substantially non-fluid substance. Once the water vapor passes into the hydrogen gas generator 16 , the substantially non-fluid substance reacts with the water vapor, consuming water vapor to generate hydrogen gas. The hydrogen gas and any residual water vapor is then directed from the hydrogen gas generator 14 to the fuel cell 1 , preferably via another conduit 18 . Once the hydrogen gas reaches the fuel cell, the hydrogen gas is reacted with oxygen gas within the fuel cell, consuming the hydrogen gas to generate electricity. Subsequently, any residual water vapor and any residual hydrogen gas are transported from the fuel cell 16 back to the water vapor generator 12 , preferably via a return line 20 .
[0043] FIG. 4 shows preferred components for the electronic control system and the overall interconnection scheme of the electrical power generator. A closed loop drive and feed back control circuit is provided for the fluid drive control and output voltage control. An important requirement is to control the pumping rate of fuel, water or water vapor, in order to maintain an adequate flow and pressure of hydrogen in the fuel cell and to accommodate the electrical power required by the load. An active control system regulates the output voltage, and for some applications, to store electrical energy in a small device such as a lithium button cell or capacitor for applications requiring very fast bursts of high electrical power. A microcontroller-based electronic circuit uses conventional components such as a voltage multiplier, pump driving circuit, signal conditioning circuit, and low power control circuit. Appropriate sensors allow internal functions to be measured and controlled. Electrical power storage systems such as a lithium button cell or a super capacitor and a gas energy reservoir (hydrogen storage) are alternate methods of providing for short high power (burst mode) operation, and initial startup from long term storage.
[0044] Preferably, all of the above mentioned component parts of the power generator including the water vapor generator, the hydrogen gas generator, the fuel cell, the optional conduits, mesopump and mesovalve are formed within a polymeric block composed of a material such as a polyethylene, a polyimide, a polycarbonate, an acrylic, or combinations thereof. A representation of the electrical power generator and its component parts formed within a polymeric block is shown in FIG. 5 . The polymer package provides protection of the gas diffusion electrodes from stresses of the outside world and allows a way to attach the fuel cell electrically to the outside world, and further allows the fuel cell cathode to passively consume oxygen from air, and further allows the anode to be plumbed into the hydrogen generator in a planar assembly. Generators in the form of a molded card are inexpensive, light weight, impermeable and inert, and the required components can be readily incorporated and linked with fluid and electrical interconnections. A representation of the electrical power generator and its component parts, in the form of a thin molded card is shown in FIG. 6 .
[0045] The inventive electrical power generator employing a MEMS PEM fuel cell with actively-regulated hydrogen generator, fueled by water and a solid chemical, has an energy density significantly greater than a lithium battery. Such may be produced in a range of standard sizes, in a similar manner to the series of batteries AAA, AA etc. Such generators are capable of supplying the following minimum characteristics: 2.7V nominal voltage (2.5 to 3.5V), 70 uA mean output current; 30 mA, 100 msec power pulses at an average rate of 1 every 10 minutes (for data Tx/Rx), 0° C. to 65° C. operation, >10 year shelf life, 1 year operation (1.6 Watt hours) and maximum 1 gram weight. The generator will be capable of lifetimes of more than 10 years by simply adding more stored fuel. Unlike alkaline or lithium batteries, the generator is capable of complete shutdown, and hence in principle offers unlimited shelf life, and operational life only limited by the stored fuel. This is an important advantage over batteries for commercial applications. FIG. 7 shows a graph of typical voltage current measurement of an electrical power generator according to the invention. FIGS. 10A-10I show the process steps for forming a MEMS fuel cell.
[0046] The invention also provides a hydrogen gas generating apparatus that utilizes a non-electrically actuated valve to regulate the flow of water vapor from a water vapor generator to a hydrogen gas generator. This apparatus is illustrated in FIGS. 11-13 . FIG. 11 is a cross-sectional side-view of a hydrogen gas generating apparatus showing the component parts of the valve. FIG. 12 is a top-view of the hydrogen gas generating apparatus showing the preferred shape and position of the component parts of the apparatus. As shown in FIGS. 11 and 12 , the valve is positioned through a conduit 44 that connects a water vapor generator 12 and a hydrogen gas generator 14 , allowing for the regulated passage of water vapor and hydrogen gas between the water vapor generator and the hydrogen gas generator. The valve itself comprises a pneumatically actuated flexible diaphragm 36 having a periphery that is fixed to the apparatus housing 48 ; a valve disc 38 positioned opposite the diaphragm 36 and mating with the conduit 44 for alternately opening and closing the conduit 44 ; a rod connector 40 having opposite ends, the rod 40 extending through a portion of the conduit 44 and attached at one of its ends to the diaphragm 36 and attached at its opposite end to the valve disc 38 ; and a seal 42 attached around a periphery of the conduit 44 and positioned for mating with the valve disc 38 when the valve disk 38 is positioned to close the conduit 44 . In a preferred embodiment of the invention, the diaphragm 36 also comprises an outer surface of the housing.
[0047] As seen in the figures, the valve is positioned through the conduit 44 for alternately opening and closing the conduit 44 . More specifically, when the conduit 44 is open, water vapor is allowed to pass from the water vapor generator 12 to the hydrogen gas generator 14 , resulting in hydrogen gas generation. When the conduit is closed, the valve disc 38 mates with the seal 42 , preventing the flow of water vapor and hydrogen gas through the conduit 44 . In the preferred embodiment of the invention, a fuel cell 16 is joined with the hydrogen gas generating apparatus, which fuel cell 16 is capable of consuming the generated hydrogen gas to generate electricity. The fuel cell 16 may be attached directly to any component of the apparatus, e.g. to water vapor generator 12 or hydrogen generator 14 , or indirectly via a suitable channel.
[0048] FIG. 13 illustrates a cross-sectional view of an alternate embodiment of a power generator including a fuel cell 16 and having an identical non-electrically actuated valve regulating the flow of water vapor from a water vapor generator to a hydrogen gas generator. In this embodiment, a water vapor generator 12 surrounds a hydrogen gas generator 14 . As water vapor is generated by the water vapor generator 12 , it preferably diffuses into a conduit 44 through a suitable membrane 46 . Membrane 46 may comprise a tensile membrane, porous plugs or a valve such as those described for the embodiments of FIGS. 1-3 . Similar to the embodiment of FIGS. 11 and 12 , a valve is positioned through conduit 44 that connects the water vapor generator 12 and hydrogen gas generator 14 , regulating the flow of water vapor from the water vapor generator 12 to the hydrogen gas generator 14 . Further, in this embodiment, there is preferably a particulate filter present between the hydrogen gas generator 14 and the fuel cell 16 that allows hydrogen gas to pass into the fuel cell 16 , but prevents the non-fluid substance from reaching the fuel cell 16 .
[0049] The actuation of the valve is controlled by the differential pressure between atmospheric pressure, i.e. external pressure, and the internal hydrogen gas pressure of the apparatus. As the internal gas pressure of the apparatus rises above atmospheric pressure due to the generation of hydrogen gas, the diaphragm 36 will bend outward slightly. This causes the connector 40 to pull the valve disc 38 against the seal 42 , closing the valve and preventing the flow of additional water vapor to the hydrogen gas generator 14 . With the valve closed, hydrogen production ceases. This also prevents the internal gas pressure from rising further. As hydrogen is consumed, such as by a fuel cell 16 , the internal gas pressure drops, allowing the valve disc 38 to disengage the seal 42 and opening the valve. Accordingly, hydrogen gas is automatically produced at the rate at which it is consumed. Further, when a fuel cell 16 is attached to the apparatus, hydrogen gas will be available for consumption by the fuel cell at all times, as some quantity of hydrogen will consistently be present in the apparatus.
[0050] In the preferred embodiment of the invention, the internal H 2 pressure of the apparatus when in the closed position is from about 1 psi to about 10 psi, more preferably from about 1 psi to about 5 psi, and most preferably from 1 psi to about 2 psi. More particularly, the valve will be fully shut when no hydrogen gas is used by the fuel cell, and will open the amount required to meet consumption rate of the hydrogen gas. In the preferred embodiment of the invention, an internal hydrogen gas pressure of greater than 1 psi will maintain the valve in the conduit closed position. In the most preferred embodiment of the invention, the internal pressure of the power generator is maintained at about 2 psi at all times, wherein when the pressure drops below about 2 psi, the valve will open slightly until the internal pressure raises to at or above about 2 psi, causing the valve to close. As described above, the valve is controlled by the pressure of the hydrogen gas and the valve also regulates the internal pressure of the hydrogen gas.
[0051] The dimensions of the component parts are preferably very small in scale but may vary with respect to the particular application of the valve. In the preferred embodiment of the invention, the diaphragm 36 preferably comprises a thin circular plate preferably having a diameter of from about 1 cm to about 3 cm, more preferably from about 1 cm to about 2 cm. The valve disc preferably has a diameter of from about 0.2 to about 1 cm, more preferably from about 0.2 cm to about 0.5 cm. In the preferred embodiment of the invention, the rod connector 40 may comprise a screw or a bolt, but any other means of connecting the diaphragm 36 to the valve disc 38 is suitable such that the valve can alternately open and close the conduit. Each of the diaphragm 36 , valve disc 38 and seal 42 may be fabricated of a suitable polymeric material, but may also comprise a metal composite material as determined by the requirements of the intended use of the valve.
[0052] While the present invention has been particularly shown and described with reference to preferred embodiments, it will be readily appreciated by those of ordinary skill in the art that various changes and modifications may be made without departing from the spirit and scope of the invention. It is intended that the claims be interpreted to cover the disclosed embodiment, those alternatives which have been discussed above and all equivalents thereto. | An improved system for generating electrical power using a fuel cell. More particularly, a system for generating hydrogen gas by reacting water vapor with a substantially non-fluid substance and transporting the generated hydrogen gas to the fuel cell which generates electrical power. Reacting water vapor with the non-fluid hydrogen generating substance rather than liquid water prevents caking of the non-fluid substance and deposition of byproducts onto the non-fluid substance that interfere with continued generation of hydrogen gas. Also, a non-electrically actuated valve for use in a hydrogen gas generating apparatus which regulates the generation of hydrogen as required by the fuel cell. | 2 |
FIELD OF THE INVENTION
[0001] The present invention relates to a bearing grease composition for hard disc drive or the like. More particularly, the invention relates to a bearing grease composition for spindle motors which are used under clean environment, as in memories such as hard disc drive (HDD) or floppy disc drive (FDD) in computers.
BACKGROUND OF THE INVENTION
[0002] In general, performances required for a bearing grease composition used in memories, for examples, HDD or FDD in computers are that dust generation (scatter) is low, torque is small, acoustic performance is excellent and life is long. In particular, in HDD used under a clean atmosphere, fine particles of gaseous oil or grease scattered from the inside of a bearing during revolution contaminates the surface of a disc, resulting in cause of wrong operation. Therefore, it is considered to be most important to suppress the amount of scatter.
[0003] A sodium complex soap-based grease comprising a mineral oil as a base oil or a lithium soap-based grease comprising as a base oil, a synthetic ester (diester oil or polyol ester oil) which is a reaction product of an organic acid and an alcohol has conventionally been used as HDD bearing grease.
[0004] The sodium complex soap-based grease comprising a mineral oil as a base oil has been used for a long time with appreciation that the amount of scatter is small. However, the grease had the problems that dispersion of a thickening agent in the grease is poor, and it is difficult to form a homogeneous mixture, so that acoustic and vibrating performances during evolution of the bearing is not good; moisture absorption is high, and the grease cures with the passage of time, so that flowability of the grease in the bearing becomes poor, causing defective lubrication.
[0005] Further, the lithium soap-based grease comprising as a base oil, a synthetic ester (diester or polyol ester oil) which is a reaction product of an organic acid and an alcohol had no problem due to that dispersibility of the lithium soap is good, and low torque property was good.
[0006] However, the lithium soap-based grease tends to scatter,and if the grease is used as it is, there is the great possibility to damage a hard disc. Therefore, in order to prevent the damage, the grease is used in combination with an expensive magnetic fluid seal which is used in a motor. This rather results in increase of cost of a motor and prevents the motor from being miniaturized. Further, for example, due to the demand of high speed revolution and high precision of the motor, this grease does not sufficiently withstand acoustic performance and torque, disorder has sometimes occurred in acoustic performance or torque.
SUMMARY OF THE INVENTION
[0007] As a result of extensive investigations to overcome the above-described problems in the prior art, it has been found that properties required for a bearing grease composition which is used under a clean environment as in, for example, memories such as HDD or FDD are satisfied by using a metallic soap-based grease comprising as a base oil a carbonate containing an organic carbonate represented by the formula (I) described hereinafter. The present invention has been completed based on this finding.
[0008] Accordingly, an object of the present invention is to provide a grease composition which can maintain stable low torque property, low noise property and low scatter property even at high speed revolution.
[0009] According to the present invention, there is provided a bearing grease composition comprising:
[0010] (a) a carbonate compound represented by the following formula (I)
[0011] wherein R and R′, which may be the same or different, each represent a branched alkyl group having 13 to 15 carbon atoms; and
[0012] (b) a group consisting of an alkali metal salt and/or an alkaline earth metal salt, which are synthesized from a hydroxide of an alkali metal or an alkaline earth metal and a higher hydroxyfatty acid having 10 or more carbon atoms or a higher hydroxyfatty acid having at least one hydroxyl group and having 10 or more carbon atoms.
[0013] The branched alkyl group R and R′ in the carbonate compound represented by the formula (I) is represented by the following formula (II):
[0014] wherein n is a number of 13 to 15 and m is a number of 0 to 6.
[0015] The representative examples of the branched alkyl group are groups represented by the following formulae (III), (IV) and (V):
[0016] The bearing grease composition of the present invention preferably comprises 70 to 95 parts by weight of component (a) of the carbonate compound, and 5 to 30 parts by weight of component (b) of the alkali metal salt and/or alkaline earth metal salt.
[0017] If the amount of component (b) of the alkali metal salt and/or alkaline earth metal salt is less than 5 parts by weight, a worked penetration becomes soft, and as a result, the grease composition leaks or scatters during revolution of a bearing, resulting in possibility of contaminating HDD, FDD and the like.
[0018] On the other hand, if the above amount of component (b) exceeds 30 parts by weight, the grease composition becomes too hard, and flowability of grease in the bearing becomes poor. As a result, there is the possibility of causing defective lubrication.
[0019] The bearing grease composition according to the present invention can contain, in addition to the components (a) and (b) described above, lubricants other than the component (a), and various additives, as a third component.
[0020] Examples of the lubricants used in the present invention include mineral oils, synthesized hydrocarbon oils, ether oils and ester oils, which are generally used as a base oil of grease compositions.
[0021] The additives used in the present invention are additives generally used in grease composition, and the examples thereof include antioxidants and rust inhibitors.
[0022] The grease composition of the present invention may further contain one or more of thickening agents.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] The present invention described in detail below.
[0024] (1) According to the preferred embodiments of the present invention, a bearing grease composition preferably comprises:
[0025] (a) a carbonate compound represented by the following formula (I)
[0026] wherein R and R′ which may be the same or different each represent a branched alkyl group having 13 to 15 carbon atoms; and
[0027] (b) a group consisting of an alkali metal salt and/or an alkaline earth metal salt, synthesized from a hydroxide of an alkali metal or an alkaline earth metal and a higher hydroxyfatty acid having 10 or more carbon atoms or a higher hydroxyfatty acid having at least one hydroxyl group and having 10 or more carbon atoms.
[0028] (2) Preferably, the bearing grease composition comprises:
[0029] (a) a carbonate compound represented by the following formula (I)
[0030] wherein R and R′, which may be the same or different, each represent a branched alkyl group having 13 to 15 carbon atoms, wherein the branched alkyl group R and R′ in the carbonate compound represented by the formula (I) is represented by the following formula (II):
[0031] wherein n is a number of 13 to 15 and m is a number of 0 to 6; and
[0032] (b) a group consisting of an alkali metal salt and/or an alkaline earth metal salt, synthesized from a hydroxide of an alkali metal or an alkaline earth metal and a higher hydroxyfatty acid having 10 or more carbon atoms or a higher hydroxyfatty acid having at least one hydroxyl group and having 10 or more carbon atoms.
[0033] (3) The bearing grease composition comprises 70 to 95 parts by weight of the carbonate compound represented by formulas (I) and (II) and 5 to 30 parts by weight of the member selected from the group consisting of an alkali metal salt and/or an alkaline earth metal salt, synthesized from a hydroxide of an alkali metal or an alkaline earth metal and a higher hydroxyfatty acid having 10 or more carbon atoms or a higher hydroxyfatty acid having at least one hydroxyl group and having 10 or more carbon atoms.
[0034] (4) The bearing grease composition for hard disc drive includes preferably a plurality of carbonate compounds.
[0035] (5) The bearing grease composition for hard disc drive in which the carbonate compound preferably has a dynamic viscosity of 10 to 50 mm 2 /sec at 40° C.
[0036] (6) Preferably, the bearing grease composition further comprises one or more thickening agents.
[0037] (7) The bearing grease composition as in any of the above-described aspects (1) to (6) comprising further lubricants and/or additives.
[0038] The carbonate compound can be used alone or as mixtures thereof.
[0039] The present invention will now be described in more detail below by referring to the following examples, but the invention should not be limited thereto.
EXAMPLES 1 TO 6
[0040] Those examples are the preparation example of the typical bearing grease composition consisting of component (a) and component (b).
[0041] A carbonate represented by the following formula (VI):
[0042] that is, in the formula (I), R is the branched alkyl group represented by the following formula (IV):
[0043] and R′ is the branched alkyl group represented by the following formula (V):
[0044] (this carbonate is hereinafter referred to as“carbonate oil A”) alone, or a mixed oil of a carbonate containing commercially available organic carbonate having different structure of an alkyl group (CYCRANT T-394, trade name, a product of Mitsui Petrochemical Industries, Ltd.) (this ester is hereinafter referred to as“carbonate ester oil B”) and the carbonate ester oil A was mixed with lithium stearate and/or lithium 12 hydroxystearate in the proportions as shown in Table 1 such that the sum of those was 100 mass %. The resulting mixture was heated to 220-230° C. while stirring until the whole of mixture became liquid. The liquid thus obtained was poured into a stainless steel vessel at a depth of 3-5 mm. The liquid was cooled at 50° C. or less and then homogenized with three rollers to obtain a grease composition.
EXAMPLES 7 AND 8
[0045] Grease compositions were obtained in the same manner as in Examples 1 to 6 above except that an alkyl diphenyl ether or a polyol ester was further used as a third component other than components (a) and (b) in the proportion as shown in Table 1.
COMPARATIVE EXAMPLES 1 AND 2
[0046] Two kinds of commercially available greases in which a base oil and a thickening agent are known were used for the sake of comparison. In Table 2, reference sign+means that such a compound is contained.
COMPARATIVE EXAMPLE 3 AND 4
[0047] Grease compositions were obtained in the same manner as in Examples 1-6 except that a base oil and a lithium soap were used in the proportions as shown in Table 2.
[0048] The grease compositions obtained in the above Examples and Comparative Examples were measured for a worked penetration and a dropping point, and were subjected to motor characteristic test, under the same conditions. The results obtained are shown in Tables 1 and 2.
[0049] The worked penetration was measured according to JIS K2220, 5.3, and the dropping point was measured according to JIS K2220, 5.4.
[0050] The motor characteristic test was conducted such that a bearing having included therein a grease composition to be tested was incorporated in a spindle motor, the motor was rotated at 10,000 rpm at a normal temperature, and noise generated, amount of evaporation (scatter) and rotating torque were measured.
[0051] Noise was measured with a microphone at a place which is 30 cm apart from a hub edge of the motor during rotation of motor.
[0052] The amount of evaporation (scatter) was determined by the difference between weight of motor before rotation and weight of motor after rotation.
[0053] The torque was determined by measuring electric current value at the rotation of motor with an ammeter, and the torque stability was determined by the difference between the maximum electric current value and the minimum electric current value.
[0054] The judgement results according to performances required for a bearing grease composition for HDD or the like on each evaluation item are shown in Table 1 (Examples) and Table 2 (Comparative Examples).
[0055] The smaller the value, the better the low noise property; the smaller the amount of evaporation (scatter), the better the low scatter property; the lower the value, the better the low torque property; and the smaller the fluctuation, the better the torque stability.
[0056] The tests were evaluated with the following four grades.
TABLE 1 Example 1 2 3 4 5 6 7 8 Thickening agent StLi 25 25 10 15 20 20 120H St-Li 15 10 5 Base oil Carbonate A 75 85 38 90 90 80 70 70 Carbonate B 37 ADE 10 POE 10 Viscosity of 18 18 50 18 18 18 25 21 base oil (40° C.) Worked 198 203 196 305 247 181 210 205 Penetration (25° C.) Dropping point (° C.) 197 194 198 193 193 195 197 195 Motor characteristic Test Low noise property A A B B B A B B Low scatter property A B A B B B A A Low torque property A A B A A A B B Torque stability A A B B B A A A Total evaluation A A B B B A B B
[0057] [0057] TABLE 1 Example 1 2 3 4 5 6 7 8 Thickening agent StLi 25 25 10 15 20 20 12OH St-Li 15 10 5 Base oil Carbonate A 75 85 38 90 90 80 70 70 Carbonate B 37 ADE 10 POE 10 Viscosity of 18 18 50 18 18 18 25 21 base oil (40° C.) Worked 198 203 196 305 247 181 210 205 Penetration (25° C.) Dropping point 197 194 198 193 193 195 197 195 (° C.) Motor characteristic Test Low noise A A B B B A B B property Low scatter A B A B B B A A property Low torque A A B A A A B B property Torque stability A A B B B A A A Total A A B B B A B B evaluation
[0058] [0058] TABLE 2 COMPARATIVE EXAMPLE 1 2 3 4 Thickening agent StLi + 25 25 12OH St-Li + Na-Complex + Base oil Carbonate ester A Carbonate ester B 75 Diester oil + 38 POE + 37 Mineral oil + Viscosity of base oil (40° C.) 26 145 18 130 Worked penetration 250 205 197 181 Dropping point (° C.) 194 >260 197 199 Motor characteristic test Low noise property C D D B Low scatter property B A D A Torque C B B D Torque stability D C D C Total evaluation C C D C
[0059] As shown in Table 1 above, the bearing grease composition of the present invention shows low evaporation (scatter), low noise, low torque property and stable torque. | A bearing grease composition used under clean atmosphere, as in a bearing of hard disc drive, which has small dust generation (scatter), a long life, excellent acoustic performance and low torque.
It has been found that especially the bearing grease composition comprising a carbonate having a branched alkyl group of 13 to 15 carbon atoms and a metallic soap shows remarkable characteristics. | 2 |
TECHNICAL FIELD
The present invention refers in general to electric devices for evaporating volatile substances, such as fragrances and/or insecticides.
In more specific terms, the present invention provides an electric evaporation device with adjustable evaporation intensity, in which the undesired condensation of vapor inside the device is prevented.
BRIEF SUMMARY OF RELATED ART
There are many known devices for evaporating volatile substances typically air-fresheners, which include a wick and means for regulating the degree of evaporation of the volatile substance.
An air-freshener of this type is described in the European Patent EP-1031446, in which a movable cap element is used to regulate the degree of evaporation by covering the wick. That cap is a top closed casing which is displaceable above the upper end of the wick, for that part of the vaporized substance reaches and condensates on the inner surface of the cap.
This undesired condensation of product inside the device, contributes to the deterioration of the same and it is unpleasant for the user.
The international publication WO 01/21226 discloses an air-freshener in which the vapor emission rate is controlled by displacing a tubular body above the upper end of the wick, for guiding to some extend the flow of vapor from the wick to the exterior of the device. Since the tubular body is movable above the wick, it is necessary to provide a large volume between
the upper part of the wick and the aperture for the exit of vapor to the exterior. This conventional structure implies that the vapor has to flow through a long path until it exist the device, which causes undesired condensation of vapor on the internal surface of the tubular body and other internal surfaces of the device.
Other example of air-freshener incorporating evaporation regulating means, is disclosed in the European Patent EP-1064957. In this case regulation is based on the variation of the chimney effect caused by the ascension of vapor. Since the chimney effect is always produced above the source of heat adjacent to the end of the wick, the regulation means have to be arranged above the wick, which again result in the condensation problems due to the long path that the vapor has to follow. This regulation technique is based on the modification of the geometry of the chimney, which results in apertures appearing in the chimney channel during the regulation through which the vapor escapes, causing the condensation of the vapor on the internal surfaces of the device.
Therefore, it has been detected the need for evaporators which are not affected by the problems associated with the vapor condensation on the interior surfaces of the evaporator.
On the other hand, it is known in the state of the art to provide a protective sleeve element covering the part of the wick extending outside the container of volatile substance. That sleeve element is used to avoid bending of the wick and maintain the correct position of the wick during its use. The U.S. Pat. No. 5,909,845 shows an example of a protected wick of this kind.
BRIEF SUMMARY
An aspect of the invention refers to an electric device for the evaporation of volatile substances, which comprises a container of volatile substances provided with a wick having an upper part protruding from said container, and a lower part inside said container in contact with the volatile substance. The wick is soaked with the volatile substance in liquid state, which raises by capillary action through the wick towards the upper end of the wick.
The device further comprises heating means suitably arranged for heating said upper part of the wick, in order to enhance therefore the evaporation of the liquid immersed in the wick and its diffusion to the surrounding environment.
A shield member is provided in the device for regulating the degree of evaporation of the volatile substance, by interfering or blocking to some extend the heat transfer from the heating means to the wick.
This shield member is displaceable along a direction substantially parallel to the longitudinal axis of the wick, and instead of moving above the wick as it is the case of the devices of the prior art, the shield member is displaceable downwardly below the upper end of the wick, for that it is not necessary to provide a large room above the wick for receiving the regulating means.
The shield member is displaceable between a minimum evaporation position and a maximum evaporation position. In the minimum evaporation position the shield member, or a major part of it, is interposed between said heating means and said upper part of the wick, in such a manner that the heat transfer to the upper part of the wick is effectively reduced and the temperature at the upper part of the wick is minimal.
In the maximum evaporation position, a part of the shield member is located below said heating means, in such a manner that a major part of the heating means is directly facing the side surface of the wick without any barrier being interposed in between, for that the temperature at the upper part of the wick is maximum.
Due to this innovative arrangement of the shield member, the upper end of the wick can be located very close to the aperture for the exit of the vapor to the exterior of the device, which has the effect that most of the vapor can exist outside the device, since the path that vapor has to follow to the exit is very short for that the condensation problems inside the device are reduced significantly.
BRIEF DESCRIPTION OF THE DRAWINGS
To supplement the description that is being made and with the object of assisting in a better understanding of the characteristics of the invention, in accordance with a preferred example of practical embodiment thereof, attached as an integral part of said description, is a set of drawings wherein by way of illustration and not restrictively, the following has been represented:
FIG. 1 —shows a front elevational view of the device with a part of the casing removed for illustration purposes.
FIG. 2 .—shows a similar representation than FIG. 1 in which the wick is provided with a protective sleeve. The figure shows the device in the minimum evaporation position, during a normal use of the device when it is plugged in an electric outlet of a wall.
FIG. 3 ,—is a representation similar to FIG. 2 , in which the device is in the maximum evaporation position.
FIG. 4 .—is a representation similar to FIG. 2 , in which the device is in an intermediate evaporation position.
FIG. 5 .—shows a sectional side view of the device, in which the regulation means are in the minimum evaporation position.
DETAILED DESCRIPTION
In the preferred embodiment of the invention shown in FIG. 1 , the electric device comprises a casing ( 1 ) and a container ( 2 ) of volatile substances which is detachably engaged with said casing ( 1 ). The container ( 2 ) in the form of a bottle, is provided with a wick ( 3 ) having an upper part
( 11 ) extending outside said container ( 2 ), and a lower part (not shown) inside the container in contact with a volatile substance.
The wick has the form of a cylindrical rod and during the normal use of the device when it is connected to an electric outlet of a wall, it is vertically arranged so that the part ( 11 ) of the wick protruding from the container is at an upper position, and the part of the wick inside the container is at a lower position.
The device includes heating means, for example a heating resistor ( 5 ) such as a cemented metal oxide resistor, or any other known type of electric heater suitable for this use.
Preferably, a single heating resistor ( 5 ) is provided fixed to the interior surface of the casing ( 1 ), adjacent to the upper end ( 19 ) of the wick ( 3 ) for heating the same. Alternatively, the device comprises more than one heating resistor ( 5 ) for heating the upper end of the wick.
The casing ( 1 ) incorporates an electric plug base ( 19 ) for supplying electric power to the resistor ( 5 ) and for supporting the device in a wall outlet in the position shown in FIG. 5 .
This resistor ( 5 ) has the shape of a rectangular prismatic body having a planar upper surface ( 14 ) located at a lower level than the top base ( 13 ) of the wick ( 3 ) during the normal use of the device. Said planar upper surface ( 14 ) is substantially orthogonal to the axis of the wick, when the container is coupled with the casing.
A large side surface ( 15 ) of the resistor ( 5 ) is facing the side surface ( 16 ) of the wick ( 3 ) and it is substantially parallel to the axis of the wick ( 3 ).
Alternatively, the heating resistor ( 5 ) is shaped as toroid and it is arranged around the wick.
The device further comprises a shield member ( 4 ) which is interposed between the heating means and the wick to act as a barrier for the transfer of heat from the heating means to the wick. This shield member is displaceable
so as to block the heat transfer in a lesser or greater extend for regulating the degree of evaporation of the volatile substance.
In the preferred embodiment of FIGS. 2 to 4 , a sleeve ( 6 ) is tightly covering the part of the wick protruding from the container except for the upper end ( 19 ) of the same which is open to the air. This upper end ( 19 ) of the wick open to the air, extends from the top ( 20 ) of the sleeve ( 6 ) and the upper base ( 13 ) of the wick.
This sleeve ( 6 ) serves to protect and retain the wick in a desired straight position and contributes to thermally isolate the wick from the heat generated by an electric heater, except for said upper end ( 19 ) of the wick.
The inner diameter of the shield member ( 4 ) is slightly larger than the outer diameter of the sleeve ( 6 ) as it can be appreciated for example in FIG. 5 .
In the embodiment of FIG. 1 in which the wick is not provided with that sleeve ( 6 ), the shield member ( 4 ) itself around the wick also serves to some extend to avoid undesired bending of the wick.
In the minimum evaporation position shown in FIGS. 2 and 5 , a major part of the shield member ( 4 ) is interposed between said resistor ( 5 ) and said upper end ( 19 ) of the wick, so that the temperature at the upper part of the wick is minimum and the degree of evaporation of the volatile substance in this configuration of the device is also minimum. In this minimum evaporation position, a major part of the shield member is positioned at the same level, that is at the same high, than the resistor ( 5 ) in an operational position of the device.
In the maximum evaporation position shown in FIG. 3 , a major part of the shield member ( 4 ) is located below said resistor ( 5 ), so that a major part of the shield member is not interposed between the resistor and the wick, thus the temperature at the upper part of the wick is maximum.
In this preferred embodiment of the invention, the shield member ( 4 ) is configured as a tubular body, preferably a tubular cylinder, having open upper and lower bases ( 17 , 18 ), and it is arranged in such a manner that the wick ( 4 ) is located inside said tubular cylinder. The shield member is supported by said casing, so that it can move vertically in a guided manner and coaxially with respect to the wick.
As shown in FIG. 2 , in the minimum evaporation position, the upper base ( 17 ) of the shield, is located at a lower level than the upper base ( 13 ) of the wick, and slightly above the upper surface ( 14 ) of the resistor.
In turn, a part of the resistor ( 5 ) is located above or at a higher level than the top edge ( 20 ) of the sleeve ( 6 ), so that a part of the resistor is facing directly the upper end ( 19 ) of the wick, or in other words a part of the resistor is at the same level than the upper end ( 19 ) of the wick.
The height of the tubular sleeve ( 4 ) is similar or slightly larger than the height of the resistor ( 5 ).
Alternatively, the shield member ( 4 ) may comprise a planar wail or a C-shaped wall, also arranged between the resistor and the wick, and being vertically displaceable in a direction parallel to the axis of the wick.
The device includes a mechanism for moving the shield member up and down for regulating the degree of evaporation. In this preferred embodiment, this mechanism comprises a gear wheel ( 9 ) rotatably mounted about a shaft ( 8 ) fixed to the casing ( 1 ), and a toothed rack ( 7 ) provided on a side surface of the shield member, wherein the gear wheel and the toothed rack are meshed so that rotation of the gear wheel causes the vertical displacement of the shield member ( 4 ) to cover or uncover the wick progressively.
The gear wheel ( 9 ) is accessible from the outside of the casing by means of a knob ( 12 ), so that the user can move the shield member up and down by actuating in that knob, and set shield member at any desired intermediate fixed position between the maximum and minimum end positions.
An opening ( 10 ) is provided at the upper part of the casing ( 1 ) for the passage and diffusion of the evaporated substance to the exterior of the device, for that this opening ( 10 ) is located over the upper end ( 13 ) of the wick.
Since the shield member ( 4 ) is displaceable from the level of the resistor towards the bottom of the device, there is no need to have a large space between the upper end of the wick and the opening ( 10 ). As it can be appreciated in the attached figures, the upper end of the wick ( 13 ) can be arranged very close to the opening ( 10 ) compared with the air-fresheners of the state of the art, so that the risk of having part of the vapor dispersed and condensate inside the casing is significantly reduced.
Further preferred embodiments of the invention are described in the dependent claims. | The present invention refers to an electric evaporation device with adjustable evaporation intensity, wherein a shield member ( 4 ) is displaceable between a minimum evaporation position in which it is interposed between a heating resistor ( 5 ) and an upper part of a wick ( 3 ), and a maximum evaporation position in which part of the shield member is located below said resistor ( 5 ). Since the shield member ( 4 ) is moved downwardly below the resistor ( 5 ), the upper end ( 13 ) of the wick ( 3 ) be located very close to an aperture ( 10 ) for the exit of the vaporized substance. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates to car-top carriers for boats such as canoes and car-top rowboats, and more particularly refers to a lightweight carrier which may be mounted onto the gunnels of a boat or canoe and which supports and retains the boat or canoe by means of tie lines on the car top during travel.
Prior Art
Many sportsmen such as fishermen and hunters utilize boats in the pursuit of their sport. Since lightweight boats or canoes often are satisfactory for use in engaging in such sports, the boats are mounted on top of the cars utilized for transportation, since it is simpler and less expensive to transport a small boat on a car top than to pull the boat on a trailer. Car-top carriers for boats have been disclosed in the art. However, such carriers are quite expensive to fabricate and in some cases difficult to mount.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a car-top carrier for a boat such as a car-top rowboat or canoe.
It is a further object to provide a car-top carrier which is light and easily mountable.
It is still further an object to provide a car-top carrier which is inexpensive to produce and which provides reliable service over extended periods of time.
It is still an additional object to provide a car-top carrier which does not mar the finish of the car roof.
It is another object to provide a car-top carrier which snaps onto the gunnels of the boat before mounting, and remains in place as the boat is lifted and placed on the car top.
Still other objects will suggest themselves to one skilled in the art upon reference to the following specification, drawings, and claims.
According to the invention, a car-top boat carrier is provided comprising a pair of boat carrier members, each having a longitudinal groove, preferably arcuate, to permit the members to be snapped onto the gunnels of a boat such as a rowboat or canoe. Lines are provided to tie each end of the boat to the car bumpers. The carrier members are preferably formed from a plastic foamed material such as foamed polystyrene. The carrier members are readily molded, are lightweight, provide suitable support for the boat, and are sufficiently non-abrasive so that they do not mar the finish of the car top and yet provide sufficient friction to maintain the boat in position.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings,
FIG. 1 is a top view of a boat carrier member showing an arcuate channel particularly designed for carrying canoes.
FIG. 2 is a side elevational view of the boat carrier shown in FIG. 1.
FIG. 3 is an end view of the support member taken at the lines III--III of FIG. 1, looking in the direction of the arrows.
FIG. 4 is a top view of a canoe having a pair of support members mounted on the gunnels thereof.
FIG. 5 is a rear end view showing the canoe of FIG. 4 mounted on top of a car.
FIG. 6 is a front end view of the canoe and car shown in FIG. 5.
FIG. 7 is a top view showing a car-top carrier member particularly designed for supporting rowboats.
FIG. 8 is a side elevational view of the carrier member shown in FIG. 7.
FIG. 9 is a end view taken at the line IX--IX of FIG. 7, looking in the direction of the arrows.
FIG. 10 is a top view of a rowboat having a pair of boat carrier members mounted on the gunnels thereof.
FIG. 11 is a rear end view of a car having a rowboat mounted thereon by the carrier members of the invention, and
FIG. 12 is a front end view of the car and rowboat of FIG. 11.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIGS. 1-3, a boat carrier member 10 is shown comprising an elongate body 11 of generally rectangular form. The carrier member 10 is preferably formed of a molded plastic foam material such as polystyrene foam. Alternatively, foams of such material as phenolformaldehyde, polyvinyl chloride, polystyrene, polyurethane, etc., may be utilized. A substantially rigid foam is preferred, although elastomeric foams may be utilized for lighter weight boats. The plastic foam body 11 is provided with an arcuate vertically oriented channel or groove 12 adapted to receive the gunnel of a boat or canoe. The carrier member shown in FIGS. 1-3 is particularly adapted to be utilized for supporting canoes. The curvature of the arcuate channel is so designed that it receives the boat gunnel, but is of such thickness and such curvature that in order to receive the boat gunnel within the channel, the carrier member must undergo a small amount of distortion. As a result of this arrangement, the gunnel snaps into the channel and the carrier member remains engaged over the gunnel even when the boat or canoe is inverted. A plurality of transverse channels 13, 14, and 15 are provided communicating with the arcuate channel 12 and with a side wall 11a of the body 11. The transverse grooves are provided to receive the thwart 19 of a canoe (FIG. 4). Although a single transverse groove, as for example channel 14 is sufficient for most purposes, additional channels 13 and 15 may be provided to render the carrier member 10 more versatile, and to permit the boat or canoe to be placed in different positions, dependent upon its length.
Referring to FIG. 4 a canoe 16 is shown having gunnels 17 and 18, a thwart 19 and seats 20 and 21. Rings or eyes 22 are provided for towing the canoe and for affixing tie-down lines. In FIG. 4 the carrier members 10 have been mounted one on each gunnel of the canoe, with the gunnels being sufficiently grasped by the sides of the arcuate channel 12 so that the carrier members remain affixed to the gunnels even when the canoe is inverted.
Referring to FIGS. 5 and 6, the canoe 16 is shown mounted on a car 23, supported by carrier members 10 engaging the gunnels 17 and 18 of the canoe. As shown in the drawings, the canoe is fastened to the bumper of the automobile in the rear by means of lines 24 and 25 engaged by the ring 22 at one end, and by lines 26 and 27 in the front attached to the ring 22 at the other end and to the front bumper.
In preparing the canoe for mounting on a car top, the two carrier members are snapped on, one on each gunnel, with the middle slot 14 used to receive the thwart. The forward slot 15 or rear slot 13 may be used to change the position of the carrier members and canoe on the vehicle, dependent on the size of the canoe. The canoe is then turned upside down and set down upon the roof or top of the vehicle. The four pieces of line, as for example 3/8 inch nylon rope 24, 25, 26, and 27, are utilized as tie-downs. The front tie-down system shown in FIG. 6 consists of two lengths of line which may be provided with S-hooks 28 on each end of each line. Two S-hooks with attached ropes are hooked to the eye or ring 22 of the canoe. This attachment should be made both at one point. The other end of each rope is hooked by means of S-hooks, or otherwise tied, under the front bumper at the lower right and lower left side. When affixed, each line arrangement resembles an inverted-V and provides both forward and side movement stability. The canoe is then pushed to the rear of the vehicle until one end of each support member is raised approximately two inches. The rear tie-down assembly is then applied comprising the two nylon rope lines 24 and 25, two 9-inch rubber tension straps 29 and 29a, and six S-hooks 28. The nylon lines are cut nine inches shorter and the 9-inch rubber tension straps 29 and 29a connected to the ends thereof by S-hooks and attached at the other end to the bumper by S-hooks 28. When attached, the tension strap should be in a slightly stretched condition. This permits both front and rear tie-downs to be tight while the tension straps allow for the shock of travel.
Referring to FIGS. 7-9, a boat carrier member 30 is shown particularly adapted for carrying rowboats. The carrier member 30 is formed of a plastic foam block body 31 similar to that shown in FIGS. 1-3. The carrier member 30 is provided with a longitudinal channel 32 designed to receive the gunnel of a rowboat and to snap on thereto and to remain affixed to the gunnel. As seen in FIG. 7, one side of the arcuate channel 32 has a smaller curvature than that at the other side. This is designed to accommodate the decreased curvature of a rowboat. If desired, both sides may have a decreased curvature. The carrier member shown in FIG. 7-9 may be molded in the same mold as that shown in FIGS. 1-3. However, in order to provide the change in contour of one side the arcuate groove 32, modified inserts may be provided in the mold. The carrier member 30 is additionally provided with transverse channels 34, 35, and 36 connecting the arcuate channel 32 with the inner face 31a of the carrier member. The transverse channels are provided to clear the oarlocks 51 and 52 and other structures which may be present in the gunnels of the rowboat. If desired, only a single transverse channel may be utilized, although the presence of more than one provides greater versatility in the positioning of the rowboat and carrier members on the car top and accommodates boats of various sizes.
Referring to FIG. 10, a rowboat 37 is shown having a bow 38 having an eye or ring 39, a stern 40, and gunnels 52 and 53. Oarlocks 50 and 51 are mounted on the gunnels 52 and 53, respectively. The boat is additionally provided with seats 54, 55, and 56 and a bottom 57. Handles or hooks 41 and 42 are mounted on the stern 40.
In mounting, the boat is inverted and placed on the top of the car 43 as shown in FIGS. 11 and 12. The front end of the rowboat is tied down in the manner similar to that discussed in regard to the canoe, by means of two nylon rope lines 46 and 47 with S-hooks provided on each end of each line. The S-hooks at one end are engaged to a ring or eye 39. The other ends of the line are hooked by means of S-hooks to the bumper. The square end of the boat is tied down as follows. One tie-down line 44 is hooked by means of an S-hook to a handle or hook 42 at the left corner of the boat. The other tie-down line 45 is hooked by means of an S-hook to a handle or hook 41 at the right side of the boat. Nine-inch elastic tension straps 48 and 49 are connected to the lines 44 and 45, respectively, by means of S-hooks. S-hooks provided at the other end of the tension straps 48 and 49 are hooked to the bumper. When completely tied, the tie-lines are in the form of an "X", eliminating side motion during travel. If the bow of the boat is also square, crossed tie-lines may be utilized in the same manner, but it is not necessary to utilize tension straps at the front end.
The boat support members of the present invention and the tie-line assembly for anchoring the boat to the car have a number of advantages over prior art structures. First, the support members may be very easily and inexpensively molded from lightweight inexpensive plastic foam materials. Second, the support members are resilient to absorb shocks. There is sufficient friction at the bottom of the support members to prevent sliding of the boat during travel, and yet the material is sufficiently soft so that the car top paint is not scratched. The structure may be readily varied by means of inserts provided in the mold to change from canoe-accommodating support members to rowboat-accommodating support members. Transverse channels are provided to clear structures on the boat or canoe such as oarlocks or thwarts. The inverted V or X-type of tie-line arrangement together with hooks and elastic tension straps secure the boat firmly in place and yet provide for a small amount of movement due to vibration and jostling to be absorbed. The support members together with the tie-lines may be readily stored in small spaces.
It is to be understood that the invention is not to be limited to the exact structures or procedures shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art. | A car-top boat and canoe carrier comprising a pair of carrier members each comprising an elongate block of a foamed plastic material having a longitudinal groove provided therein for receiving in snap-on engagement the gunnels of a boat such as a canoe or car-top rowboat. Additionally, lateral or transverse slots are provided for receiving the thwart of a canoe or the oarlocks of a rowboat. After the carrier members have been snapped onto the boat, the boat is inverted, placed on the roof of a car, and the ends of the canoe or boat fastened to the bumpers with tie lines. | 1 |
BACKGROUND OF THE INVENTION
1. Technical Field
This invention relates to improvements in a method and apparatus for the distribution of seasonings, e.g., seasonings as placed on potato chips, corn chips, and like snack foods and more particularly, to a method and apparatus that permits layering of different seasoning materials during the manufacture of snack food items.
2. Description of Related Art
Food particulates are often added to foods, especially snack foods. Tortilla chips, pretzels, crackers, popcorn, and numerous other foodstuffs often have seasonings applied to them during processing. Seasonings used, usually in a powdered form, have included salt, cheese, chili, garlic, Cajun spice, ranch, sour cream and onion, among many others.
FIG. 1 is a schematic sectional elevation view of a prior art seasoning distribution system. FIG. 2 is a schematic sectional view taken along line 2 - 2 of FIG. 1 . Referring to FIGS. 1 and 2 , the apparatus 10 generally comprises a cylindrical drum 14 and a non-rotating horizontal seasoning dispenser. Unseasoned snack food 12 enters a cylindrical drum 14 at one end through a funnel 16 . Drum 14 is tilted slightly at an angle of about 5 degrees and is axially rotated in the direction indicated by arrow 18 . The speed of rotation is generally between 4 and 15 RPM. The combination of tilt and rotation causes the snack food to travel continuously down the drum to exit 20 . Baffles 21 may be positioned radially on the drum perimeter to aid in mixing the snack food. A horizontal, non-rotating seasoning dispenser 22 has a tube portion 24 extending into the drum. Within the tube 24 is an auger 26 in close tolerance with the tube inner wall. The auger is rotated by a power source 28 such as an electric motor. This tumbling drum arrangement and the application in general of seasoning falling from a tube to snack food therein is well known and conventional in the art. Seasoning 30 , such as barbeque, sour cream, etc., is fed to the dispenser via a hopper 32 and is conveyed along the tube 24 by the auger 26 . A series of apertures in the bottom of the far end of the tube 24 , opposite the hopper 32 , allows the seasoning to drop by gravity onto the snack food. As indicated by arrows, the seasoning is distributed in the form of a dispersion “curtain”.
The seasoning dispenser 22 may be positioned offset from the cross-sectional center of the drum, as shown in FIG. 2 , in order to distribute the seasoning over the location of maximum concentration of snack food. Because of the drum rotation, the snack food tends to migrate up the drum wall, and thus the maximum concentration is located at a point other than the lowest portion of the drum. The optimum position for the dispenser is, of course, dictated by the degree of migration of the snack food, which in turn is dependent on the speed of rotation and tilt angle of the drum, and the size and number of baffles along the drum perimeter. Those skilled in the art can readily ascertain the proper location for the dispenser based upon a given set of the above process parameters.
Achieving the optimum compromise between uniform seasoning coverage of the snack product along with minimum product breakage requires careful selection of tumbler drum size. A longer tumbler drum can result in higher, undesirable product breakage.
One problem with this prior art apparatus is the difficulty of providing a layered seasoning. For example, sour cream and onion seasonings often consist of a larger parsley flake seasoning mixed in with the smaller fine particulate seasoning. The smaller fine particulate seasoning, however, can cover and obscure the parsley making it appear as though less parsley is present than actually is present. Further, some fine, particulate seasoning may partially obscure the parsley flake, which can dull or dilute the green color. Thus, it is difficult to produce a snack food product having a clear color contrast. Unfortunately, prior art seasoning distribution systems currently require the two seasonings to be mixed and applied then applied to the substrate.
One solution to this problem is to add a second seasoning dispenser 22 having a series of apertures in the bottom of the near end of the tube 24 , closer to the hopper 32 , but situated such that seasoning curtain resides within the drum. Unfortunately, the space constraints of the flavoring drum make the use of multiple screw conveyors impractical, and also the cost of such a system may be prohibitive.
Another solution may be to use a second apparatus 10 as depicted in FIG. 1 in series with a first apparatus 10 and thereby route the substrate through two seasoning drums having different seasonings. This solution, however, fails because in addition to significant capital costs for a second apparatus, such a configuration would result in higher than desirable product breakage.
Similarly, patents that relate to snack food seasoning in the prior art all fail to provide an economical apparatus that provides a layered seasoning on a snack food substrate. For example, U.S. Pat. Nos. 4,543,907, 5,090,593, 5,846,324, 6,619,226, and 6,588,363 all fail to disclose an apparatus capable of providing a layered seasoning on a snack food substrate.
Consequently a need exists for an apparatus that can provide a layered, uniform seasoning coverage onto snack products while minimizing product breakage. The method and apparatus should be adaptable to an existing product line where seasoning is applied to a snack food substrate. In addition, the apparatus should not result in an increase in product breakage. Thereby snack products with uniform layered seasoning coverage can be produced in an economical manner while avoiding product breakage.
SUMMARY OF THE INVENTION
The invention relates to a method and apparatus for layering a plurality of seasonings upon a snack food product. In one aspect, the invention comprises a rotating drum having a snack food product, and a vibratory scarf plate having a wall that divides the scarf plate into a first section and a second section. The first section terminates at a first edge and transports a first seasoning. The second section terminates at a second edge and transports a second seasoning. Scarf plate vibration causes the respective seasoning to fall off its respective edge to a first seasoning curtain and a second seasoning curtain. As snack food passes under the first seasoning curtain, the snack food acquires a first layer of seasoning. Similarly, when the snack food passes under the second seasoning curtain, the snack food acquires a second layer of seasoning.
Hence, this invention produces a method and apparatus whereby difference seasonings can be layered upon a snack food product to achieve a snack food product having superior aesthetic or organoleptic properties. The above as well as additional features and advantages of the present invention will become apparent in the following written detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features believed characteristic of the invention are set forth in the appended claims. The invention itself, however, as well as a preferred mode of use, further objectives and advantages thereof, will be best understood by reference to the following detailed description of illustrative embodiments when read in conjunction with the accompanying drawings, wherein:
FIG. 1 is a schematic sectional elevation view of a prior art seasoning distribution system.
FIG. 2 is a schematic sectional view taken along line 2 - 2 of FIG. 1 .
FIG. 3 a is a partial cut-away perspective view of one embodiment of a seasoning distribution system in accordance with one embodiment of the present invention.
FIG. 3 b is a schematic sectional elevation view of the seasoning distribution system in depicted in FIG. 3 a.
FIG. 3 c is a schematic top view of the seasoning distribution system depicted in FIG. 3 a.
FIG. 3 d is a product outlet end view of the seasoning distribution system depicted in FIG. 3 a.
FIG. 4 a is a schematic top view of the seasoning distribution system in accordance with one embodiment of the present invention.
FIG. 4 b is a product outlet end view of the seasoning distribution system depicted in FIG. 4 a.
FIG. 5 is a top view of a snack product seasoned in accordance with one embodiment of the present invention.
DETAILED DESCRIPTION
FIG. 3 a is a partial cut-away perspective view of a seasoning distribution system in accordance with one embodiment of the present invention. A vibratory scarf plate 40 can be partially inserted into a seasoning drum 14 . A vibratory scarf plate 40 is available from Wright Machinery (bttp://www.wright.co.uk) of Oxbridge, England can be used. A first seasoning, flavoring or illustrative bits 50 can be metered from a first seasoning delivery device 52 (partially shown) onto a first scarf plate section 54 . Similarly a second seasoning, flavoring or illustrative bits 50 can be metered from a second seasoning delivery device 62 (partially shown) onto a second scarf plate section 64 . Although discharge portion of the seasoning device 52 62 is depicted as a round pipe, any way of placing metered seasoning onto the respective scarf plate sections can be used. For example, an endless conveyor or a half pipe can be used. The seasoning delivery device 52 62 can be a volumetric or gravimetric feeder. A metering screw feeder, available from Rospen Industries (http://www.rospen.com/) of Oldends Lane, Stonehouse, Gloucestershire can be used. Equivalent feeders are also available from Acrison (http://www.acrison.com/) of Moonachie, N.J.
A wall 70 disposed within the scarf plate 40 defines a first scarf plate section 54 and a second scarf plate section 64 . Termination of the first scarf plate section 54 within the seasoning drum 14 defines a first edge 56 . Similarly the second scarf plate section 64 terminates at a second edge 66 . The first scarf plate section 54 is the portion of the scarf plate 40 that transports the first seasoning 50 from the first seasoning delivery device 52 to the first edge 56 . Similarly, the second scarf plate section 64 is the portion of the scarf plate 40 that transports the second seasoning 60 from the second delivery device 62 to the second edge 66 . The wall 70 ensures no mixing of the first seasoning 50 with the second seasoning 60 within the confines of the scarf plate 40 .
In one embodiment, the first edge 56 when viewed from above, forms a bias cut or diagonal having an angle Θ that is less than about 45 degrees. Similarly, in one embodiment, the second edge 66 , when viewed from above, forms and angle that is less than 45 degrees. In the embodiment shown in FIG. 3 a , the first edge 56 and second edge 66 comprise equal angles and form a continuous edge. However, it should be noted that the angles can be different and the first edge 56 and second edge 66 may be non-contiguous. In one embodiment, each edge 56 66 comprises a knife-like edge having a small bevel on the underside.
Upon exit from the first seasoning delivery device 52 , scarf plate 40 vibration causes the first seasoning 50 to travel from the seasoning end of the scarf plate 40 along the first scarf section 54 to the first edge 56 . The seasoning 50 then falls off the first edge 56 to create a first seasoning curtain 55 . Similarly, upon exit from the second seasoning delivery device 62 , scarf plate vibration 40 causes the second seasoning 60 to travel from the seasoning end of the scarf plate 40 along the second scarf section 64 to the second edge 66 .
FIG. 3 b is a schematic sectional side view of the seasoning distribution system in depicted in FIG. 3 a . Unseasoned snack food 12 enters the rotating cylindrical drum 14 at one end through, for example, a funnel 16 . Due to drum 14 rotation and tilt, the snack food travels continuously down the inside of the drum 14 towards the exit 80 . Baffles 21 can be positioned to aid in mixing the snack food. A snack food disposed within the upstream section of the drum 14 is first contacted with the first seasoning 50 as it travels beneath the first seasoning curtain 55 . The snack food 12 now having a first seasoning layer is next contacted with the second seasoning 60 as it travels beneath the second seasoning curtain 65 in the seasoning drum 14 . In one embodiment, the scarf plate 40 is substantially level in both the longitudinal and transverse directions.
FIG. 3 c is a sectional top view of the seasoning distribution system depicted in FIG. 3 a . As shown by FIG. 3 c , once seasoning 50 60 exits its respective seasoning delivery device 52 62 , the seasoning can tend to pile immediately below its respective delivery device. Scarf plate 40 vibration alone may not uniformly spread the seasoning about the width of either scarf plate section 54 64 . If seasoning 50 60 is not uniformly distributed about the width, it may impact seasoning curtain 55 65 uniformity. Thus, in one embodiment (not shown), the seasoning delivery device 52 62 terminates across the width of the respective scarf plate section to minimize piling and provides a uniform amount of seasoning about the width of the scarf plate section 54 64 .
In an alternative embodiment, a spreader bar 72 is mated to the bottom of both the first scarf plate section 54 and the second scarf plate section 64 and extends the width of each section. The spreader bar 72 , in conjunction with the vibration caused by the scarf plate 40 , functions as a dam and causes seasoning to thinly spread out about the width of the respective scarf plate section 54 64 as seasoning 50 60 flows over the spreader bar 72 . The spreader bar 72 thus helps to uniformly spread the seasoning about the width of each scarf plate section 54 64 . Although the spreader bar 72 height can vary depending upon such factors including, but not limited to, vibration frequency, vibration pattern, spreader bar shape, and seasoning characteristics such as seasoning size and density, the height, in one embodiment, ranges from about 3 millimeters to about 6 millimeters. It is also preferable that the surface of the respective scarf plate sections 54 64 be highly polished to facilitate even flow of the seasoning.
The location of the wall 70 separating the first scarf plate section 54 and the second scarf plate section 64 can be based on a number of factors including, but not limited to, the physical properties (e.g. density, particle size) of the first and second seasoning, the desired finished appearance of the seasoned snack product, and the desired organoleptical properties (taste, smell, and texture) of the desired finished product. The physical properties of the seasonings may influence wall 70 placement because the rate of travel and thus final seasoning amount may be affected by the density and/or particle size of the seasoning. The desired finished appearance may influence wall 70 placement based upon the desired aesthetic appearance produced by the relative placement density of the first seasoning 50 and second seasoning 60 on the snack food product. The desired organoleptical properties may influence wall 70 placement based upon the desire for a snack food product to vary the intensity of an initial taste, smell, or texture aspect of a snack food product. For example, a seasoning having a strong smell may be used as a second seasoning 60 . In such a case, the second edge 66 may be longer than the first edge 56 . Thus, depending upon the desired finished product, the wall 70 can be placed anywhere within the scarf plate 40 .
FIG. 3 d is a product outlet end view of the seasoning distribution system depicted in FIG. 3 a . It should be noted that, unlike clothes in a household clothes dryer, the snack food product after it migrates upward with drum rotation 18 , gently rolls or slides down the side of the drum 14 and is generally not “spun” or “flung” around inside the seasoning drum 14 . Thus, the figure substantially portrays the relative location of the snack food product bed inside the seasoning drum 14 . In one embodiment, a snack food piece tumbles (follows the drum rotation up the sidewall of the drum and then rolls back down) between about 2 and about 9 times as the snack food navigates through the first curtain 55 . In one embodiment, a snack food piece tumbles about 2 times and about 9 times as the snack food navigates through the second curtain 65 . While snack food product generally is not carried beyond the top half of the drum, it is possible for seasoning to adhere to the sides of the drum. The potential then exists for such seasoning to fall onto the scarf plate 40 . This is undesirable because of the potential for the first seasoning 50 to fall into the second scarf plate section 64 or for the second seasoning 60 to fall into the first scarf plate section 54 , resulting in undesirable mixing of seasonings. Thus, in one embodiment, a protective hat (not shown) is disposed above the scarf plate 40 to shield the scarf plate from any potential contaminants. The scarf plate 40 is preferably placed off-center within the drum such that the seasoning curtains 55 65 fall substantially upon the snack food product bed below.
Although FIGS. 3 a - 3 d depict only one inner wall 70 on the scarf plate to form two scarf plate sections, those skilled in the art will recognize that additional walls 70 could be placed in the scarf plate 40 to increase the number of layers of seasoning disposed upon a seasoned snack food product.
FIG. 4 a is a schematic top view of the seasoning distribution system in accordance with an alternative embodiment of the present invention. FIG. 4 b is a product outlet end view of the seasoning distribution system depicted in FIG. 4 a . In this embodiment, the scarf plate 40 is placed into the drum at a diagonal and the first scarf plate edge 56 and second scarf plate edge 66 are substantially parallel to the longitudinal axis of the drum 14 . As a result, the first curtain 55 and second curtain 65 also reside in a plane parallel to the longitudinal axis of the drum 14 . In such an embodiment, the angle Θ can be less than about 30 degrees, more preferably less than about 20 degrees and most preferably less than about 10 degrees to permit optimal placement of the seasoning curtains over the snack food within the drum.
FIG. 5 is a top view of a snack food product seasoned in accordance with one embodiment of the present invention. As indicated by the figure a snack food product having a layered seasoning is achieved. In the embodiment shown, the second seasoning 60 providing a second layer is disposed upon first seasoning 50 providing a first layer.
In one embodiment, the second seasoning 60 comprises an average particle size that is different from the first seasoning 50 . In one embodiment the second seasoning comprises a texture that is different from the first seasoning. In one embodiment, the second seasoning comprises a color that is different from the first seasoning. In one embodiment, the second seasoning comprises a flavor different from the first seasoning. In one embodiment, the second seasoning comprises barley.
The instant invention results in a snack food product having a layered seasoning. There are several advantages with this invention. First, because the second seasoning is not obscured from mixing with the first seasoning, a lesser amount of a second seasoning can be used for the same apparent density. Second, the invention provides for a way to provide a more aesthetically pleasing snack food product. Because the second seasoning is not obscured by the first seasoning, the snack food product is able to exhibit a clear color contrast. Third, the invention provides a way to season a snack food with two or more distinct colors. Fourth, the invention provides a way to maximize the texture attributes of different seasonings. For example, if it is desired to have an outer (second) seasoning having a rougher texture and an inner (first) seasoning having a fine texture to produce a desired mouthful, the rough outer texture is not diluted by mixing with the fine inner texture seasoning. Further, in such an example, because the second seasoning is the outermost seasoning, addition of a second seasoning having strong texture attributes can be more fully appreciated upon initial consumption by a consumer. Fifth, because the second seasoning is the outermost seasoning, the first seasoning and second seasoning flavors can be varied to maximize desired flavor profiles.
While this invention has been particularly shown and described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention. | An apparatus and method for providing a layered seasoning to snack food products such as potato chips or tortilla chips using a vibratory scarf plate that is divided into two or more sections by one or more walls. A different seasoning is placed in each section. The scarf plate is placed into a rotating drum having snack food product. A seasoning from each section falls off the scarf plate to form a curtain. Each curtain provides a layer of seasoning on the snack food product. | 0 |
RELATED APPLICATIONS
[0001] This application is related to a co-pending application entitled, “Steering Wheel Vapor Collection and Sensing System Using Suction,” which describes a related apparatus and method for detecting vapors in an automotive steering wheel structure, and which was filed on Jul. 26, 2004 as Ser. No. 10/899,826.
INCORPORATION BY REFERENCE
[0002] Applicant hereby incorporates herein by reference, the U.S. patents and U.S. patent applications, described in the Description of Related Art section of this application; specifically by document number: 20030087452; 4,090,078; 4,277,251; 4,363,635; 4,649,027; 4,749,553; 4,849,180; 4,905,498; 5,055,268; 5,220,919; 5,376,555; 5,743,349; 6,075,444; 6,097,480; 6,183,418; 6620108.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] This invention relates generally to vapor collection systems and especially to the detection of trace amounts of an alcohol containing substance carried by vapors, such as a person's breath, or vapor evaporation from skin surfaces. This invention is related to analyzers used by law enforcement agencies where the breath of a driver is subject to analysis; and more particularly to a steering wheel mounted structure for collection detection of such vapors as minute partial pressures.
[0005] 2. Description of Related Art
[0006] The following art defines the present state of this field and each of these disclosures is hereby incorporated herein by reference:
[0007] Ratogi, et al. 20030087452, discloses is a method of making a bismuth molybdate precursor solution using a metallorganic decomposition (MOD) process consisting of the formation of a precursor sol of hexanoates of Bismuth (Bi) and Molybdenum (Mo). The precursor solution is used to make thin film of Bismuth molybdate by spin coating and spray pyrolysis. The bismuth molybdate films have the useful alpha and gamma phases having high sensitivity to ethanol gas, the detection of the ethanol gas is based upon the change of electrical conductivity of a thick film of the semiconductor oxide sensing element resulting from the ethanol gas in an oxygen-containing atmosphere. When the drying is effected by spray pyrolysis, quite thick films with high adhesion have been produced over different substrates, including quartz. The thin film of the present invention made by spray pyrolysis has a very fast response to ethanol detection eg typically 5 seconds.
[0008] Heim, U.S. Pat. No. 4,090,078 describes a method for determining the alcohol content in the exhaling respiratory air using an alcohol measuring instrument and measuring the alcohol content when the exhaling air transmits the determined value of the alcohol concentration. This determined value of alcohol concentration occurs when the time variation related to the height of the alcohol signal is below a predetermined threshold value and the velocity of flow of the exhaling air is above a given value and is maintained without interruption for a given time. The apparatus includes an infrared measuring instrument which is connected into the respiratory air current and measures the alcohol concentration of the exhaling air. This value is applied to an indicator through a linear gate when an AND-gate is triggered by threshold comparators and a timing element activated by a threshold comparator.
[0009] Leichnitz, U.S. Pat. No. 4,277,251 describes a method of determining the alcohol content of air exhaled by a person using a flow through testing tube having an alcohol indicating material therein and a sampling tube to which the air is directed which has a material therein for retaining the alcohol of the breathing air and also using a suction pump comprises cooling the sampling tube, passing the exhaled air through the cooled sampling tube, measuring a volume of the air passing through the cooled sampling tube, heating the sampling tube and connecting the suction pump to the sampling tube to suck flushing air through the heated tube and then through the testing tube. The sampling tube advantageously contains a silica gel to retain the alcohol therein. The volume measuring device may be a measuring bag.
[0010] Hutson, U.S. Pat. No. 4,363,635 describes a method and apparatus for discriminating between alcohol and acetone in a breath sample and accurately measuring the alcohol level when acetone is present in the sample. The breath sample is measured with two different types of detectors and their outputs compared. One detector uses the principles of infrared (IR) absorption, the other detector is a semiconductor, commonly called a Taguci cell, or its equivalent. Automatic correction is provided for variations in sensitivity of the semiconductor.
[0011] Talbot, U.S. Pat. No. 4,649,027 describes a battery-operated portable breath tester. The breath tester includes a housing which defines a sleeve for receiving a wand. The wand defines an internal sample chamber, with a lamp at one end for providing infrared energy and a detector at an opposite end for receiving the infrared energy after it has passed through the sample to be tested. The wand defines opening extending from the internal sample chamber to the outside of the wand. The wand has an external shape providing a snug fit within the sleeve. As the wand is moved within the sleeve, gas is purged from the wand. The wand is connected to the housing by means of an electrical coil. The housing encloses a digital voltmeter including a digital display for providing a test readout. The digital voltmeter includes an oscillator which is coupled through a frequency divider and a transistor switch to the lamp. The lamp is switched on and off in accordance with the frequency output of the frequency divider to modulate the infrared energy emitted from the lamp at a selected frequency. A voltage regulator is connected to the lamp, and the lamp and voltage regulator are located in heat-exchange relationship with the sample chamber. This aids in raising the temperature of the sample chamber during testing in order to alleviate condensation.
[0012] Lopez, U.S. Pat. No. 4,749,553 describes a breath alcohol detector measuring and compensating for distance between the mouth of the individual exhaling breath into the ambient air and the detector, the atmospheric pressure, and the temperature. Blood alcohol content information is calculated using these compensation factors and a signal obtained from an electrochemical fuel cell which is indicative of the amount of alcohol or other gas contained in the sample. The detector also includes a reciprocally acting electromagnetically energized motor which drives a diaphragm pump to draw the sample into the electrochemical fuel cell.
[0013] Fukui, U.S. Pat. No. 4,849,180 describes an alcohol selective gas sensor including a detecting electrode and a semiconductor detecting element in contact with the detecting electrode, the semiconductor detecting element comprising tin oxide (SnO 2 ) and a metal oxide of at least one of alkaline earth metals (Be, Mg, Ca, Sr, Ba) carried by the tin oxide, the metal oxide being contained in an amount of about 0.5 mol % or above.
[0014] O'Donnell et al., U.S. Pat. No. 4,905,498 describes a gaseous detection system for detecting the existence of a certain gas and further the detection of a certain level or percentage of that certain gas within a certain environment. An example is use of the gas detection system in a motor vehicle to aid in determining when a driver of the motor vehicle may be driving under the influence of alcohol, and for providing an appropriate warning signal that may be viewed from the exterior of the motor vehicle. The system includes a sensor unit for sensing ethanol in the atmospheric contents of the motor vehicle's interior, for example, a unit for providing an actuation signal in response to the sensing unit, and a signal unit that generates a signal which can be utilized for many purposes, for example, causing at least some of the exterior lights on the motor vehicle to alternately flash on and off in a substantially non-standard pattern. The sensing unit may also be coupled with a digital read-out device or the like to indicate the amount of blood alcohol content of a person for evidentiary or like purposes.
[0015] Martin, U.S. Pat. No. 5,055,268 describes an air-borne chemical sensor system including a motor and impeller to draw an air sample into a housing containing a sensor which will provide a signal for display related to the amount of a particular air-borne chemical in a given air sample. The system is controllable by different duration activation of a single activating switch which can further control a secondary function, such as a flashlight.
[0016] Phillips, U.S. Pat. No. 5,220,919 describes a gaseous detection system for detecting the existence of a certain gas and further the detection of a certain level or percentage of that certain gas within a certain environment. An example is use of the gas detection system in a motor vehicle to aid in determining when a driver of the motor vehicle may be driving under the influence of alcohol, and for providing an appropriate warning signal that may be viewed from the exterior of the motor vehicle. The system includes a sensor unit for sensing ethanol in the atmospheric contents of the motor vehicle's interior, for example, a unit for providing an actuation signal in response to the sensing unit, and a signal unit that generates a signal which can be utilized for many purposes, for example, causing at least some of the exterior lights on the motor vehicle to alternately flash on and off in a substantially non-standard pattern. The sensing unit may also be coupled with a digital read-out device or the like to indicate the amount of blood alcohol content of a person for evidentiary or like purposes.
[0017] Forrester et al., U.S. Pat. No. 5,376,555 describes a method and infrared sensing device for determining the concentration of alveolar alcohol in a breath sample exhaled by a subject into an infrared sensing device. The presence of alcohol from the upper respiratory tract of the subject is detected by continuously monitoring alcohol and carbon dioxide, normalizing alcohol values with respect to carbon dioxide, calculating a difference between normalized alcohol concentration and carbon dioxide concentration over time, integrating (summing) the difference, and comparing the integrated difference with a threshold. This technique accurately and consistently detects the presence of mouth alcohol in the sample before the presence of carbon dioxide which originates in deep lung breath.
[0018] Steinberg, U.S. Pat. No. 5,743,349 describes a vehicle ignition interlock system including a non-invasive reader of a person's blood-alcohol concentration in combination with ignition interlock circuitry that prevents operation of a vehicle by an intoxicated person. The non-invasive blood-alcohol concentration reader, termed alcoh-meter, utilizes optical spectroscopic electromagnetic radiation technology to determine the alcohol levels in the blood. The alcoh-meter is preferably a dash mounted sensor for receiving a person's finger and absorbing incident light from a multiple wavelength light source and causing a light absorption reading to be generated based on the person's blood alcohol concentration in the finger tissue. After registering a reading, the results are compared electronically against a table of impaired/non-impaired levels of blood alcohol concentration. The impaired/non-impaired results are communicated to interlock circuitry that either enables, or disables start-up of the vehicle. If an impaired status is determined, the results are displayed instructing the operator to wait, or find a non-impaired operator.
[0019] Soheege et al., U.S. Pat. No. 6,075,444 describes an arrangement for blocking the operation by an intoxicated operator of a machine or a motor vehicle. The arrangement has a measuring apparatus which determines the blood alcohol content of the operator and an evaluation unit connected to the machine or motor vehicle. The evaluation unit receives measurement data supplied by the measurement apparatus and enables the machine or motor vehicle when the measurement data satisfies at least one predetermined condition. The arrangement is improved in that the sobriety of the operator is recognized before the starting operation of the machine or motor vehicle without it being necessary to supply a breath sample. The measuring apparatus includes a gas sensor which is a sensor for measuring the blood alcohol content via permeation through the skin of the operator. The measuring apparatus is configured so that it can be worn by the operator preferably on the leg or arm.
[0020] Kaplan, U.S. Pat. No. 6,097,480 describes a vehicle interlock system which utilizes non-invasive, optically based methods for detecting and measuring levels of certain target chemical substances in the blood or tissues of a user in preventing operation of the vehicle by persons exhibiting higher (or lower) than prescribed levels of such chemicals. The system of the present invention is not limited to simply measuring blood alcohol levels as are presently available breathalizer-based interlock systems, but lends itself to use in detecting unacceptable systemic levels of virtually any chemical for which the system if programmed to measure. In addition, the present system includes components for positively identifying, and during the course of vehicle operation, re-identifying the intended user and alcohol or drug user testee.
[0021] Kuennecke, U.S. Pat. No. 6,183,418 describes the process for detection and for quantitative determination of substances emitted or perspired through the skin is derived from flow diffusion analysis. The measuring system conceived for this purpose uses a diffusion half cell through which an acceptor medium flows and which is closed by a membrane. For the duration of the measurement, the membrane is brought into contact with the skin or a closed gas volume formed over the skin. With the process and the related measuring system, the blood alcohol level can be determined with a good degree of precision indirectly via the quantity of (gaseous) ethanol emitted through the skin.
[0022] Duval, U.S. Pat. No. 6,620,108 describes an apparatus and method for assuring that a machine operator is not under the influence of a chemical, comprising a first sensor positioned proximally to the machine operator and adapted for measuring a vapor concentration proximal thereto, a second sensor positioned distally from the machine operator and adapted for measuring the vapor concentration distally from the operator, a device for comparing the proximal and distal vapor concentrations, and an automated remediating element responsive to the comparing device when the ratio of the first and the second vapor concentrations are within a specified range.
[0023] Our prior art search with abstracts described above primarily teaches the use of analyzing vapors produced in the exhalant of an individual. Thus, the prior art shows several solutions to the collection and analysis of minute partial pressures of vapors. However, the prior art fails to teach a simple system that can avoid the use of deliberate breath analysis and yet be inexpensive by avoiding the very high sensitivity required of room air analyzers. The present solution employs a steering wheel having an integral chemical element which is able to detect alcohol vapors from a users hands, i.e., excreted through the skin; analyze the vapors and produce a control signal. This enablement allows automatic monitoring and the initiation of remedial actions when necessary for the safety of the individual and the public at large. The present invention fulfills these needs and provides further related advantages as described in the following summary.
SUMMARY OF THE INVENTION
[0024] Data has been collected on the number of accidents and accident related deaths on U.S. highways each year that are, at least in part, related to alcohol or other substances within the blood stream of drivers. This data shows that it would be wise to take steps to prevent motorists from driving when they are under the influence of such substances. One solution to this problem is to install a device in existing and new automobiles, and other types of vehicles that will monitor and possibly prevent such driving. The present invention teaches certain benefits in construction and use of such devices which give rise to the objectives described below and forms at least a partial solution to this problem.
[0025] The invention is a detection system installed onto or into a steering wheel of a vehicle wherein a chemical sensor is able to detect alcohol vapors emitted by the driver. Such vapors may be from the driver's breath, his or her clothing, or from the driver's hands as they touch and come into contact or merely just close proximity to a sensor element. It may be used on automobiles, trucks, buses, boats and other vehicles. Such detection may trigger a warning or other action, including shutting down the ignition system of the vehicle. In a best mode preferred embodiment of the present invention, a solid state vapor sensor is made an integral part of the steering wheel. In an alternate embodiment, the vapor sensor is part of a steering wheel cover and is adapted to be placed onto an existing steering wheel. The vapor sensor may be any one or more of the substances described in the cited prior art, and it may be coated, bonded or otherwise placed on the steering wheel or within one or more grooves in the steering wheel's exterior surface. The sensory element(s) may be part of a detection and alarm circuitry built into the steering wheel/steering column structures or may be connected to such circuitry by fine wire signal conductors or by wireless means. Such circuitry may be placed behind a control or dash board of the vehicle. Such a circuit may be enabled for controlling an ignition circuit of the vehicle. Alternately, the control circuit might control audible or visual devices to inform the driver that he/she is driving dangerously, or might control other devices as deemed necessary to protect the driver, any passengers and the general public.
[0026] A primary objective of the present invention is to provide an apparatus and method of use of such apparatus that yields advantages not taught by the prior art.
[0027] Another objective is to assure that an embodiment of the invention is capable of integrating vapor collection with a steering wheel assembly.
[0028] A further objective is to assure that the vapor is received by the steering wheel assembly.
[0029] A further objective is to assure that the vapor comes into contact with a vapor detector within the steering wheel assembly.
[0030] A still further objective is to assure that an electrical signal is generated or modified by the vapor detector so as to generate an alert signal.
[0031] Other features and advantages of the embodiments of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of several possible embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The accompanying drawings illustrate the best mode embodiments of the present invention.
[0033] In such drawings:
[0034] FIG. 1A is a perspective exploded view of the present invention wherein, in one embodiment, a chemical sensory element is placed within a steering wheel cover, an interior surface of the cover free to be bonded to a steering wheel;
[0035] FIG. 1B is an enlarged perspective view thereof;
[0036] Figure 1C is an enlarged perspective view similar to that of FIG. 1B , wherein the chemical sensory element provides an inner surface for bonding to the steering wheel and is covered exteriorly by the steering wheel cover which may be bonded or tied in place around the steering wheel and the sensory element;
[0037] FIG. 2 is a rear perspective view of a steering wheel and steering column structures showing electrical wiring of a retrofit version of the invention;.
[0038] FIG. 3A is a partial sectional view, taken along cutting plane line 3 - 3 in FIG. 2 , showing placement of the sensory element of the invention within a groove in the steering wheel and internal electrical wires engaged therewith;
[0039] FIG. 3B is a partial sectional view, taken along cutting plane line 3 - 3 in FIG. 2 , showing placement of the sensory element of the invention within a groove in the steering wheel and an internal a wave energy transmitter engaged therewith; and
[0040] FIG. 4 is a perspective view of the invention as installed in a vehicle.
DETAILED DESCRIPTION OF THE INVENTION
[0041] The above described drawing figures illustrate the present invention in two of its preferred, best mode embodiments, which is further defined in detail in the following description. Those having ordinary skill in the art may be able to make alterations and modifications in the present invention without departing from its spirit and scope. Therefore, it must be understood that the illustrated embodiments have been set forth only for the purposes of example and that they should not be taken as limiting the invention as defined in the following.
[0042] In one embodiment of the present invention shown in detail in Figs. 1A and 1B , a vapor sensory element 20 , having sensitive specificity to ethyl alcohol, is placed within a steering wheel cover 70 . Both the element 20 and the cover 70 are configured for encircling a steering wheel 10 . The element 20 is shaped to correspond with the steering wheels surface conformation, as a generally crescent shape. The sensory element 20 is of an alcohol sensitive material as will be described below, or may be a mere coating of such material placed on a support. In the embodiment of Fig. 1B , the sensory element 20 is inserted into the steering wheel cover 70 and cover surface 76 is adhesively bonded to the steering wheel. In the embodiment of Fig. 1C , the sensory element 20 is merely covered by the steering wheel cover 70 so that surface 26 is placed into adhesive contact with steering wheel 10 . In both cases, the cover 70 has plural apertures 72 which allow vapors to reach the element 20 . When vapors are excreted from the hands of a person holding the steering wheel, vapors evolve and flow through the apertures 72 and contact the element 20 . The vapors flow naturally without being drawn in any way to the sensor 20 . Should the person holding the steering wheel 10 have alcohol in their blood stream, from alcoholic beverages for instance, vapors excreted by the hands will contain trace amounts of ethyl-alcohol. These vapors are detected by sensory element 20 which, then, produces an electric circuit effect and such effect enables a circuit 60 in the steering wheel itself, the steering wheel column 80 , or elsewhere in the vehicle ( FIG. 4 ) to product an alarm signal. Electrical conductors 50 , such as copper wires, join the sensor element 20 with circuit 60 thereby establishing electrical signal communication therebetween for establishing control of an ignition circuit of the motor vehicle (not shown), or for setting off an alarm or for enabling other appropriate actions.
[0043] The cover 70 is preferably of an organic material such as rubber or leather, and may be permanently bonded to the steering wheel 10 or it may be removable as is well known in the art. As shown in FIGS. 1B and 1C , such a cover 70 may fully enclose the sensor element 20 , or it may merely form an outer protective layer over the sensor material 20 .
[0044] As shown in FIG. 4 , the wires 50 may be routed from the sensor element 20 via the steering column 80 , externally or internally, to the circuit 60 which is typically mounted within a dash board for a car, truck, boat or aircraft. The circuit 60 preferably provides means for triggering an alarm or other action depending upon the reaction of element 20 to the vapors. Such triggering or other circuit performance is well known in the art. Instead of using wires 50 to join element 20 with circuit 60 , as shown in FIG. 3A , a wireless data communication method may be employed as is also well known in the art. Such a wireless method employs a transmitter element 15 mounted within the steering wheel 10 , as shown in FIG. 3B .
[0045] In the alternate embodiments shown in FIGS. 3A and 3B , the steering wheel 10 is molded with one or more grooves 11 in its surface. The grooves 11 are fitted with the sensory element 20 . In this embodiment, the element 20 may be of a type that requires physical contact with the skin of the driver, or at least very close proximity between skin and sensory element 20 .
[0046] In operation the vapor sensitive material 20 may be tin oxide (SnO 2 ) and a metal oxide of at least one of the alkaline earth metals (Be, Mg, Ca, Sr, Ba) carried by the tin oxide, the metal oxide being contained in an amount of about 0.5 mol % per Fukui, or it may employ the gas sensor of Soheege et al. Also, the process of using a diffusion half-cell described by Kuennecke may be employed. In a still further alternate approach, as per Ratogi, et al. a bismuth molybdate precursor solution may be employed. In each case, the materials for sensing low levels of ethyl alcohol are well known in the art and are included by reference herein.
[0047] The enablements described in detail above are considered novel over the prior art of record and are considered critical to the operation of at least one aspect of one best mode embodiment of the instant invention and to the achievement of the above described objectives. The words used in this specification to describe the instant embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification: structure, material or acts beyond the scope of the commonly defined meanings. Thus if an element can be understood in the context of this specification as including more than one meaning, then its use must be understood as being generic to all possible meanings supported by the specification and by the word or words describing the element.
[0048] The definitions of the words or elements of the embodiments of the herein described invention and its related embodiments not described are, therefore, defined in this specification to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the invention and its various embodiments or that a single element may be substituted for two or more elements in a claim.
[0049] Changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalents within the scope of the invention and its various embodiments. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements. The invention and its various embodiments are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted, and also what essentially incorporates the essential idea of the invention.
[0050] While the invention has been described with reference to at least one preferred embodiment, it is to be clearly understood by those skilled in the art that the invention is not limited thereto. Rather, the scope of the invention is to be interpreted only in conjunction with the appended claims and it is made clear, here, that the inventor(s) believe that the claimed subject matter is the invention. | A vapor sensitive material is configured for encircling a steering wheel. The material is held within a flexible cover over the steering wheel or is bonded directly to the steering wheel or is held against the steering wheel by the cover, or is placed within a groove in the steering wheel. The material forms one element of an electrical sensory circuit able of detecting ethyl alcohol vapor partial pressures in the breath or sweat of the hands of a person holding the steering wheel. | 1 |
RELATED APPLICATION
[0001] The present application claims priority to, and the benefits of, U.S. Provisional Application Ser. Nos. 60/765,144, filed Feb. 4, 2006, and 60/842,074, filed on Sep. 1, 2006, the entire disclosures of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to safety helmets and, in particular, to helmet straps and their adjustment.
BACKGROUND OF THE INVENTION
[0003] Helmets for head protection are worn in a variety of environments and for various purposes. Helmets are often secured to a wearer's head by a flexible chin strap. The chin strap may include multiple segments of flexible strap material that are secured at either side of the helmet and pass below the chin, where the segments are releasably joined. In some helmets the strap segments on either side of the helmet are attached to the helmet at two positions, in front of and behind the wearer's ear. When joined, the two strap segments form a single strap that may be adjusted in length. Many of the available approaches to connecting the strap segments are cumbersome and lack security. In some cases, for example, the wearer must pass one end of the strap through a buckle or a pair of “D-rings” with a return loop, making it difficult to quickly remove the helmet in an emergency. In other cases, a quick release “snap” lacks security due to the possibility of accidental release. Two-finger release mechanisms, while more secure, typically attach to the ends of the strap segments and thus require intervening length in line with the straps. This makes it difficult to place the fastener near the chin, which can be important to the stability of the helmet.
[0004] Simplifying the strap arrangements may reduce the awkwardness of disengagement, but often at the price of reduced helmet stability. For example, single-strap systems may allow play in the helmet when worn. Indeed, even multiple-strap systems can allow helmet movement if the straps are not aligned so as to maintain consistent lines of tension.
SUMMARY OF THE INVENTION
[0005] The present invention provides practical and reliable solutions to the foregoing problems. In various embodiments, the invention provides a secure retention system for protective helmets that facilitates easy adjustment. In particular, the stability of a protective helmet is improved when the straps that connect to the helmet on each side have substantially straight, continuous lines of tension extending through the buckle that joins them. Accordingly, in preferred embodiments, two V-shaped strap segments are drawn into an “X” configuration that channels the tension in the straps along continuous lines, rather than allowing the tension to dissipate in an intervening length of strap.
[0006] For example, a releasable two-part buckle in accordance with the invention may comprise a male component attached at one end to a flexible strap segment and having at least two fingers extending from the other end of the component, which can snap-engage a female component. The engagement can be released by simultaneously pressing the two fingers. In a preferred embodiment, the female component has a pass-through area along its underside, parallel to the direction of introduction of the male component, through which a second flexible strap segment may be passed. Flush abutment between flat surfaces of the male and female components without significant intervening linear space helps maintain tension between the strap components.
[0007] In one embodiment, a system of flexible straps comprises a chin-holding component having one strap segment passing below the chin and another strap segment passing between the chin and the lower lip; retention components on left and right sides of the helmet having one strap segment connecting to the front portion of the helmet and another strap segment connecting to a rear portion of the helmet; and a connecting device of the present invention joining the chin-holding component to the retention component on one side of the wearer's head such that the strap segments intersect substantially in the shape of the letter “X”.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:
[0009] FIG. 1 is a plan view of the male and female components of a buckle in accordance with the present invention.
[0010] FIG. 2 is a plan view of the buckle of FIG. 1 in the connected position.
[0011] FIG. 3 is an exploded view of the buckle of the present invention showing the flexible straps to which the male and female components are to be connected.
[0012] FIG. 4 shows another embodiment of the present invention in plan view.
[0013] FIG. 5 shows the two embodiments of the female component of the buckle taken from FIG. 1 and FIG. 4 to illustrate the critical geometry of the present invention.
[0014] FIG. 6 is a side view of a protective helmet with straps connected at the chin using a buckle constructed according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0015] With reference to FIG. 1 , a buckle in accordance with the present invention comprises a male component 51 and a female component 54 coupling together flexible straps comprising, with respect to male component 51 , strap segments 57 a , 57 b , and with respect to female component 54 , strap segments 60 a , 60 b . Male and female components 51 , 54 are preferably molded from a strong, flexible, resilient plastic material such as Nylon or Delrin. The fingers 63 a , 63 b and guide member 66 are received within a receptacle area 69 of the female component 54 using normal manual pressure. During this coupling movement, fingers 63 a and 63 b deflect laterally toward guide member 66 until engaging features 72 a , 72 b have cleared surfaces 75 a , 75 b of the female component 54 . At this point, the flexibility of the fingers 63 a , 63 b cause them to return outwardly to their uncompressed position, so that surfaces 75 a , 75 b resist return movement of engaging features 72 a , 72 b , thereby preventing separation of the male component 51 from the female component 54 . The female component 54 has openings 78 a , 78 b that afford access to fingers 63 a , 63 b following insertion of the male component 51 into the female component 54 .
[0016] With reference to FIGS. 2 and 3 , fingers 63 a , 63 b are sufficiently exposed through the openings in the female component 54 to permit the wearer to pinch the fingers and flex them inwardly, thereby freeing the engaging features 72 a , 72 b from surfaces 75 a , 75 b and allowing the male component 51 to be withdrawn from the female component 54 . A flexible intermediate strap 81 passes through a slot 79 in male component 51 , and a flexible intermediate strap 87 is secured to female component 54 through a pass-through area 87 .
[0017] In the preferred embodiment, intermediate strap 81 is sewn or otherwise permanently affixed to the flexible strap components 57 a , 57 b . As illustrated, the components 57 a , 57 b are part of the same single length of strap, which is folded to form a V-shaped configuration. Alternatively, however, components 57 a , 57 b can be separate strap segments that are joined to form the same configuration. In either case, the apex of the V is substantially aligned (i.e., flush) with the abutment face 90 of male component 51 , which, when the male and female components are locked, makes contact with a complementary abutment surface 93 of the female component 54 . As a result, the edges of the V-shaped straps at their apices are substantially in contact along the entire apex edge length.
[0018] Similarly, the pass-through area 84 in the female component accepts intermediate strap 87 , which is sewn or otherwise affixed to strap segments 60 a , 60 b and positioned so that the apex of the V is substantially flush with the abutment surface 93 . The pass-through area 84 is oriented parallel to the direction of introduction of the male component 54 , and locates the tensioning region of the strap segments 60 a , 60 b adjacent the front surface 93 of the female component 54 , very close to the point where the female component joins the male component.
[0019] It is also possible to utilize the invention with single linear strap segments rather than V-shaped segments. In this case, the male component 51 may be connected to one of the single straps directly through the slot 79 (see FIG. 2 ) instead of employing the intermediate strap 81 , and the female component 54 may be connected directly to the other single strap using the pass-through area 84 , thereby obviating the need for the intermediate strap 87 . Another alternative is to use one free, single strap and one V-shaped strap, in which case it is advantageous for the male component 51 to be connected to the single strap directly through the slot 79 and the female component 54 to be connected to the V-shaped strap via intermediate strap 87 .
[0020] FIG. 4 illustrates another embodiment 54 ′ of the female component. The component 54 ′ has many of the same features as the female component 54 shown in previous figures, including receptacle area 69 , surfaces 75 a , 75 b , and openings 78 a , 78 b which cooperate with features of the male component 51 as described previously. Straps 60 a , 60 b are attached to the component 54 ′ via mounts such as the slots 95 a , 95 b . This embodiment is particularly well suited to applications where two straps are joined at the female side with one or two straps on the male side.
[0021] FIG. 5 shows how both female components 54 and 54 ′ share the critical geometry that allows tension to pass through the buckle without being dissipated by intervening linear space. The dotted lines A-A′ and B-B′ follow the tension in the flexible straps 60 a , 60 b respectively. The slots 95 a , 95 b are angled toward each other so that the lines of tension A-A′ and B-B′ intersect each other at or very near the front surface 93 of the female component. As can be seen in FIG. 5 , both embodiments 54 and 54 ′ of the female component provide this geometry. When the male and female components are engaged, these lines of tension are substantially continuous—that is, the lines A-A′ and B-B′ shown in FIG. 5 are substantially congruent with complementary lines from the V-shaped strap of the male component. This is because when the male and female portions of the buckle are locked, the V-shaped straps come together to form the letter “X,” so that tension in the opposed straps are aligned. This has been found to substantially improve helmet stability.
[0022] FIG. 6 shows a system of helmet straps employing the buckle of the present invention to secure a protective helmet 96 . A chin-holding component comprises the strap segment 57 a , which passes between the chin and the lower lip, and the strap segment 57 b , which passes below the chin and is joined to the male component 51 of the buckle. The retention strap segment 60 a is connected to the side of helmet toward the front, and the strap segment 60 b is connected to the side of the helmet toward the rear. These are joined, as described above, to the female component 54 of the buckle. When the male component 51 is inserted into the female component 54 , the strap segments 57 a , 57 b and 60 a , 60 b abut to form the letter “X” because the buckle does not occupy significant space between them. The result is improved stability of the helmet 96 with respect to the wearer's head.
[0023] Having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. The described embodiments are to be considered in all respects as only illustrative and not restrictive. | A mounting buckle for a safety helmet includes at least one mating member configured for attachment to a V-shaped strap having an apex, the apex of the strap being substantially flush with the abutment surface. This configuration channels the tension in the straps along continuous lines, rather than allowing the tension to dissipate in an intervening length of strap. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 10/682,418, filed Oct. 10, 2003, which claims priority to Japanese Application No. 2002-299521, filed Oct. 11, 2002, the disclosures of which are expressly incorporated herein by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to image processing technology suitable for shooting games.
[0004] 2. Description of the Related Art
[0005] Japanese Patent Application Laid-Open No. H11-86038 discloses image processing technology for shooting games using computer graphics. In such shooting games, while a status of a player-character which the player operates, and an enemy-character, which is the target of the shooting of the player who shoot at each other are displayed as an image viewed from a:predetermined viewpoint on a screen, a shooting game is performed, but in image processing, if the shooting input is detected in a status where the shooting target and the coordinates of the aiming position match in a frame the image of the shooting target being shot at is written in the frame memory, and this is converted into video signals and displayed as an image in the next frame, so the status of the bullet flying is not displayed on the screen, only the flying locus of the bullet is temporarily displayed.
[0006] In the above image processing, however, the flying time of the bullet is virtually so if the player-character is fired at by an enemy character, the player-character is always shot at and cannot avoid the bullet as long as the player-character and the aim match. Particularly in the case of a beginner whose skill level is not high, the game ends in a short time, so improvements that players do not become bored are necessary.
SUMMARY OF THE INVENTION
[0007] With the foregoing in view, it is an object of the present invention to provide an image processing technology suitable for shooting games.
[0008] To solve the above problem, the computer program product of the present invention is a computer program product where a player-character, who virtually fires bullets responding to the input operation of a player, and an enemy-character, who is computer-controlled to virtually fire bullets at the player-character, are disposed in a virtual space, and a computer program for causing a computer system to execute processing for displaying a status in the virtual space viewed from a virtual viewpoint on a screen is recorded in a computer-readable recording medium, wherein the computer program causes this computer system to determine whether a visual effects request for requesting visual effects processing was input by a player, and if the visual effects request was input, the computer program causes the computer system to execute image display processing with visual effects such that the display speed of at least the enemy-character and each one of the bullets fired from the enemy-character becomes slower than the display speed of the object displayed in association with the player operation, causes the computer system to determine whether at least one of the enemy-characters to be the shooting target and the bullet fired from the enemy-character will collide with the moving locus of the bullet fired from the player-character, and if the shooting target will collide with the moving locus of the bullet fired from the player-character, the computer program causes the computer system to display the image of the shooting target being shot at on the screen, and displays the progress amount of the remaining time when image display processing with visual effects can be executed on the screen.
[0009] According to the present invention, the player voluntarily requests visual effects processing on the condition that the enemy-character transits to bullet firing wait status, then the enemy-character and the bullet fired from this enemy character are slowly regenerated, therefore the player can shoot aiming at the enemy character or at this bullet with extra time, which makes a shooting game more exciting.
[0010] In the computer program product-of the present invention, the computer program causes the computer system to determine whether processing transits to bullet fire wait status where a bullet is fired from the enemy-character to the player-character at least within a predetermined time, and if processing transits to the bullet fire wait status, the computer program causes the computer system to determine whether a player input the visual effects request
[0011] In the computer program product of the present invention, the computer program causes the computer system to measure the elapsed time amount at which image display processing with visual effects is not executed; and increase the remaining time according to the elapsed time amount. By this, time when the visual effects processing can be executed can be increased, so a shooting game can be more exciting.
[0012] In the computer program product of the present invention, the computer program causes the computer system to determine whether the mode is a mode where two or more players play, and update the remaining time so that the increasing amount of remaining time, when it is determined that the mode is a mode where two or more players play, becomes different from the increasing amount of remaining time in a mode where one player plays. By this, time when the visual effects processing can be executed can be adjusted according to the play mode, so a shooting game can be more exciting.
[0013] In the computer program product of the present invention, the computer program causes the computer system to determine whether the image display processing with visual effects is being executed, and if determined that the image display processing with visual effects is being executed, the computer program causes the computer system to execute image effects processing for changing the display mode visually before end after the image display processing with visual effects is executed for at least the enemy-character. By executing the image effects processing so that the display mode of the enemy-character is changed before and after the visual effects processing, a shooting game can be more exciting.
[0014] It is preferable that the visual effects request input is a control signal which is output to the computer system when a foot pedal, connected to the computer system, is stepped on by a player. In a shooting game, manual input is normally used, but by controlling input using the foot, a player can focus only on manual input for shooting.
[0015] For the computer readable recording-medium, an optical recording medium an optical recording media where data can be optically read, such as CD-RAM, CD-ROM, OVDRAM, DVO-ROM, OVD-R, PO disk, MD disk and MO disk), a magnetic recording medium (a recording medium where data can be magnetically read, such as a flexible disk, magnetic card and magnetic tape), or a portable recording medium, such as a memory cartridge comprising a memory element (a semiconductor memory element such as DRAM, a ferroelectric memory element such as FRAM), are preferable.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a block diagram depicting the hardware of a game machine according to the present embodiment;
[0017] FIG. 2 is a diagram depicting the moving vector of an object;
[0018] FIG. 3 is a flow chart depicting the procedure of visual effects processing of the present embodiment; table;
[0019] FIG. 4 is a table showing the registration content of a time scale conversion
[0020] FIG. 5 is a diagram depicting the-game screen in a-shooting game; and
[0021] FIG. 6 is a diagram depicting the game screen in a shooting game.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings.
[0023] FIG. 1 is a block diagram depicting the hardware of a game machine according to the present embodiment As FIG. 1 shows, to the game-machine 10 , gun type controllers 20 and 21 and foot pedals 22 and 23 as the input means for the player to control the game, a video monitor (CRT display) 24 as the image display means for displaying the game, and a speaker 25 as the sound output means for outputting sound effects, are connected respectively. The gun type controller 20 and the foot pedal 22 are the means for player A to control input, and the gun type controller 21 and the foot pedal 23 are the means for player B to control input. In other words, in a same virtual space, two players can execute a shooting game simultaneously. The present embodiment shows the system configuration for two players as an example, but the system is not limited to this, but is designed such that a plurality of players can play by adding gun type controllers.
[0024] Gun type controllers 20 and 21 are controllers which have such an appearance as a machine gun, pistol, rifle and shot gun, and comprise trigger switches 208 and 21 a for the player to instruct firing bullets, and infrared emitters 20 b and 21 b for emitting infrared radially. By the input operation of the trigger switches 20 a and 21 a, infrared is emitted from the infrared emitters 20 b and 21 b to the video monitor 24 . On the video monitor 24 , a plurality of light receiving sensors 24 a are disposed surrounding the frame of the screen 24 b, and the sensor output of the light receiving sensor 24 a is written to the input/output interface 11 . The input signals (trigger control signals) of the trigger switches 20 a and 21 a by the player are output to the input/output interface 11 in the game machine 10 . Foot pedals 22 and 23 , on the other hand, are input means for the player to execute foot input for the main CPU 12 to execute the later mentioned visual effects processing, and if it is detected that foot pedals are pressed down with a predetermined stepping amount, a foot input signal is output to the input/output interface 11 . The visual effects processing will be described in detail later.
[0025] The game machine 10 is -comprised of an -input/output-interface 1 - 1 ; main CPU 12 , ROM 13 , work RAM 14 , video processor 15 , frame memory 16 , D/A converter 17 , sound processor 18 and sound memory 19 . The input/output interface 11 determines the aiming position of the player, the presence of a fired bullet, and the number of fired bullets from the sensor output signals and the trigger control signals of the light receiving sensor 24 a, and writes the corresponding flag to a predetermined address in the work RAM 14 . The work RAM 14 is a random access memory which functions as a work area for the main CPU 12 to execute various operations for game processing. In the ROM 13 , a game program 13 a, polygon data 13 b, geographic data 13 c and time scale conversion table 13 d are stored respectively. When the system is started up, the game program 13 a, loaded in the work RAM 14 , is command-interpreted and executed by the main CPU 12 , and game processing is executed.
[0026] The polygon data 13 b is a data group of the relative coordinates or the absolute coordinates of each vertex of a plurality of polygons constituting various objects (e.g. characters and game backgrounds) to be displayed on the game screen. The geographic data 13 c, where a virtual viewpoint moves in the virtual space according to developments of the game, is a data group of relative coordinates or absolute coordinates of each vertex of polygons, which have relatively rough settings, required for displaying a desired game screen. The time scale conversion table 13 d is a table where the values of the time scale of all the objects displayed on the game screen are stored, and are set such that the time scale of a predetermined object is changed at the later mentioned visual effects processing. Here the time scale is a multiplication coefficient of a moving vector (or moving amount) of an object in one frame unit, and is normally set to 1.0.
[0027] For determining the contact of the aiming and the shooting target, it is determined which position on the two-dimensional coordinates that a player is aiming at by the sensor output signal of the light receiving sensor 24 a, then the two-dimensional coordinates are converted into three-dimensional coordinates, and a bullet is virtually fired in the depth direction. If the later mentioned visual effects processing is not executed, the image of the target being shot at is displayed at the aiming position, and the status of the bullet flying is not displayed, but if the visual effects processing is executed, the status of the bullet flying is written in the frame memory 16 for several frames, and the flying bullet is displayed on the video monitor 24 for a predetermined time.
[0028] In the above description, a light receiving sensor 24 a is disposed on the video monitor 24 , and the aiming position of a player is judged from the output signal of this sensor, but the present invention is not limited to this, and it is acceptable that a plurality of infrared light emitting elements, instead of the light receiving sensor 24 a, are disposed on the video monitor 24 , lights emitted from the light emitting elements are detected by the light receiving sensor disposed in a gun type controller, and the aiming position of the player is determined according to the received light intensity from each infrared light emitting element.
[0029] FIG. 2 is a diagram depicting the moving vector of an object. In FIG. 2 , if it is assumed that the position vector of an object at the nth frame is pos, the position vector of an object at the (n+1) the frame is next_pos, and the moving vector of an object is spd*time_ratio, then next_pos=pos+spd’*time_ratio is established. Here spd is a moving speed (moving amount for each frame) of an object, and time_ratio is a time scale. When the visual effects processing, such as slow regeneration, is executed, the moving speed of the object can be set to 1/n of normal speed by changing the time scale from 1.0 to 1/n (h:n). In the time scale conversion table 13 d, an object for which the time scale is changed when the visual effects processing, such as slow regeneration, is executed and the corresponding time scale of the object before and after time scale conversion, are stored in advance.
[0030] FIG. 4 shows the content of the data registered in the time scale conversion table 13 d, where the time scale of an enemy-character and the bullet fired by this enemy-character are registered respectively. Here the time scale before conversion is 1.0 and the time scale after conversion is 1/n.
[0031] The main CPU 12 reads the polygon data 13 b, geographic data 13 c and time scale conversion table 13 d based on the game program 13 a, determines the coordinate value of each object in the world coordinate system based on the control signal from such input means as the gun type controllers 20 and 21 , and converts this coordinate value into the visual field coordinate system in a conversion matrix. The video processor 15 pastes texture to the object converted into the visual coordinate system, and writes the drawing data to be displayed in the (n−1)th frame in the frame. memory 16 , and also reads the drawing data to be displayed in the nth frame from the frame memory 16 by double buffering, performs D/A conversion by the D/A converter 17 , and displays the computer graphics image on the video monitor 24 . The sound processor 18 , on the other hand, writes digital sound data to the sound memory 19 so as to output sound corresponding to the game scene, and reads this, performs D/A conversion, and outputs such sound as sound effects via the speaker 25 .
[0032] FIG. 5 shows a screen example in the shooting game, In FIG. 5 , 31 a, 31 b and 31 c are enemy-characters, 32 a, 32 b and 32 c are lock on cursors, 33 is the slow gauge, 34 is the remaining number of bullets that a player can fire, 35 is an icon to display weapons that can be selected, and 36 is the score that a player amassed. In the virtual space, a player character operated by the player is disposed in addition to the enemy-characters 31 a, 31 b and 31 c shown in FIG. 5 , and an image viewed from a predetermined -virtual-viewpoint-is-displayed ‘on-the-video-monitor: 24 as a game-screen, In this case, the virtual viewpoint is set near the head of the player-character, and an image viewed from the viewpoint of the player-character (subjective viewpoint) is displayed, but the image is not limited to this, and an image viewed from an objective viewpoint, where both the player-character and the enemy-characters 31 a, 31 b and 31 c are displayed on the game screen, may be displayed (this is the same for the later mentioned description in FIG. 6 ). In this case, as FIG. 5 shows, an image viewed from the subjective viewpoint of the player-character is displayed,
[0033] The enemy-characters 31 a, 31 b and 31 c are programmed so as to fire bullets at the player-character according to a predetermined attack pattern based on computer control. Each one of the lock on cursors 32 a, 32 b and 32 c is a cursor which moves tracking each enemy-character 31 a, 31 b and 31 c respectively, and the firing of a bullet from an enemy character 31 a, 31 b or 31 c is shown to the player by changing the color from green (indicated by a dotted line) to red (indicated by a solid line). The present invention can be applied even if the lock on cursors 328 , 32 b and 32 c are not displayed. The slow gauge 33 will be described in detail later. In the example shown in FIG. 5 , the lock on cursor 32 a which is locked to the enemy-character 31 a is displayed in green, but the lock on cursors 32 b and 32 c locked to the enemy characters 31 b and 31 c are displayed-in red. If the enemy characters 31 b and 31 c fire bullets here, and if the aim matches with the coordinates of the player-character, the player is instantaneously shot and damaged, without any time to avoid the bullet. This is because it has been programmed such that the image of the player-character being shot is displayed in a frame next to the frame where the enemy characters 31 b and 31 c fired the bullets.
[0034] Therefore in the present invention, the visual effects processing is performed on the game screen under predetermined conditions (hereafter called •visual effects processing-enable-conditions”) to provide the player extra time to avoid a bullet. The visual effects processing enable conditions are conditions to be prerequisites to perform the visual effects processing on the game screen, and, for example, these conditions are met when the status transits to the status where an attack from the enemy-character 31 starts, that is when the status transits to the bullet firing wait status, such as when the green color of the lock on cursor 32 changes to red. The main CPU 12 sets the visual effects processing enable flag to u1 G in the work RAM 14 when the visual effects processing enable conditions are established (when the status transits to the bullet firing wait status). The visual effects processing is when, for example, when slow regeneration processing is performed only for the enemy-character 31 and the bullet by changing the time scale of the enemy-character 31 and the bullet fired by the enemy-character 31 to 1/n. By such visual effects processing, the operation speed of the player-character can be virtually quickened. In other words, the moving speed of the enemy-character and the bullet thereof become 1/n that of the player-character, so the player can avoid the bullet with sufficient extra time, and also the player can blast the bullet by aiming at this bullet. For the value of n, n=10 for example is preferable.
[0035] FIG. 6 shows a screen example of s shooting game when the visual effects processing of-the present embodiment is performed. Identical reference numerals as FIG. 5 indicate identical composing elements for which detailed explanations are omitted. When the lock on cursors 32 b and 32 c, locking the enemy characters 31 b and 31 c, turn from green to red, the visual effects processing enable conditions are established. Then shortly after this, the bullets 40 a and 40 b are fired from the enemy-characters 31 b and 31 c. If the player inputs a visual effects request when the visual effects processing enable conditions are established, the main CPU 12 generates a game screen where the visual effects processing is performed, so the player performs the desired processing such as changing of the time scale. For the visual effects request input, a control signal, when the player inputs by stepping on the foot pedals 22 and 23 , for example, is preferable. This foot control signal is output to the input/output interface 11 and is detected by the main CPU 12 . However the visual effects request is not limited to foot pedals, but may be the input control of a switch for a visual effects request input, which is disposed on the gun type controllers 20 and 21 . Also the visual effects request may be the input control of a switch for slow regeneration, which is disposed on the body of the game machine 10 , without using the gun type controller. When the visual effects request input from the player is detected, the main CPU 12 converts the time scale for a predetermined object (the enemy-character 31 and bullet 40 in this case), and performs slow regeneration processing.
[0036] Then the bullets 40 a and 40 b, which have not been visually displayed, are displayed on the game screen in slow regeneration. In this case, many lines 60 , which are like after images extending from the edge of the screen to an area roughly at the center, are displayed, which is image effects processing as if the player-character were virtually moving at high-speed. By this, the player can experience the sensation-as if they were moving at high speed, and can avoid the bullets 40 a and 40 b with the extra time, since the moving speed of the enemy-characters 31 b and 31 c and the bullets 40 a and 40 b is slow, and the player also can blast the bullets 40 a and 40 b by adjusting the orientation of the gun type controllers 20 and 21 , pulling the trigger switches 20 a and 21 a with aligning the aiming cursors SOa and SOb at the bullets 40 a and 40 b. Here the aiming cursor 50 a is an aiming cursor of the player A, and the aiming cursor 50 b is the aiming cursor of the player B. The blast processing of the bullet 40 by the aiming cursors 50 a and 50 b can be performed with a normal operation :time. In other words, the-time from the player executing the bullet firing operation to the bullet reaching the shooting target, the time from the player selecting a weapon displayed at the icon 35 to the weapon being displayed on the screen in response to the selection, and the display speed of an object related to player operation, such as the moving time of the aiming cursors SOa and SOb, are based on the normal display speed before the visual effects processing is executed. The slow gauge 33 is for indicating the progress of time when slow regeneration processing, as the visual effects processing, can be executed, which is designed such that the value of the gauge decreases as the time for executing the visual effects processing elapses, and the visual effects processing cannot be executed as game processing if this value becomes 0. As FIG. 6 shows, the display of the slow gauge 33 is enlarged on screen while visual effects processing is being executed, where the remaining time, when the visual effects processing can be executed, is indicated for the player.
[0037] FIG. 3 is a flow chart depicting the procedure of the visual effects processing executed by the main CPU 12 . At first, the main CPU 12 monitors the work RAM 14 and checks whether “1” is set at the visual effects processing enable flag (step S 1 ). If it is detected that “1” is set at the visual effects processing enable flag (step 81 : YES), the main CPU 12 checks whether the foot pedals 22 and 23 are stepped on, and the foot input signal is detected (step S 2 ). If the stamp input signal is detected (step S 2 : YES), the main CPU 12 changes the time scale of a predetermined character (enemy-character 31 and bullet 40 in this case) to 1/n (step S 3 ), and executes the visual effects processing based on slow regeneration (step S 4 ). And if the time, when the visual effects processing can be executed in a status where the foot pedals 22 and 23 are stepped on, has elapsed (step S 5 : YES), the main CPU 12 returns the time scale of the above mentioned predetermined character to the original value (that is, time_ratio=1.0) (step S 6 ), and sets the visual effects processing enable flag to “0” (step S 7 ); This may be constructed such•that the time scale of-the above mentioned predetermined character is returned to the original value in the stage when the player releases their foot from the foot pedals 22 and 23 , regardless the processing in step S 5 .
[0038] While the visual effects processing is performed, slow regeneration processing is executed only for the objects related to the enemy-character 31 , and the speed of the player-character and the objects related to the operation of the player-character, such as the speed of the value of the slow gauge 33 decreasing, the speed of the remaining number of bullets 34 decreasing, the speed of the display mode of the icon 35 , and the speed of the increasing/decreasing speed of the number of points of the acquired score 36 , are at normal speed, for which it is programmed such that slow regeneration processing cannot be executed. In the above description, the moving speed of the enemy-character 31 and the bullet 40 fired by this enemy-character 31 are set to 1/n, and the moving speed of the objects related to the player's operation is maintained at 1.0, but the present invention is not limited to this, and it may be constructed such that the moving speed of the enemy-character 31 and the bullet 40 fired by the enemy-character 31 is set to 1/n, and the moving speed of the objects related to the player's operation are set to 11 m using n and m which relationship is n>-m→1. In other words, the-objects-related-to the player operation is also displayed somewhat slower, but the moving speed of the enemy-character 31 and the bullet 40 is regenerated slower than this.
[0039] When the duration of the visual effects processing exceeds a predetermined value, the value of the slow gauge 33 becomes 0, and visual effects processing can no longer be executed, but it may be constructed such that the value of the slow gauge 33 . is increased according to the duration in normal operation status, where the visual effects processing is not performed. In this case, it can be programmed •such that the maximum value of the slow gauge:• 33 is, 6000 points (10 seconds if converted into time), and after a predetermined time (e.g. 2 seconds) has elapsed since the value of the slow gauge 33 becomes 0, the value of the slow gauge 33 is increased at every 2 paints for 5 frames. If constructed in this way, the value of the slow gauge 33 recovers, so the player can use the visual effects processing again. In the case of the two player play mode, the recovery points of the slow gauge 33 may be set to be different from the recovery points of the one player play mode. It also may be constructed such that for the recovery processing of the slow gauge 33 , a predetermined number of points (e.g. 4 points) are recovered if a bullet is fired at the enemy-character 31 , a predetermined number of points (e.g. 8 points) are recovered if the enemy-character 31 is shot, a predetermined number of points (e.g. 1200 points) are recovered if a vital point of the enemy-character 31 is shot, and a predetermined number of paints (e.g. 20 points) are recovered if the enemy-character 31 is hit continuously two or more times. In this way, according to the present embodiment, only the enemy-character 31 and the bullet 40 are slow-regenerated by the player stepping on the foot pedals 22 and 23 when the visual effects processing enable conditions are established, so even a player whose game control is-not very good can avoid the-bullet 40 , which allows implementing a shooting game that is not boring. If the player has an advanced skill level, the bullet 40 can be aimed at and blasted while the bullet 40 fired from the enemy-character 31 is slow-regenerated, so a more exciting shooting game can be provided. In the present embodiment, an example when the player-character and the enemy-character fight each other was shown, but the present invention is not limited to this, but can be applied, for example, to a shooting game where an object simulating a fighter aircraft or a combat vehicle are operated. | An object of the present invention is to propose image processing technology whereby even a player with a low skill level can enjoy a shooting game with more, excitement. To achieve this object. according to the present invention; if a player outputs a slow regeneration request signal when processing transits to the status where an enemy-character is about to fire a bullet, the enemy-character and the bullet fired by the enemy-character are regenerated slowly. By this, the player can aim at the bullet with extra time. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 61/354,696 filed on Jun. 14, 2010. This application is hereby incorporated by reference in its entireties for all of its teachings.
FIELD OF INVENTION
[0002] The present invention is generally directed to an article of manufacture for use in conjunction with beverage cups of type having a smooth cylindrical surface or tapered sidewall and no handle. The present invention is directed to an insulating sleeve having an insert that is customizable for personal use. More particularly, the present invention is directed to reusable insulating sleeve and an insert to securely fit around a beverage cup such that the sleeve and the insert insulates the user's hand against temperature differences from the beverage of choice and assists the user in firmly grasping and handling the cup.
BACKGROUND
[0003] Conventional disposable cups, of formed paperboard or an appropriate food-compatible synthetic resin or plastic, are normally of a thin wall construction with a strength little more than that required to contain the beverage for which the cup is designed. Such cups are for the most part sufficient for their intended purposes, and require a minimal amount of material resulting in cost advantages.
[0004] However, to overcome these deficiencies and to further protect the user, some use loose jacket paper holders, that are made of corrugated paper to provide insulation. Further, they can be used only once and they have to be disposed. In order to reduce waste a better solution needs to be proposed.
SUMMARY
[0005] The present disclosure provides an insulated protective sleeve which can be readily slipped onto the outside surface of a conventional tapered hot drink cup and which is effective to insulate the fingers of the user from the heat and cold of the content.
[0006] In one embodiment, the cup holder is made of a surface A and surface B. In another embodiment, surface A has two sheets that are sealed together. In another embodiment, the two sheets enclose a third sheet before they are sealed together. In another embodiment, two sets of first sheet and second sheet enclosing a third sheet are sealed together at the edges to form a cup holder.
[0007] In one embodiment, a synthetic material is used as first sheet and second sheet. In another embodiment, a thermal insulating material is used as a third sheet.
[0008] In another embodiment, the sleeve is folded in a flat configuration, using little space. The structure allows easy unfolding and quick attachment to a cup, thereby reducing the possibility of spilling the contents of the cup.
[0009] In one embodiment, the user, by writing on the sleeve, is able to customize their preference, name and order on the sleeve. The user can indicate his drink preference by writing on the insert. The user can write their name for the order and the service provider can be efficient to serve in a short time as he does not have to write the drink preference or the customer name.
[0010] The insert is also made of insulating material, which would provide additional layer of insulation with the sleeve. The insert can be made of colored material and preprinted with service provider specific logo. In another embodiment the sleeve may be customizable with different non transparent colored material.
[0011] In another embodiment, the sleeve may be transparent to show the logo or the writing of the insert.
[0012] In another embodiment, the surface A and surface B may be heat sealed at the edges. Edges of the sleeve may be closed at the ends with no openings, hence offered as a one piece product. In another embodiment, the insulating sleeve can be tapered or be uniform to fit the cup snugly and enables the user to comfortably grasp and hold the cup for use.
[0013] In one embodiment, surface B may have specific area for printing and/or writing personal name, a logo, product preference; request a barcode to indicate the preferences, a sensor for payment. In another embodiment, the sensor may be used for at least one of the following functions such as uploading the preference to preorder via internet, communicate with the store window to print a slip, make payment and a talking sign for hearing impaired, visually impaired and/or both to communicate their order with the store personnel.
[0014] The product and method of making the product disclosed herein may be implemented in any means for achieving various aspects. Other features will be apparent from the accompanying drawings and from the detailed description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Example embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings, in which like references indicate similar elements and in which:
[0016] FIG. 1 is a view of the sleeve and the insert as a cup holder.
[0017] FIG. 2 is a view of the surface A design on the sleeve showing a print area for a logo.
[0018] FIGS. 3A and 3B is a view of the surface B area with various areas for printing and/or writing on the sleeve.
[0019] FIG. 4 illustrates a diagrammatic view of using the sleeve with the cup.
[0020] FIG. 5 is a diagrammatic view illustrating different sheets and their configuration to form a sleeve according to one embodiment.
[0021] FIG. 5B shows a magnetic strip being implanted between the sheets for being used for various activities.
DETAILED DESCRIPTION
[0022] The present invention is directed to an insulating sleeve having an insert that is customizable for personal use and re-use. Although the present embodiments have been described with reference to specific example embodiments, it will be evident that various modifications and changes may be made to these embodiments without departing from the broader spirit and scope of the various embodiments.
[0023] FIG. 1 is a representation of a sleeve 120 to be used as a cup holder and insulate an individuals hand from hot and cold temperature of the contents of the cup. The sleeve 120 comprises of a surface “A” 110 and a surface “B” 112 . The sleeve 120 is larger than the insert 130 . The insert 130 can be placed into the sleeve 120 . The sleeve 120 can be wrapped around a cup to insulate the users from temperature variances. The sleeve 120 has a surface A 110 and surface B 112 that are heat sealed on right side 122 and left side 126 to form a union of the surface A 110 and surface B 112 . The bottom side 124 and the top side 128 are sealed individually to create an opening for the sleeve 120 to be placed around the cup.
[0024] As shown in FIG. 2 , in surface A design 200 , the sleeve 120 has a specific area for logo 210 . The logo may be imprinted, embossed and/or pasted on to surface A 110 . Surface A may be made up of transparent material and the logo 210 may be visible that has been printed on the inside insert 130 . The surface A and B may be made up of vinyl material or any flexible material that is pliable, soft and easy to grip.
[0025] As shown in FIG. 3A , the surface B design 300 A has specific areas to write a personal name 310 , to write a product preference 312 and for a request 318 that could indicate a specific request. In FIG. 3B it shows that there may be additional area wherein a sensor 320 may be placed that would enable the user to place orders and/or make payments. The surface B may also have a speaker 324 area attached to it for enabling personnel to communicate with a provider of goods. It may have an amplifier or a translator as well.
[0026] The sleeve 120 can be used to surround a cup 410 , as shown in FIG. 4 , to prevent the user from getting injured from thermal differences between the body and the cup 410 . The sleeve 120 may be adjusted up or down to fit the contour of the cup 410 . The sleeve may be reused as it is made of reusable material and will reduce waste production. It can be used as a personal or promotional item and companies may promote their brand by providing logos to be printed in area logo 210 .
[0027] FIG. 5 shows a view of the sleeve 120 . The sleeve 120 is made of dual layer material and has two surfaces, surface A 110 and surface B 112 . Both the surfaces are parallel to each other and are bound on two sides. The sealing of the edges can be done by contiguous manufacturing in one embodiment, heat sealed or glued. The bonding enables the surface A 110 and surface B 112 to form a opening and accommodate the cup 410 within the opening.
[0028] The sleeve 120 may be made of transparent material in one embodiment. The transparent and/or opaque material may be temperature resistant, humidity resistant, slip resistant, and stain resistant. In one embodiment the material for the first sheet, the second sheet and third sheet may be biodegradable, plastic, nylon, polymers, vinyl, styrofoam and/or card board. The material may be rigid or elastic. For example, if the cup size is different elastic material would enable a user to expand the sleeve 120 to wrap around the cup 410 and hold it safely.
[0029] In one embodiment the sleeve may be semi-transparent or opaque on both surface A 110 and surface B 112 of the sleeve. In another embodiment it can be transparent on surface A 110 and semi-transparent on surface B 112 . In another embodiment surface A 110 can be transparent and surface B 112 can be opaque.
[0030] In another embodiment, the sleeve is made of unitary piece of insulated material. Yet another embodiment, the insulating sleeve is unitary, seamless and transparent in nature such that indicia and graphics on the insert may be viewed through the sleeve. The shape of the sleeve 120 may be such that it is convenient to wrap it around a cup 410 of any size.
[0031] In FIG. 5 , the sleeve 120 parts are shown in greater detail. The third sheet 512 is smaller in size than the first sheet 510 and second sheet 514 . The smaller size makes it easy to place it in between the first and second sheets. The sealing of the edges comprising of the first sheet and the second sheet is convenient and stronger. The third sheet 512 can be made of a thin material or a thicker material to provide extra insulation to the user from thermal variations of the content of the cup 410 . The edges A 1 and A 2 , B 1 and B 2 , C 1 and C 2 and D 1 and D 2 are sealed together to form an edge. A first pair of first sheet and second sheet form surface A and second pair of first sheet and the second sheet form surface B and both pairs have a third sheet between the first sheet and the second sheet to provide insulation.
[0032] The insert 130 may be made of iridescent material or plain colored material. It may have a magnetic strip or any other means for payment, as shown in FIG. 3B . The strip may be pre-programmed to contain the user product preference 312 , personal name 310 and request 318 . A provision for a prepaid card to be installed inside the first surface and the second surface may be made as well. The payment mode may be enabled to be recharged using internet type of mode.
[0033] The service provider can preprint their logo 210 or sell blank sleeves to users with or without the logo 210 . The logo may be placed by at least one of printing, embossing, drawing and hand crafting. The third sheet 512 can be made of foam material to provide comfort and insulation. The light button may be placed underneath each preference and may be activated to display the product preference 312 or request 318 for the service provider by the user. The color code 330 may be press activated to create a color of choice. All the areas such as request 318 , product preference 312 , and the bar code 322 may be made of the same material for color coded information display.
[0034] The surface of the sleeve 120 may be smooth, rough or raised. For example, the rough surface may prevent it from slipping.
[0035] In addition, it will be appreciated that the various embodiments, materials, and shapes can be interchangeable used in the current embodiments and various combinations of the cup and the cup holder may be possible. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense. | A sleeve containing an insert forming a cup holder is described. The inserts are placed in the sleeve. The sleeve is customizable by varying the color, writing and bar coding. The individual business may also display their logo on the sleeve or insert. These cup holders are personal to the user and can be repeatedly used. This enables the individual business to save money. The sleeve and insert as cup holder can be made up of recyclable material. The user may use a device implanted on or in a sleeve to pay and/or order the product using the sleeve. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIOINS
[0001] This application is a continuation of U.S. patent application Ser. No. 09/546,041 filed on Apr. 10, 2000, now abandoned, which is a continuation in part of U.S. patent application Ser. No. 09/266,953 filed Mar. 12, 1999, now abandoned, which is a continuation of U.S. patent application Ser. No. 08/781,779 filed Jan. 9, 1997, now U.S. Pat. No. 5,916,175 issued Jun. 29, 1999.
FIELD OF THE INVENTION
[0002] The invention relates to a device for tissue removal in biopsy procedures. In particular, the invention relates to a manually operated biopsy device containing an adjustable biopsy needle.
BACKGROUND OF THE INVENTION
[0003] Biopsy needle devices with handpieces containing an actuating apparatus which activates the motion of a biopsy needle are known. For example, U.S. Pat. No. 4,958,625 to Bates et al. discloses a biopsy device containing a handpiece and stylet which projects independently of a cannula and wherein the handpiece contains an attachment means for the cannula. The insertion guide used in such systems includes a cannula guide made up of a hollow small tube in which the proximal end bears a trigger, and is equipped with an attachment means, as well as a luer lock for a syringe to introduce a medicament to the site after tissue removal.
[0004] Procedures using actuated biopsy needles typically involve first inserting the biopsy needle and cannula insertion guide into the patient's body by positioning the distal end of the needle in proximity to the object to be sampled. Upon determining the desired position by magnetic resonance (CAT scan) or other technique, the stylet and cannula cutting edge are sequentially activated to obtain the sample. Once the sampling step has been performed, the attachment means are released and the biopsy needle withdrawn from the cannula insertion guide to check the sample. If the sample is incorrect or otherwise insufficient, a new biopsy needle is inserted into the cannula insertion guide and the sampling sequence is repeated. After obtaining the desired sample, a medicament can be administered to the site by applying a syringe to the insertion guide.
[0005] One disadvantage of such systems is that variation or adjustments of sample length and needle cutting stroke are not feasible, since the stylet or cannula cutting edge are not adapted to adjust feed stroke beyond the tip of the insertion guide. Control of biopsy procedures is important when the tissue to be sampled is in proximity to vital organs or bones and positioning of the insertion guide or biopsy needle is such that the feed stroke of the stylet and cannula-cutting edge can potentially further damage the vital tissues, organs or bone.
[0006] There is a need in the biopsy device field for devices having improved control capabilities to permit the practitioner to avoid unnecessary tissue damage as well as obtain tissue samples with more specific parameters.
SUMMARY OF THE INVENTION
[0007] The invention disclosed is an adjustable biopsy device having the ability to vary the size of the sample to be removed. The biopsy device includes biopsy needle assembly and cannula insertion guide co-axially aligned therewith such that longitudinal adjustment of the cannula insertion guide likewise adjusts the exposure of the stylet and cutting edge of the biopsy needle assembly thereby changing the size of the resulting sample. The cannula insertion guide is connected to the housing of the device through a longitudinal adjusting element. The invention is particularly useful in biopsy procedures where improved control over sample size and cutting stroke are desirable.
[0008] The biopsy device generally contains a biopsy needle assembly, a housing having a control device for operation of the biopsy needle assembly therein, a cannula insertion guide co-axially aligned with and accommodating a portion of the biopsy needle assembly, and a longitudinal adjusting element positioned between (and connecting) said housing and insertion guide. The longitudinal adjusting element is adapted to adjust the position of the cannula insertion guide lengthwise relative to the biopsy needle assembly of the device. The housing containing the control device is generally configured as a handpiece and the control device per se is manually operated by the user or practitioner and actuates the biopsy needle assembly therein.
[0009] The biopsy needle assembly extends beyond the distal portion of the housing and includes a perforating stylet having proximal and distal portions which is positioned within a cannula having a cutting edge. The proximal portion of the perforating stylet is coupled to and operates relative to the cannula (and cutting edge) as activated by the control device within the housing. The medial portion of the stylet extends beyond the distal portion of the housing and co-axially through both the longitudinal adjustment element and the cannula insertion guide attached thereto. The distal portion of the stylet is positioned at the distal portion of the cannula insertion guide and contains an indentation (or groove) to accommodate and retain tissue.
[0010] The cannula insertion guide comprises a proximal attachment means adapted for removable attachment to the distal portion of the longitudinal adjustment element and for internal positioning of the biopsy needle assembly of the device. The cannula insertion guide and biopsy needle assembly are configured to operatively interact with one another such that the cannula cutting edge and perforating stylet of the biopsy needle assembly function at the distal tip of the cannula insertion guide. Rapid sequential motion between the stylet and cannula cutting edge beyond the distal tip of the cannula insertion guide severs or cuts the tissue to be sampled. The extent to which the biopsy needle assembly (cannula cutting edge and perforating stylet) extend beyond the distal tip of the cannula insertion guide is controlled by the longitudinal adjusting element of the device.
[0011] The longitudinal adjustment element is positioned between (and connects) the distal portion of the housing and the proximal portion of the cannula insertion guide and contains a lumen adapted for placement of the biopsy needle assembly therein. The longitudinal adjusting element has a proximal portion and distal attachment means, the proximal portion being adapted for engagement with and movement (e.g., rotatable motion) relative to the distal portion of the housing and the distal attachment means being adapted for removable attachment to the proximal attachment means of the cannula insertion guide such that adjustment of the longitudinal adjusting element results in corresponding adjustment of the cannula insertion guide in the same direction. In operation, the adjustment of the cannula insertion guide and corresponding the distal exposure of the biopsy needle assembly controls the degree of exposure of the stylet indentation and thus controls the amount of tissue to be accommodated therein.
[0012] Thus, there is disclosed a biopsy device comprising a biopsy needle assembly having a perforating stylet within a cannula having a cutting edge; a housing having a control device for operation of the biopsy needle assembly; a cannula insertion guide co-axially aligned with and accommodating the biopsy needle assembly and having proximal attachment means; and longitudinal adjusting element positioned between the housing and cannula insertion guide and having a proximal portion and distal attachment means and a lumen adapted for placement of the biopsy needle assembly; wherein the longitudinal adjusting element is adapted to co-axially adjust the position of the cannula insertion guide relative to the biopsy needle assembly of the device.
[0013] In a further embodiment, there is disclosed a biopsy device according to the invention comprising a longitudinal adjusting element adapted for engagement with and rotational movement relative to the housing of the device. In yet another embodiment, there is disclosed a biopsy device according to the invention further comprising an indicator means for indicating position and longitudinal displacement of the cannula insertion guide relative to the housing.
[0014] There is also disclosed a method of obtaining a tissue sample having a pre-deteremined size from a tissue site using a biopsy device according to the invention comprising the steps of inserting and positioning the cannula insertion guide and biopsy needle assembly of the device in proximity to the tissue sampling site; and actuating the biopsy needle assembly to obtain the sample; wherein the sample size is determined prior to actuating the biopsy needle assembly by adjustment of the longitudinal adjusting element of the device.
[0015] The invention also includes a kit for performing biopsy procedures comprising the biopsy device according to the invention.
[0016] Among the advantages of the device according to the invention is that it permits the user or practitioner to vary needle cutting stroke and therefore vary sample size. Another advantage is that a single device can be used to obtain multiple samples of varying sizes. Yet another advantage of the invention is that unnecessary damage of tissues and organs can be avoided as a result of the improved control over the sampling procedure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The invention is further illustrated by the drawings below together with the numerical references which remain consistent throughout:
[0018] [0018]FIG. 1 is an overall perspective view of one embodiment of the assembled device according to the invention.
[0019] [0019]FIG. 1A is a detailed view of one embodiment of the longitudinal adjustment element of the device as positioned in the housing and having indicating means.
[0020] [0020]FIG. 1B is a detailed view of one embodiment of the distal portions of the biopsy needle assembly and cannula insertion guide of the device according to the invention.
[0021] [0021]FIGS. 1C and 1D together schematically depict the adjustment of the biopsy needle assembly of the device relative to the cannula insertion guide which will produce different sample sizes after adjustment of the device.
[0022] [0022]FIG. 2 is a perspective view of one embodiment of the device according to the invention without the cannula insertion guide attached thereto.
[0023] [0023]FIG. 3 is a perspective view of the cannula insertion guide portion of the device.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The biopsy device according to the invention is shown assembled in FIG. 1 and depicted with the cannula insertion guide detached in FIG. 2, the cannula insertion guide shown separately in FIG. 3.
[0025] In general, the biopsy device 30 includes a housing 1 containing a control device (not shown) for operating the biopsy needle assembly (which contains the perforating stylet 2 positioned within a cannula with cutting edge 3 ), a cannula insertion guide 20 , and longitudinal adjusting element 6 positioned between the distal portion 4 of the housing 1 and the proximal portion 23 of the cannula insertion guide 20 .
[0026] The stylet of the biopsy needle assembly of the device contains an indentation (or groove) located near the distal portion of the stylet proximal to the tip 2 which permits encroachment of the tissue to be sampled when the biopsy needle portion is positioned in proximity to the tissue to be sampled. Typically, the stylet contains a tip configuration which facilitates perforation or piercing through tissue to reach the site. Referring now to FIG. 1B, the distal tip of the stylet 2 is shown in an extended position with the stylet indentation fully exposed beyond both the cannula cutting edge 3 and distal portion of the cannula insertion guide 20 .
[0027] The control device (not shown) for operation of said biopsy needle assembly can comprise any suitable manually operated actuating mechanism adapted to co-axially, sequentially and rapidly move or displace the stylet relative to the cannula cutting edge. For example, a spring-loaded assembly with a trigger mechanism can be used.
[0028] As can be seen in FIG. 3, the cannula insertion guide 20 includes a cylindrical hollow cannula 21 having proximal and distal ends, 23 and 22 respectively, and is adapted for co-axial alignment and internal accommodation and placement of the biopsy needle assembly of the device. The proximal portion 23 of the cannula insertion guide 20 can be of any suitable configuration or structure provided it includes a proximal attachment means. In a preferred embodiment, the proximal attachment means of the cannula insertion guide is a removable attachment means, i.e., one which can be reversibly detached from and mechanically compatible with the corresponding attachment means positioned on the longitudinal adjusting element 6 . In one embodiment and as shown in the figures, the proximal portion 23 of the cannula insertion guide 20 comprises a tang 24 and attachment means in the form of a twist lock component 25 adapted for engagement with the corresponding receiving component of the distal attachment means 9 located on the longitudinal adjusting element 6 of the device.
[0029] Various attachment systems can be used in accordance with the invention to couple the cannula insertion guide to the longitudinal adjusting element provided they together enable continuity of placement for the biopsy needle assembly therethrough. Examples of suitable attachment systems include, but are not limited to, a luer lock assembly, superimposed fitting components, channel and groove, screw-type assembly, and the like.
[0030] The longitudinal adjusting element 6 of the device is positioned between the distal portion 4 of the housing 1 and proximal portion 23 of the cannula insertion guide 20 and includes proximal portion and distal attachment means 9 and a lumen (not shown) adapted for placement of the biopsy needle assembly. The longitudinal adjusting element 6 is adapted to co-axially adjust the position of the cannula insertion guide 20 relative to the biopsy needle assembly of the device.
[0031] The longitudinal adjusting element and distal portion of the housing can be configured in a variety of ways to accomplish the same result provided the longitudinal adjusting element can be incrementally and controllably adjusted in a preecise manner. In a preferred embodiment and as shown in the figures, the longitudinal adjusting element 6 of the device comprises a threaded body 7 adapted for engagement and rotatable movement with a threaded channel 5 located in the distal portion 4 of the housing. In other words, the longitudinal adjusting element can be in the configuration of a screw-like component which adjusts the space between the cannula insertion guide 20 and the housing 1 upon rotation as shown by arrow F 1 in FIG. 1.
[0032] In a further embodiment, the biopsy device of the invention further comprises an indicating means. The indicating means according to the invention can comprise any suitable structure, indicia or combination thereof which indicates the position and longitudinal displacement of the cannula insertion guide relative to the housing in an externally viewable manner. In one embodiment, the indicator means comprises one or a series of calibrated marking(s) on the housing from which to reference a point located on the longitudinal adjusting element of the device. The point located on the longitudinal adjusting element can be the truncated proximal end of the element or, alternatively, a viewable indicia or marking(s) located on the longitudinal adjusting element per se.
[0033] [0033]FIG. 1A illustrates one embodiment of an indicating means according to the invention. In this embodiment, externally viewable calibrated markings 11 are located on the body of the distal portion 4 of the housing 1 and are located proximal to a reading window 10 , which permits a viewable reference to the proximal end of the longitudinal adjusting element 6 . Accordingly, the markings 11 are calibrated to correspond to and measure the distance of the exposed stylet tip 2 beyond the distal end of the cannula 21 of the insertion guide 20 , the practitioner can obtain a precise length of sample in operation.
[0034] [0034]FIGS. 1C and 1D together depict the biopsy needle assembly motion relative to the cannula insertion guide after adjustment of the device. FIG. 1C illustrates a first position of the device wherein the tip of the stylet 2 and indentation have been adjusted to obtain a full length sample. In this depiction, the stylet tip 2 and cannula cutting edge 3 are both extended beyond the distal tip 22 of the cannula 21 of the cannula insertion guide 20 . When positioned within tissue and actuated, the cannula cutting edge 3 stroke will sever and obtain a sample having the size depicted as S 1 .
[0035] [0035]FIG. 1D illustrates the positioning of the distal end 22 of the cannula insertion guide 20 relative to the biopsy needle assembly after adjustment of the longitudinal adjusting element (not shown). Rotational movement of the longitudinal adjusting element with the cannula insertion guide attached thereto (as seen in FIG. 1, for example) in a direction away from the distal portion of the housing incrementally and precisely moves the distal end 22 of the cannula insertion guide 20 over the stylet thereby reducing the exposure of the indentation on the stylet and, thus, reduces the amount of tissue which contacts the stroke of the cutting edge 3 . Accordingly, after insertion and actuation of the device, a sample having a size S 2 is obtained which is smaller in comparison to a sample obtained prior to longitudinal adjustment.
[0036] The invention also includes a method of obtaining a tissue sample having a predetermined size from a tissue site using a biopsy device as described herein comprising the steps of a) inserting and positioning the cannula insertion guide and biopsy needle assembly of the device in proximity to the tissue sampling site, and b) actuating the biopsy needle assembly of the device to obtain a sample, wherein the sample size is determined prior to actuating the biopsy needle assembly by adjustment of the longitudinal adjusting element of the device.
[0037] In use, the practitioner can view the indicator means such as that depicted in FIG. 1A to determine the length of the cutting stroke of the biopsy needle assembly and makes the desired adjustment prior to actuating the device and obtaining the sample. Viewing the indicator means in conjunction with adjusting of the longitudinal adjusting element of the device allows the practitioner to obtain a sample of a particular size and, if circumstances require, avoid more damage than necessary to tissues surrounding the sampling site.
[0038] The components of the device can be made and assembled using various conventional materials, techniques and equipment known in the art. In general, the components of the device can be made from rigid materials such as plastics and metals and metallic alloys. Typically, the housing and some of the components of the control device for the biopsy needle assembly can be composed of plastic, whereas the cannula components and stylet can be composed of metals such as stainless steel. Components such as the longitudinal adjusting element, for example, can be composed of either plastic or metal.
[0039] The invention also includes a kit for performing biopsy procedures comprising the biopsy device according to the invention. In addition to the biopsy device as described herein, the kit can include those instruments and equipment which are typically associated with biopsy procedures. Examples of such instruments and equipment include, but are not limited to, syringes (and needles), local anaesthetics, microscope slides, scalpels, rulers, drapes, swabs, vials, labels, storage solutions, forceps, sponges, bandages, cups and wraps. Packaging or containers which house the biopsy device of the invention along with the other components used in the biopsy kit can also be included.
INDUSTRIAL APPLICABILITY
[0040] The present invention permits practitioners to increase the level of control during biopsy procedures. Accordingly, biopsies can be performed with the lesser extent of tissue damage and damage to surrounding areas as compared to conventional biopsy techniques, and can be performed with more precision in accordance with the practitioner's preferences and the patient's needs. Furthermore, a single device can be used to obtain a multitude of sample sizes.
[0041] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that reasonable variations and modifications are possible from the foregoing disclosure without departing from either the spirit or scope of the present invention as defined by the claims. | The invention relates to a biopsy device having the ability to adjust the size of the sample to be removed. The biopsy device includes biopsy needle assembly and cannula insertion guide co-axially aligned therewith such that longitudinal adjustment of the cannula insertion guide likewise adjusts the exposure of the stylet and cutting edge of the biopsy needle assembly thereby changing the size of the resulting sample. A longitudinal adjusting element is positioned between and connects the cannula insertion guide and housing of the device. The invention is particularly useful in biopsy procedures where improved control over sample size and cutting stroke are desirable. | 0 |
CONTINUING APPLICATION DATA
[0001] This application is a continuation in part of the U.S. Provisional Application No. 60/727,700, having a filing date of Oct. 17, 2005.
NOTICE
[0002] This invention was made with Government support under Grant No. GM47157, awarded by the National Institutes of Health. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to FGF-1 and mutants of FGF-1 affecting the signaling of cellular growth, differentiation, and angiogenesis.
[0005] 2. References
[0006] Various publications are referred to in parentheses throughout this application. Each of these publications is incorporated by reference herein. Complete citations of scientific publications are set forth below, or in the text of the specification.
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(1995) Acidic and basic fibroblast growth factor bind with differing affinity to the same heparan sulfate proteoglycan on BALB/c 3T3 cells: implications for potentiation of growth factor action by heparin. J Cell Biochem, 58, 6-14. Burgess, W. H., Shaheen, A. M., Ravera, M., Jaye, M., Donohue, P. J. and Winkles, J. A. (1990) Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue. J Cell Biol, 111, 2129-2138. Comoglio, P. M., Boccaccio, C. and Trusolino, L. (2003) Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr Opin Cell Biol, 15, 565-571. DiGabriele, A. D., Lax, I., Chen, D. I., Svahn, C. M., Jaye, M., Schlessinger, J. and Hendrickson, W. A. (1998) Structure of a heparin-linked biologically active dimer of fibroblast growth factor. Nature, 393, 812-817. Eliceiri, B. P. (2001) Integrin and growth factor receptor crosstalk. Circ Res, 89, 1104-1110. Friedlander, M., Brooks, P. C., Shaffer, R. W., Kincaid, C. M., Varner, J. A. and Cheresh, D. A. (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science, 270, 1500-1502. Friesel, R. E. and Maciag, T. (1995) Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction. Faseb J, 9, 919-925. Frisch, S. M. and Screaton, R. A. (2001) Anoikis mechanisms. Curr Opin Cell Biol, 13, 555-562. Fromm, J. R., Hileman, R. E., Weiler, J. M. and Linhardt, R. J. (1997) Interaction of fibroblast growth factor-1 and related peptides with heparan sulfate and its oligosaccharides. Arch Biochem Biophys, 346, 252-262. Goodsell, D. S. and Olson, A. J. (1990) Automated docking of substrates to proteins by simulated annealing. Proteins, 8, 195-202. Hynes, R. O. (2002) Integrins: bidirectional, allosteric signaling machines. Cell, 110, 673-687. Kaplow, J. M., Bellot, F., Crumley, G., Dionne, C. A. and Jaye, M. (1990) Effect of heparin on the binding affinity of acidic FGF for the cloned human FGF receptors, flg and bek. Biochem Biophys Res Commun, 172, 107-112. Klint, P. and Claesson-Welsh, L. (1999) Signal transduction by fibroblast growth factor receptors. Front Biosci, 4, D165-177. Kwabi-Addo, B., Ozen, M. & Ittmann, M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer 11, 709-24 (2004). LaVallee, T. M., Prudovsky, I. A., McMahon, G. A., Hu, X. and Maciag, T. (1998) Activation of the MAP kinase pathway by FGF-1 correlates with cell proliferation induction while activation of the Src pathway correlates with migration. J Cell Biol, 141, 1647-1658. Lishko, V. K., Kudryk, B., Yakubenko, V. P., Yee, V. C. and Ugarova, T. P. (2002) Regulated unmasking of the cryptic binding site for integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry, 41, 12942-12951. Liu, J., Huang, C. and Zhan, X. (1999) Src is required for cell migration and shape changes induced by fibroblast growth factor 1. Oncogene, 18, 6700-6706. Morris, G. M., Goodsell, D. S., Halliday, R. S., Fig Huey, R., Hart, W. E., Belew, R. K. and Olson, A. J. (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comp. Chem., 19, 1639-1662. Morris, G. M., Goodsell, D. S., Huey, R. and Olson, A. J. (1996) Distributed automated docking of flexible ligands to proteins: parallel applications of AutoDock 2.4. J Comput Aided Mol Des, 10, 293-304. Pages, G., Lenormand, P., L'Allemain, G., Chambard, J. C., Meloche, S. and Pouyssegur, J. (1993) Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci USA, 90, 8319-8323. Pellegrini, L., Burke, D. F., von Delft, F., Mulloy, B. and Blundell, T. L. (2000) Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature, 407, 1029-1034. Plotnikov, A. N., Hubbard, S. R., Schlessinger, J. and Mohammadi, M. (2000) Crystal structures of two FGF-FGFR complexes reveal the determinants of ligandreceptor specificity. Cell, 101, 413-424. Powers, C. J., McLeskey, S. W. and Wellstein, A. (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer, 7, 165-197. Prater, C. A., Plotkin, J., Jaye, D. and Frazier, W. A. (1991) The properdin-like type I repeats of human thrombospondin contain a cell attachment site. J. Cell Biol., 112, 1031-1040. Presta, M., Dell'Era, P., Mitola, S., Moroni, E., Ronca, R. and Rusnati, M. (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev, 16, 159-178. Rusnati, M., Tanghetti, E., Dell'Era, P., Gualandris, A. and Presta, M. (1997) alphavbeta3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells. Molecular Biology of the Cell., 8, 2449-2461. Sahni, A. and Francis, C. W. (2004) Stimulation of endothelial cell proliferation by FGF-2 in the presence of fibrinogen requires alphavbeta3. Blood, 104, 3635-3641. Saphire, E. O., Parren, P. W., Pantophlet, R., Zwick, M. B., Morris, G. M., Rudd, P. M., Dwek, R. A., Stanfield, R. L., Burton, D. R. and Wilson, I. A. (2001) Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science, 293, 1155-1159. Schlessinger, J. (2000) Cell signaling by receptor tyrosine kinases. Cell, 103, 211-225. Schwartz, M. A. and Assoian, R. K. (2001) Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways. J Cell Sci, 114, 2553-2560. Schwartz, M. A. and Ginsberg, M. H. (2002) Networks and crosstalk: integrin signalling spreads. Nat Cell Biol, 4, E65-68. Shimaoka, M. and Springer, T. A. (2003) Therapeutic antagonists and conformational regulation of integrin function. Nat Rev Drug Discov, 2, 703-716. Takagi, J., Erickson, H. P. and Springer, T. A. (2001) C-terminal opening mimics ‘inside-out’ activation of integrin alpha5beta1. Nat Struct Biol, 8, 412-416. Tanghetti, E., Ria, R., Dell'Era, P., Urbinati, C., Rusnati, M., Ennas, M. G. and Presta, M. (2002) Biological activity of substrate-bound basic fibroblast growth factor (FGF2): recruitment of FGF receptor-1 in endothelial cell adhesion contacts. Oncogene, 21, 3889-3897. Thornton, S. C., Mueller, S. N. and Levine, E. M. (1983) Human endothelial cells: use of heparin in cloning and long-term serial cultivation. Science, 222, 623-625. Ullrich, A. and Schlessinger, J. (1990) Signal transduction by receptors with tyrosine kinase activity. Cell, 61, 203-212. Wang, W. and Malcolm, B. A. (1999) Two-Stage PCR Protocol Allowing Introduction of Multiple Mutations, Deletions and Insertions Using QuikChange™ Site-Directed Mutagenesis. BioTechniques, 26, 680-682. Yokoyama, K., Erickson, H. P., Ikeda, Y. and Takada, Y. (2000) Identification of amino acid sequences in fibrinogen y-chain and tenascin C C-terminal domains critical for binding to integrin αvβ3. J. Biol. Chem., 275, 16891-16898. Yokoyama, K., Zhang, X. P., Medved, L. and Takada, Y. (1999) Specific binding of integrin αVβ3 to the fibrinogen γ and αE chain C-terminal domains. Biochemistry, 38, 5872-5877. Zhu, H., Anchin, J., Ramnarayan, K., Zheng, J., Kawai, T., Mong, S. and Wolff, M. E. (1997) Analysis of high-affinity binding determinants in the receptor binding epitope of basic fibroblast growth factor. Protein Eng, 10, 417-421.
[0051] 3. Description of Related Art
[0052] Fibroblast growth factors (FGFs) constitute a family of heparin-binding polypeptides involved in the regulation of biological responses such as growth, differentiation, and angiogenesis. They are also implicated in inflammation, excess wound healing, and resistance of tumor cells to chemotherapeutic agents (chemoresistance).
[0053] The FGF family currently consists of 24 members, with FGF-1 (acidic FGF) and FGF-2 (basic FGF) the most extensively studied. The biological effects of FGFs are mediated by four structurally related receptor tyrosine kinases, denoted FGFR1, FGFR2, FGFR3, and FGFR4. The binding of FGF to its receptor results in receptor dimerization and subsequent autophosphorylation on specific tyrosine residues within the intracellular domain (Klint and Claesson-Welsh, 1999; Powers et al., 2000; Presta et al., 2005; Ullrich and-Schlessinger, 1990)
[0054] Integrins are a family of cell adhesion receptors that recognize extracellular matrix ligands and cell surface ligands (Hynes, 2002). Integrins are transmembrane α-β heterodimers, and at least 18 α and β subunits are known (Shimaoka and Springer, 2003). Integrins transduce signals to the cell upon ligand binding, and their functions are in turn regulated by the signals from within the cell (Hynes, 2002). Ligation of integrins triggers a large variety of signal transduction events that serve to modulate cell behavior including proliferation, survival/apoptosis, shape, polarity, motility, gene expression, and differentiation. Integrin-stimulated pathways are very similar to those triggered by growth factor receptors and are intimately coupled with them. It has been proposed that many cellular responses to soluble growth factors, such as epidermal growth factor, platelet-derived growth factor, and thrombin, are dependent upon the cell's adherence to extracellular matrix ligands via integrins. Integrins lie at the basis of such anchorage-dependent cell survival and proliferation (Assoian, 1997; Frisch and Screaton, 2001; Schwartz and Assoian, 2001).
[0055] It has been proposed that FGF-2-induced angiogenesis requires integrin signaling from the extracellular matrix (crosstalk between integrins and FGF receptors). Indeed antibody against integrin αvβ3 blocks FGF-2-induced angiogenesis (Brooks et al., 1994a; Brooks et al., 1994b). It has been reported that FGF-2 enhances αvβ3 expression during angiogenesis (Brooks et al., 1994a). Antibody or cyclic peptide antagonist of αvβ3 inhibits this αvβ3 upregulation (Brooks et al., 1994a; Brooks et al., 1995; Friedlander et al., 1995). It has been shown that integrin and growth factors are colocalized under certain condition. For example coimmunoprecipitation studies revealed direct biochemical interaction between αvβ3 and FGFR1 in the presence of both FGF-2 and fibrinogen (Sahni and Francis, 2004). These findings suggest integrin and FGFR are colocalized on the membrane in the presence of FGF-2. It has not been established how integrins and FGFR crosstalk in FGF-2 signaling.
[0056] It has been reported that substrate-bound FGF-2 promotes endothelial cell adhesion by interacting with integrin αvβ3 (Rusnati et al., 1997) and induces endothelial cell proliferation, motility, and the recruitment of FGFR1 in cell substrate contact (Tanghetti et al., 2002). Anti-αvβ3 antibodies block cell proliferation on immobilized FGF-2, but deletion of the tyrosine kinase portion of FGFR blocks cell proliferation induced by immobilized FGF-2. Thus it has been proposed that αvβ3 is required but not sufficient to transduce mitogenic signals of FGF-2 (Tanghetti et al., 2002). It is unclear how integrins interact with FGF-2 or whether this interaction is biologically relevant since heat-denatured FGF-2 still supports integrin binding (Tanghetti et al., 2002).
SUMMARY OF INVENTION
[0057] The invention relates to an isolated amino acid comprising at least a portion of the FGF protein amino acid sequence, and including a mutation in the integrin αvβ3 binding region of FGF-1.
[0058] In one preferred embodiment, the isolated amino acid comprises a mutation in the region Asn-33, GIy-34, GIy-35. In another preferred embodiment, the isolated amino acid comprises a mutation in the region His-36, Arg-39, Leu-41. In a further preferred embodiment the isolated amino acid comprises a mutation in the region Asp-43, Thr-45, Val-46. In a different preferred embodiment, the isolated amino acid comprises a mutation in the region Asp-47, GIy-48, Thr-49.
[0059] In a further preferred aspect of this embodiment, the isolated amino acid comprises a mutation in the region Arg-50, Asp-51, Arg-52. In a further preferred aspect of this embodiment, the isolated amino acid comprises a glutamine substitution for Arg-50. In a still further preferred aspect, the isolated amino acid is the protein R50E.
[0060] In a further preferred embodiment, the isolated amino acid comprises a mutation in the region Ser-53, Asp-54.
[0061] In a different preferred embodiment, the isolated amino acid comprises a mutation in the region Lys-127, Lys-128, Asn-129. In a further preferred aspect of this embodiment, the isolated amino acid comprises a glutamine substitution for Lys-127 and Lys-128. In a still further preferred aspect, the isolated amino acid is the mutant 4xE.
[0062] In a different preferred embodiment, the isolated amino acid comprises a mutation in the region Gly-130, Ser-131, Cys-132. In a different preferred embodiment, the isolated amino acid comprises a mutation in the region Lys-133, Arg-134, Arg-137. In a further preferred aspect of this embodiment, the isolated amino acid comprises a glutamine substitution for Lys-133 and Arg-134. In a still further preferred aspect, the isolated amino acid is the mutant 4xE.
[0063] In a different preferred embodiment, the isolated amino acid comprises a mutation in the region 138, GIy-141, GIn-142.
[0064] In a different preferred embodiment, the isolated amino acid binds to FGFR, and preferably acts as a dominant negative mutant against FGF inducing activity.
[0065] In another aspect of the invention, the isolated amino acid comprises a mutation in the region where the amino acid blocks the angiogenesis inducing activity of FGF-1. In a further aspect of this preferred embodiment, the isolated amino acid blocks the tumor growth inducing activity of FGF. In a different aspect of the invention, the isolated amino acid blocks the inflammation inducing activity of FGF. In still different aspect of the invention, the isolated amino acid blocks the excess wound healing inducing activity of FGF. In a further aspect of the invention, the isolated amino acid blocks the resistance of tumor cells to chemotherapeutic agents.
[0066] The isolated amino acid preferably acts as an antagonist to FGF signaling.
[0067] In a different embodiment, the isolated amino acid comprises at least a portion of the FGF protein amino acid sequence, and includes a mutation in the FGFR binding region of FGF-1. The isolated amino acid preferably binds to integrin αvβ3. In one preferred embodiment, the isolated amino acid comprises a mutation in the region of amino acids 100 to 110 of FGF-1. In a further such embodiment, the isolated amino acid is the mutant 3xA. The isolated amino acid preferably acts as a dominant negative mutant against FGF inducing activity.
[0068] The invention further comprises a pharmaceutical composition containing the amino acid. The pharmaceutical composition preferably is selected from the group of pharmaceutical compositions consisting of a diagnostic agent, a preventive agent, and a therapeutic agent for disease condition involving accelerated or abnormal cell growth.
[0069] In a different aspect of the embodiment, the accelerated or abnormal cell growth is selected from the group of conditions consisting of angiogenesis, cancer growth, inflammation and excess wound healing.
[0070] In a further aspect of the embodiment, the cancer growth condition is selected from the group of conditions consisting of acute myelogenous leukemia, breast cancer, prostate cancer, colon cancer, hepatic, cancer, myeloma, uterine leiomyoma, malignant tumor, or solid tumor.
[0071] In a still different aspect of the embodiment, the inflammation condition is selected from the group of conditions consisting of rheumatoid arthritis (RA), lupus (SLE), inflammatory bowel diseases (IBD), experimental allergic encephalomyelitis (EAE), multiple sclerosis (MS), and diabetic retinopathy.
[0072] In another aspect of the embodiment, the angiogenesis condition is selected from the group of conditions consisting of cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis and psoriasis.
[0073] In one preferred embodiment, the pharmaceutical composition will further comprise a carrier.
[0074] The invention also provides a method of reducing FGF signaling activity in a mammal, the method comprising dosing the mammal with an effective amount of the pharmaceutical composition. In one preferred aspect of the invention, the pharmaceutical composition is administered to the mammal orally. In another preferred embodiment, the mammal is a human.
[0075] In a different preferred aspect of the invention, the pharmaceutical composition is administered to the mammal topically. In a still different preferred aspect of the invention, the pharmaceutical composition is administered to the mammal intravenously.
[0076] The method preferably involves a mammal that has, or is at risk for developing, a vascularized solid tumor or metastases from a primary tumor.
[0077] In a further preferred embodiment, the method comprises the step of administering to the mammal another compound that inhibits tumor angiogenesis. In a preferred such aspect of the invention, the additional compound is chosen from a group comprising CV 3988, WEB 2086, INF-2.alpha., TNP-470, endostatin, SU 5416, SU 6668, batimistat, angiostatin, and celecoxib.
BRIEF DESCRIPTION OF THE DRAWINGS
[0078] FIG. 1 . Direct binding of FGF-1 to integrins
[0079] A. Recombinant soluble αvβ3 bound to immobilized FGF-1 and FGF-2.
[0080] Wells of 96-well microtiter plates were coated with 10 μg/ml FGF-1 or FGF-2 and remaining protein binding sites were blocked with 1 mg/ml BSA. Recombinant soluble αvβ3 (50 μl/well at 5 μg/ml in Hepes-Tyrode buffer supplemented with 1 mM MnCl 2 ) was added to wells and incubated for 1 h at room temperature. Soluble αvβ3 was incubated with 10 μg/ml 7E3 (white bar) or mouse IgG (black bar) for 10 min on ice prior to adding to the wells. BSA (circle) was used as a negative control. Data is shown as means+/−SD of triplicate experiments.
[0081] B. Competition of FGF-1 with γC for binding to soluble αvβ3.
[0082] FGF-1 (10 μg/m) was immobilized to the plastic plate. Soluble αvβ3 was added to the wells together with increasing concentrations of soluble γC. Binding was determined as described in A. Data is shown as percent binding+/−SD of triplicate experiments with no addition of γC as 100.
[0083] C. FGF-1 supported adhesion of αvβ3-K562 cells that express integrins αvβ3 and α5β1.
[0084] Wells of 96-well microtiter plates were coated with FGF-1 at the indicated concentrations and remaining protein binding sites were blocked with 1 mg/ml BSA. Hepes-Tyrode buffer supplemental with 1 mM MnCl 2 ) was used for adhesion assays. Prior to incubation with immobilized FGF-1, αvβ3-K562 cells were treated with 10 μg/ml anti-β3 function-blocking antibody 7E3 (triangle), anti-a5 function-blocking antibody KH72 (square), both 7E3 and KH72 (circle), or mouse IgG (diamond). BSA (cross) was used as a negative control. Data is shown as means+/−SD of triplicate experiments.
[0085] D. FGF-1 supported adhesion of mock-transfected K562 cells that express α5β1.
[0086] K562 cells were treated with 10 μg/ml anti-α5 function-blocking antibody KH72 (square) or mouse IgG (diamond) for 10 min on ice. Hepes-Tyrode buffer supplemented with 1 mM MnCl 2 ) was used for adhesion assays. Bound cells were quantified by measuring endogenous phosphatase activity. BSA (cross) was used as a negative control. Data is shown as means+/−SD of triplicate experiments.
[0087] FIG. 2 . Docking simulation of FGF-1-αvβ3 interaction.
[0088] A. Effect of heat denaturation on αvβ3 binding.
[0089] FGF-1 (10 μg/m) was heat-treated at indicated temperature for 10 min prior to immobilization. Binding of soluble αvβ3 was determined as described in FIG. 1 . Data is shown as percent binding+/−SD of triplicate experiments.
[0090] B and C. Docking simulation of FGF-1-integrin interaction.
[0091] Docking simulation of interaction between FGF-1 (PDB code 1AXM) and integrin αvβ3 (PDB code 1L5G) was performed as described in the Method section using AutoDock3. Histogram of the docked conformations (2 angstrom RMSD) (B) shows that they are nicely clustered with the lowest docking energy −26.3 Kcal/mol (cluster 1). The simulation predicts that the conformations in cluster 1 (shown in C) represent the most stable conformation of FGF-1 when FGF-1 interacts with integrin αvβ3.
[0092] D. Mutations made to FGF-1.
[0093] As described herein and shown in the figure, various mutations were made to FGF-1.
[0094] FIG. 3 . Effect of FGF-1 mutations on FGF-1 signaling.
[0095] A. The R50E mutation of FGF-1 blocked the binding to integrin αvβ3.
[0096] Amino acid residues in the integrin-binding site or in the FGFR-binding site were mutated individually or in groups. Wild-type (diamond), R50E (open square), N33A (closed square), 4xE (circle), 3xA (triangle) were coated to a plastic plate various concentration as indicated and the binding of soluble αvβ3 was determined as described in FIG. 2 . BSA (cross) was used as a negative control. The results show that mutations in the predicted integrin-binding site blocked αvβ3 binding, but that those in the FGFR-binding site did not. “4xE” represents the K127E/K128E/K133E/R134E mutant. “3xA” represents the E102A/Y109A/Q110A mutant.
[0097] B. The 3xA mutation of FGF-1 effectively blocked the binding of the FGFR1 but the 4xE or R50E mutation did not.
[0098] One μg/mi biotinylated FGF-1 and increasing concentrations of unlabelled FGF-1 or FGF-1 mutants were incubated for 1 h at RT with immobilized FGF receptor D2D3 fragments. Then the plate was washed and the bound biotinylated FGF were measured using an avidin conjugated HRP. Unlabeled wild-type (diamond) FGF-1, the R50E (square), 4xE (circle), and 3xA (triangle) FGF-1 mutants were used.
[0099] C. The 4xE mutation of FGF-1 completely blocked heparin binding but the R50E or 3xA mutation did not.
[0100] Partially purified wt and mutant FGF1 in 100 mM NaCl and 50 mM Tris (pH 7.4) were applied to a heparin sepharose column (1 ml bed volume). The column was washed with the same buffer and bound proteins were eluted with a stepwise increase in NaCl concentration from 0.1 to 1.2 M. Fractions were analyzed by SDS-polyacrylamide gradient gel electrophoresis. Proteins were visualized by Coomassie Brilliant Blue staining.
[0101] D. Positions of the amino acid residues critical for integrin binding (red), both heparin 1R and integrin binding (purple) and FGFR binding (blue).
[0102] FIG. 4 . FGF-1 mutations that block integrin binding blocked FGF-1 induced DNA synthesis.
[0103] Balb 3T3 cells were plated on cover slips in 6-well culture plates, serum starved (DMEM, 0.4% fetal calf serum) for 48 h, and stimulated with 5 ng/ml wild-type and mutant FGF-1s in the presence of 5 μg/ml heparin for 24 h. BrdU was added to the medium for the last 6 h of the incubation. Cells were fixed and incubated with anti BrdU antibody. BrdU incorporated cells were stained with DAB. The mean value of BrdU positive cells from wild type-treated culture was set to 100%, and the corresponding results from mutant-treated cultures were scaled accordingly. Results are shown as means±S.D. Asterisks indicate significant differences (p<0.05) compared with wild type treatment.
[0104] FIG. 5 . FGF-1 mutations that block integrin binding blocked FGF-1 induced ERK1/2 activation.
[0105] Serum starved Balb3T3 cells were stimulated with wild-type and mutant FGF-1s (5 ng/ml) in the presence or absence of 5 μg/ml heparin for 10 min at 37° C. Cell lysates were analyzed by western blotting with anti-phospho ERK1/2 (anti phospho-ERK). Total amount of ERK1/2 in each lane was determined by blotting with anti-ERK1/2. Controls contain medium alone (none) or medium containing 10% fetal calf serum (FCS).
[0106] FIG. 6 . FGF-1 mutations that block integrin binding blocked FGF-1 induced migration of Balb 3T3 cell.
[0107] A. Scratch wound healing assays.
[0108] Confluent serum-starved Balb 3T3 cells were scratched. After washing with serum-free medium, cells were incubated in DMEM containing 5 μg/ml heparin and 5 ng/ml wild-type or mutant FGF-1s for 24 h at 37° C. Controls contain medium alone (none) or medium containing 10% fetal calf serum (FCS).
[0109] B. Chemotaxis assays.
[0110] The bottom of the polycarbonate filter of the Transwell apparatus was coated with 10 μg/ml of fibronectin. The lower chamber contained 600 μI of serum-free DMEM containing 5 ng/ml wild-type or mutants FGF-1. Balb 3T3 cells (10 5 cells/filter) were plated on filter and incubated 37° C. for 24 h, and cells were stained with crystal violet. Cells that migrated to the bottom side of the membrane were counted. Results are expressed as means of the number of migrated cells in 2 fields.
[0111] FIG. 7 . A potential role of integrin-FGF interaction in FGF signaling.
[0112] The present study establishes that FGF mutations that block integrin binding blocked FGF1-induced cell proliferation, MAP kinase activation, cell migration and chemotaxis. This shows that direct binding of integrins to FGF is required for FGF signaling. Heparin did not reverse the inhibitory effects of the R50E mutation in FGF-1 signaling, suggesting that integrins and heparin play distinct roles in FGF signaling. Mutations that block integrin binding did not block FGFR binding and vise versa, showing that integrins and FGFR can simultaneously interact with FGF on the cell surface, though the formation of ternary complex could not be shown in this study. In this model integrins bind to FGF instead of extracellular matrix ligands.
[0113] Also shown is that integrins and FGFR are co-localized in the focal contacts, and many signaling molecules in the growth factor and integrin signaling pathways are recruited. Integrin antagonists can block the FGF-integrin crosstalk and thereby FGF signaling as in the current model. This may be one mechanism of the integrin FGF crosstalk.
[0114] FIG. 8 . FRS2 Phosphorylation.
[0115] FIG. 8 shows the effect of mutations of FGF1 on phosphorylation of MAP kinase, focal adhesion kinase (FAK), and FGF receptor substrate-2 (FRS2α) in mouse fibroblasts. The same cell lysates as described above were analyzed by western blotting with anti-phospho FRS2 or anti-FRS2, where; 1: Wild type; 2: R50E; 3: 4xE; 4: 3xA; 5: None; and 6: FBS.
[0116] FIG. 9 . Tube formation by endothelial cells.
[0117] FIG. 9 demonstrates the suppression of tube formation by HMVEC on Matrigel by the integrin-binding-defective FGF1 mutants. Digital images were taken by using a fluorescent microscope and analyzed by using ImageJ, using human microvascular endothelial (HMVE) cells added to the matrix-coated wells of 96-well plates at 2×104 cells/well in medium M-131 plus 0.1% hydrocortisone and 0.1% FBS for. Cells were incubated for 24 h in the presence of wt or mutant FGF. To enhance images, calcein AM was added to the medium.
[0118] FIG. 10 . Chemoresistance.
[0119] In FIG. 10 , results are provided showing suppression of FGF-induced drug resistance in M21 melanoma cells. Resistance of melanoma cells was to etoposide-induced apoptosis. M21 human melanoma cells were cultured in DMEM with 1% FBS for 48 h, and then treated with etoposide (0.1-100 μM) in the presence or absence of wt or mutant FGF for 48 h, with cell viability determined.
[0120] FIG. 11 . Chemoresistance.
[0121] FIG. 11 shows the effect of the R50E FGF1 mutant on etooposide-induced caspase activation in M211 human melanoma cells.
[0122] Caspases 3/7 activity was determined to demonstrate resistance of melanoma cells to etoposide-induced apoptosis. M21 human melanoma cells were cultured in DMEM with 1% FBS for 48 h, and then treated with etoposide (0.1-100 μM) in the presence or absence of wt or mutant FGF for 48 h.
DETAILED DESCRIPTION OF THE INVENTION
[0123] Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors and are critically involved in cell proliferation and migration. While integrins play a critical role in FGF signaling through “FGFR-integrin crosstalk,” the molecular mechanism of the crosstalk is unclear. Immobilized FGF-1 binds to integrin αvβ3 and α5β1. The αvβ3-binding site in FGF-1 is close to or overlaps with the heparin-binding site of FGF-1 but is distinct from that of FGFR. The αvβ3 and heparin binding sites in FGF-1 are distinct since one mutation (R50E) blocked the binding to integrin but did not affect the binding to heparin. The FGF-1 mutants that do not bind to integrin were defective in inducing DNA synthesis, ERK1/2 activation, migration, and chemotaxis. These results show that direct binding of FGF-1 to integrins play a significant role in FGF-1 signaling, and that FGFR and integrins crosstalk on the cell surface through direct binding to FGF-1.
[0124] The results demonstrate how integrins interact with FGF-1, another pro-angiogenic FGF. It is shown that immobilized FGF-1 binds to integrin αvβ3 and α5β1. This interaction requires intact FGF-1 since heat treatment of FGF-1 blocked integrin binding. The αvβ3-binding site of FGF-1 was localized by docking simulation and site-directed mutagenesis. The FGF-1 binding site is located close to or overlapping with the heparin-binding site of FGF-1. The αvβ3 and heparin binding sites are distinct since one mutation (the R50E mutation) blocked integrin binding but not heparin binding. Mutations that block integrin binding did not block FGFR1 binding to FGF-1, and mutations that block binding to FGFR-1 did not affect integrin binding, suggesting that αvβ3 and FGFR bind to FGF-1 in distinct manners.
[0125] The FGF-1 mutations that do not bind to integrins are defective in inducing DNA synthesis, ERK1/2 activation, migration, and chemotaxis of fibroblasts. These results show that the direct binding of FGF-1 to integrins plays a critical role in FGF-1 signaling, and that FGFR and integrins crosstalk on the cell surface through direct binding to FGF-1. FGF mutants, such as those described herein, are anti-FGF agents that may be used to block angiogenesis, cancer or tumor growth and excess wound healing.
Binding of Integrins to Immobilized FGF-1
[0126] To identify the role of integrins in FGF signaling, a test was conducted as to whether FGF-1, another major FGF, interacts with integrins. To show integrin specific binding, recombinant soluble αvβ3 was used for ELISA-type integrin binding assays. It was discovered that soluble αvβ3 bound to immobilized FGF-1 and FGF-2 (as a positive control), but did not bind to BSA ( FIG. 1A ). MAb 7E3 blocked the binding of soluble αvβ3 to FGF-1 and FGF-2, suggesting that binding to FGF-1 and FGF-2 is specific to αvβ3. Whether FGF-1 binds to αvβ3 in a manner similar to known integrin ligands was tested. A known ligand for αvβ3, the fibrinogen γ chain C-terminal domain (γC) (Yokoyama et al., 2000; Yokoyama et al., 1999), was shown to effectively block FGF-1-αvβ33 interaction ( FIG. 1B ), suggesting that FGF-1-binding site overlaps with that of γC.
[0127] To test whether this integrin-FGF-1 interaction occurs in more biological systems, cell adhesion to immobilized FGF-1 was tested. It was found that both K562 erythroleukemia cells that over-express αvβ3 (designated αvβ3-K562 cells) and mock-transfected K562 cells bound to immobilized FGF-1 in a dose-dependent manner in adhesion assays. K562 cells express endogenous α5β1. The binding of αvβ3-K562 cells to FGF-1 was suppressed by anti-α5 mAb (monoclonal antibody) KH72 and anti-β3 mAb 7E3 and required both antibodies to effectively block adhesion to FGF-1 ( FIG. 1C ). The binding of K562 cells was suppressed by anti-α5 mAb KH72 ( FIG. 1D ). These results suggest that both α5β1 and αvβ3 bind to FGF-1 in this assay system.
Mapping Integrin-Binding Sites in FGF-1 by Docking Simulation and Mutagenesis.
[0128] It has been reported that the binding of FGF-2 to integrins involves the DGR motifs in FGF-2 (Rusnati et al., 1997), but FGF-1 does not have the DGR motif or any known integrin-binding motifs. It has also been reported that αvβ3 binds to heat-denatured FGF-2 (Rusnati et al., 1997), but it was discovered that soluble αvβ3 did not bind to heat-denatured FGF-1 ( FIG. 2A ), indicating that the intact three-dimensional structure of FGF-1 is required for integrin binding.
[0129] To identify the mechanism of FGF-1-integrin interaction, a docking simulation and site-directed mutagenesis was used. AutoDock is a set of docking tools widely used for predicting the conformation of small ligands bound to receptors (Goodsell and Olson, 1990; Morris et al., 1998; Morris et al., 1996), and the methods are being extended to predict protein-protein complex conformations (Saphire et al., 2001). Docking simulation of FGF-1-integrin αvβ3 interaction was done using AutoDock. 50 dockings were performed, each one starting with a random initial position and orientation of FGF-1 (PDB code 1AXM) with respect to the integrin αvβ3. The results were clustered together by positional RMSD (root mean square distance) into families of similar conformations ( FIG. 2B ). Many of the docking conformations clustered well with the lowest docking energy −26.1 Kcal/mol (cluster 1), which is comparable to that of a known integrin ligand (fibrinogen γ chain C-terminal domain) (Yokoyama et al., 1999) (docking energy −24.3 Kcal/mol) in a similar docking simulation (data not shown).
[0130] These results predict that the docking conformation of cluster 1 ( FIG. 2C ) represents the most probable stable FGF-1 conformation upon binding to αvβ3. This model predicts that the integrin-binding interface of FGF-1 with integrin αvβ3 is distinct from the FGFR-binding site (Pellegrini et al., 2000), but is close to or overlapping with the heparin-binding site.
[0131] Several mutations were induced within the predicted interface of FGF-1 with integrin αvβ3 (Table 1), to identify critical residues for integrin binding. Mutant FGF-1 were generated in E. coli and purified as described in the methods section.
[0132] It was found that mutating 4 positively charged residues (Lys127/Lys128/Lys133/Arg134) simultaneously to Glu (designated the 4xE mutation) effectively blocked the binding of soluble αvβ3 to FGF-1 ( FIG. 3A ).
[0133] The Arg-50 to Glu (R50E) mutation also effectively blocked the binding of soluble αvβ3 to FGF-1.
[0134] Mutating three residues in the FGFR binding sites (the Glu102/Tyr109/Asn110 to Ala mutant, designated 3xA mutant), which are predicted from FGF1-FGFR2 complex structure (Pellegrini et al., 2000; Zhu et al., 1997) and mutagenesis data of FGF-2 (Zhu et al., 1997), did not affect integrin binding ( FIG. 3A ).
[0135] The 3xA mutation effectively blocked the binding of the FGFR1 fragment (domains 2 and 3, or D2D3), but the 4xE or R50E mutation did not block the binding of the FGFR1 D2D3 fragment ( FIG. 3B ), showing that integrin-binding sites and FGFR1-binding sites are distinct.
[0136] A test was also conducted to see if these mutations can block heparin binding to FGF-1. It was found that the 4xE mutation completely blocked heparin binding but the R50E or 3xA mutation did not ( FIG. 3C ). These results show that the integrin-binding site overlaps with, but is not identical with, the heparin-binding site, and is distinct from the FGFR1-binding site ( FIG. 3D ). These results are consistent with the prediction by docking simulation.
[0000] Effects of FGF-1 Mutations that Block Integrin Binding on DNA Synthesis and Activation of ERK1/2
[0137] It has been well established that FGF-1 is a potent mitogen (reviewed in (Powers et al., 2000) and ERK1/2 plays an important role in transducing proliferative signals from receptor tyrosine kinases (Schlessinger, 2000). The mitogenic action of the FGFs is mediated in part by the activation of ERK1/2 (LaVallee et al., 1998; Pages et al., 1993).
[0138] The effect of the mutations that block integrin binding on FGF-1-induced DNA synthesis was tested in Balb 3T3 cells ( FIG. 4 ). The FGF-1 induced BrdU incorporation was significantly blocked by the R50E and the 4xE mutations that block integrin binding. The negative control 3xA mutation that is defective in FGFR binding also blocked the BrdU incorporation. These results show that integrin binding to FGF-1 is critical for FGF-1-induced DNA synthesis besides the binding of FGF-1 to FGFR1.
[0139] The R50E mutant showed much less ability to induce ERK1/2 activation in Balb 3T3 cells than wild type FGF-1, and the 4xE mutation did not induce ERK1/2 activation at all ( FIG. 6B ), showing that the FGF-1 mutants have much reduced ability to activate ERK1/2. The negative control 3xA mutant defective in FGFR binding did not show ERK1/2 activation. These results show that integrin binding to FGF-1 besides FGFR binding are critical for FGF-1-induced DNA synthesis and ERK1/2 activation. Heparin did not enhance FGF-1-induced ERK1/2 activation or reverse the inhibitory effects of the FGF-1 mutations, showing that heparin is not a critical component for FGF-1 induced ERK1/2 activation in our assay system.
[0000] Effects of FGF-1 Mutations that Block Integrin Binding on Chemotaxis and Wound Healing
[0140] It has been well established that FGF-1 is a potent inducer of cell migration and chemotaxis (Friesel and Maciag, 1995; Liu et al., 1999). The effect of mutations that block integrin binding on wound healing and chemotaxis was tested, and it was found that the R50E and 4xE mutants, as well as a negative control 3xA mutation, effectively blocked migration of BaIb3T3 cells in scratch wound healing assays ( FIG. 6A ). The R50E and 4xE mutations blocked FGF-1-induced chemotaxis ( FIG. 6B ). The negative control 3xA mutant did not induce cell migration in scratch assays. Heparin was required for cell migration and chemotaxis assays. These results show that integrin binding to FGF-1 is critical for FGF-1's ability to induce cell migration and chemotaxis.
Binding of Integrins to FGF-1
[0141] The present study establishes that immobilized FGF-1 bound to integrins αvβ3 and α5β1 (and probably other integrins). While heat-denatured FGF-2 can bind to integrin αvβ3 (Rusnati et al., 1997) it was shown that FGF-1 requires the intact three-dimensional structure for integrin binding. Molecular docking simulation predicted the positions of amino acid residues critical for integrin binding and mutagenesis studies verified this prediction. The integrin binding site is distinct from the FGFR1-binding site, since mutations in the predicted integrin-binding site did not block FGFR1 binding, and mutations in the FGFR1-binding site did not affect integrin binding. The integrin-binding site of FGF-1 overlaps with the heparin-binding site. Since a point mutation (R50E) blocked integrin binding, but did not affect heparin binding, integrin-binding site and heparin-binding sites are not identical.
Critical Role of FGF-1-Integrin Interaction in FGF-1 Signaling
[0142] The 4xE mutant strongly blocked FGF signaling, FGF-1 binding to heparin is mediated by a set of basic and polar residues that were identified in previous structural and mutagenesis experiments (DiGabriele et al., 1998; Fromm et al., 1997). The positively charged 4 residues in the 4xE mutant are engaged in heparin binding (DiGabriele et al., 1998; Fromm et al., 1997). Thus it is possible that this inhibition is due to loss of heparin binding, or integrin binding or both. The R50E mutant, which binds to heparin but not to integrin, is useful to study the specific role of integrin binding in FGF-1 signaling. The R50E mutant showed reduced ability to induce DNA synthesis, ERK1/2 activation, migration, and chemotaxis, suggesting that direct integrin binding to FGF-1 is critical for all aspects of FGF-1 signaling tested in this study. It has been reported that heparin potentiates FGF signaling, but the mechanism of this effect is unclear (Belford et al., 1992; Brown et al., 1995; Burgess et al., 1990; Kaplow et al., 1990; Thornton et al., 1983). The mutations (e.g., the R132E mutation) (Burgess et al., 1990) that block heparin binding to FGF-1 and reduce FGF-1 signaling appear to block integrin binding. This shows that the effects of these mutations may be due to inhibition of integrin binding besides inhibition of heparin binding. Interestingly, heparin did not enhance ERK1/2 activation induced by wild type FGF-1 or reverse the inhibitory effect of the R50E mutation in FGF-1 induced DNA synthesis and MAP kinase activation, showing that integrin binding, but not heparin binding, is required for DNA synthesis and ERK1/2 activation in our assay system. It is interesting that cell migration assays (wound healing and chemotaxis) required the presence of heparin in the present study, showing that FGF-1 induced cell proliferation and migration may use distinct signaling mechanisms.
Significance of FGF-1 as an Integrin Ligand
[0143] The present study provides a new insight into the role of integrins in FGF signaling. Current theory is that the binding of integrins to extracellular matrix (ECM) ligands is required for FGF signaling that leads to gene expression, cell proliferation, and migration (Comoglio et al., 2003; Eliceiri, 2001; Schwartz and Ginsberg, 2002). The present results show that FGF-1 itself acts as an integrin ligand during the FGF/FGFR/integrin crosstalk and direct binding to integrins is critical for FGF-1 to induce DNA synthesis, ERK1/2 activation, cell migration, and chemotaxis. The present study shows that integrins and FGFR1 can simultaneously bind to FGF-1, making a ternary complex during FGF-1 signaling.
[0144] It has been reported that the integrin-binding sites are cryptic in several known integrin ligands (e.g., fibrinogen and osteopontin) (Lishko et al., 2002). Immobilization and proteolytic cleavage are common mechanisms to uncover the cryptic integrin-binding sites. It has been reported that soluble FGF-2 does not bind to integrin, but immobilized FGF-2 does (Rusnati et al., 1997). Consistently, the binding of soluble FGF-1 to integrins could not be demonstrated. However, it is highly likely that soluble FGF-1 requires integrin binding to induce signal transduction, since the R50E mutation blocked signaling from soluble FGF-1. One possibility is that soluble FGF-1 or its mutants are immobilized on the cell surface and their integrin-binding sites are exposed. It is also possible that the binding of soluble FGF-1 to FGFR exposes the integrin-binding site in FGF-1.
[0145] This study predicts that integrins and FGFR directly interact with FGF ( FIG. 7 ) instead of extracellular matrix ligands. Also, integrins and FGFR are co-localized in the focal contacts through direct binding to FGF-1, and many signaling molecules in the growth factor and integrin signaling pathways are recruited. Also integrin antagonists can block the FGF-integrin crosstalk and thereby block FGF signaling as in the current model. This is one of the mechanisms of the integrin FGF crosstalk. The FGF-1 mutants described herein may be used as anti-FGF agents (dominant negative mutants) that are useful in blocking angiogenesis, cancer or tumor growth, inflammation, excess wound healing, and resistance of tumor cells to chemotherapeutic agents (chemoresistance). Also, small molecules that bind to the integrin-binding sites of FGF can be used as antagonists to FGF signaling.
FRS2 Phosphorylation
[0146] Since MAP kinase activation and FAK phosphorylation can be mediated by either the integrin or the FGFR signaling pathway, FGF1 binding to either its FGFR or its integrin binding partner could have initiated the observed signal.
[0147] The binding of FGF to FGFR induces the dimerization of FGFR and the phosphorylation of several Tyr residues at the cytoplasmic domain of FGFR. Activation of FGFR results in tyrosine phosphorylation of the docking proteins Shc and FRS2α. FRS2α is a major intracellular substrate of the ligand-activated FGFR and is rapidly and highly tyrosine phosphorylated in cells upon FGF stimulation.
[0148] As seen in FIG. 8 , wt FGF1 induced, but the R50E, 4xE, and 3xA mutations of FGF1 abolished, FGF1-induced FRS2α phosphorylation. The results teach that the FGF1 mutations do not induce FGFR activation and subsequent phosphorylation of its downstream target FRS2α.
[0149] Similar results were obtained using Balb3T3 cells.
Tube Formation
[0150] As seen in reference to FIG. 9 , the R50E mutant was shown to block tube formation by endothelial cells on matrigel in vitro in a dose-dependent manner while wt FGF1 enhanced it.
[0151] These results suggest that the R50E mutant has potential as antagonist for angiogenesis and resistance to chemotherapy. It has been reported that FGF1 binds to all known FGFR (FGFRs 1 through 4), and thereby the R50E mutant may block the binding of other members of the FGF family.
Chemoresistance
[0152] It has been reported that FGF1 and 2 suppress apoptosis of cancer cells induced by chemotherapeutic agents (e.g., etoposide and doxorubicin). In Example 15, it was shown that the R50E mutant enhanced apoptosis induced by etoposide in M21-melanoma cells ( FIG. 10 ). Also, the R50E mutant blocked inhibition of caspase activation by wt FGF ( FIG. 11 ). Thus the R50E mutant worked as an FGF antagonist.
[0153] These results demonstrate that induced drug resistance in cancers or tumors can be diminished by the presence of competitive binding of mutant FGF, even in the presence of wt FGF.
EXAMPLES
Materials
[0154] The globular carboxyl-terminal domain of the fibrinogen γ-chain (γC) was synthesized in bacteria as an insoluble protein and refolded as previously described (Yokoyama et al., 1999). Recombinant soluble αvβ3 was synthesized in CHO K1 cells using the soluble αv and β3 expression constructs provided by Tim Springer, (Center for Blood Research, Boston, Mass.) and purified by Ni-NTA affinity chromatography as described (Takagi et al., 2001).
Example 1
Plasmid Construction, Protein Expression, and Purification of the Wild Type and Mutant FGF-1
[0155] The human FGF-1 and FGF-2 cDNAs were amplified using polymerase chain reaction (PCR) with human placenta library as a template. A Bgl II restriction site was introduced at the 5′ end, an Eco RI site at the 3′ end of the cDNA fragment with following primers: FGF-1, 5′-GCAGATCTTTTAATCTGCCTCCAGGGAAT-3′ and 5′-GCGAATTCTTAATCAGAAGAGACTGGCAG-3′. FGF-2: 5′-GCAGATCTCCCGCCTTGCCCGAGGATGGC-3′ and 5′-GCGAATTCTCAGCTCTTAGCAGAAGACATTGG-3.' The resulting fragments were digested with Bgl II and Eco RI, and subcloned into the Bam HII/Eco RI sites of the pGEX-2T (Amersham Pharmacia Biotech) vector.
[0156] Site-directed mutagenesis was performed using the QuickChange method (Wang and Malcolm, 1999). The presence of the mutations was verified by DNA sequencing.
[0157] The wild type FGF-1 and its mutants were expressed in E. coli BL21 (DE3) and purified as described by the manufacturer's instructions (Pharmacia Biotech, Brussels, Belgium). After removing GST-tag by thrombin, wild type FGF-1, the R50E and the E101A/Y108A/N109A FGF-1 mutants were purified using a heparin Sepharose column (Amersham Pharmacia Biotech). The K127E/K128E/K133E/R134E mutant was purified by gel filtration.
Example 2
Synthesis of the FGFR1 D2D3 Fragment
[0158] A DNA fragment encoding amino acid residues 140 to 365 of the immunoglobulin-like domains D2 and D3 of FGFR was amplified by PCR with the full length human FGFR1 cDNA in the pcDNA3 (gift from Ann Hanneken, the Scripps Research Institute, La Jolla, Calif.) as a template. A Bam HI restriction site was introduced at the 5′ end, Xho I site at the 3′ end of the cDNA fragment with the following primers: 5′-GCGGATCCACAGATAACACCAAACCAAACC-3′,5′-GCCTCAGTCACCTCTCTTCCAGGGCTTCC-3′. The resulting cDNA fragment was subcloned into the Bam HI/Xho I sites of the vector pET21a, and transformed into BL21 (DE3).
[0159] The protein was expressed as an insoluble protein, refolded as described (Plotnikov et al., 2000). The refolded protein was purified by affinity chromatography using the FGF-1 coupled to CNBr-activated Sepharose (Amersham Pharmacia Biotech) as an affinity matrix. FGF-1-Sepharose was incubated with crude refolded proteins 16 h at 4° C. After binding, the affinity matrix was washed with buffer containing 100 mM NaCl and 50 mM Tris (pH 7.4); and eluted with 1.2M NaCl, and 50 mM Tris (pH 7.4).
Example 3
Heparin Binding
Heparin Binding Assay
[0160] Wild type and mutant FGF-1 in 100 mM NaCl and 50 mM Tris/HCI (pH 7.4) were applied to heparin sepharose column (1 ml bed volume). The column was washed with same buffer, and bound proteins were eluted with a stepwise increase in NaCl concentration from 0.1 to 1.2 M. Fractions were analyzed by SDS-polyacrylamide gradient gel electrophoresis. Proteins were visualized by Coomassie Brilliant Blue staining.
Example 4
Docking Simulation
[0161] In the AUTODOCK 3.05 program, the ligand is presently compiled to a maximum size of 1024 atoms. The solvent-exposed Mg 2+ octahedral vertex was left empty in the model during docking calculations. Atomic solvation parameters and fractional volumes were assigned to the protein atoms by using the AddSol utility, and grid maps were calculated by using AutoGrid utility in AutoDock 3.05. A grid map with 127×127×127 points and a grid point spacing of 0.603 Angstrom included the whole MIDAS-containing face of the I-like domain of β3 and the β-propeller domain containing repeats 2-4, which are large enough to accommodate the FGF-1 structure. Kollman “united-atom” charges were used. AutoDock 3.05 uses a Lamarckian Genetic Algorithm (LGA) that couples a typical Darwinian genetic algorithm for global searching with the. Solis and Wets algorithm for local searching. The LGA parameters were defined as follows: the initial population of random individuals had a size of 50 individuals; each docking was terminated with a maximum number of 1×10 6 energy evaluations or a maximum number of 27,000 generations, whichever came first; mutation and crossover rates were set at 0.02 and 0.80, respectively. An elitism value of 1 was applied, which ensured that the top ranked individual in the population always survived into the next generation. A maximum of 300 iterations per local search was used. The probability of performing a local search on an individual was 0.06, whereas the maximum number of consecutive successes or failures before doubling or halving the search step size was 4. This set of parameters was used for all dockings.
Example 5
Soluble Integrin Binding Assay
[0162] Binding assays were performed as previously described (Takagi et al., 2001). Native or heat-denatured FGF-1 in 0.1 M carbonate buffer, pH 9.4, were incubated in a polystyrene 96-well non-tissue culture plates surface overnight at 4° C. Unbound FGF-1 was removed, and 200 μl of 0.1% bovine serum albumin in PBS was added and incubated for 60 min at room temperature. The wells were washed with PBS and soluble integrin αvβ3 in 50 μl in Hepes-Tyrode buffer supplemented with 1 mM Mn 2+ were added to the wells and incubated at room temperature for 60 min. After non-bound soluble integrin were removed by rinsing the wells with the same buffer. Horseradish peroxidase (HRP) conjugated anti His-tag mouse IgG was added to well and incubated 60 min. Non-bound antibodies were removed by rinsing the wells with the same buffer, bound integrins were quantified by measuring the absorbance of 450 nm developed from adding the substrate (3,3′,5,5′-tetramethylbenzidine) of HRP unbound protein was aspirated, and the wells were washed with PBS three times.
Example 6
Inhibition of FGF-1-αvβ3 Interaction by γC
[0163] FGF-1 (10 μg/ml) was immobilized to wells of 96-well plates. Soluble αvβ3 integrin was added to the wells with various concentration of γC. Bound integrin was detected by using HRP-conjugated anti-6His antibodies and its substrate as described above.
Example 7
Cell Adhesion Assay
[0164] Wells of polystyrene 96-well non-tissue culture plate were coated with wild type or mutants FGF-1 as above. In adhesion assay, cells (10 5 cells/well) in 100 μl of Hepes-Tyrode buffer supplemented with 1 mM Mn 2+ were added to the wells and incubated at 37° C. for 1 h. After non-bound cells were removed by rinsing the wells with the same buffer, bound cells were quantified by measuring endogenous phosphatase activity (Prater et al., 1991)
Example 8
DNA Synthesis
[0165] DNA synthesis was measured by BrdU incorporation. Balb 3T3 cells were plated on sterile cover slips in 6-well culture plates and serum starved in DMEM supplemented with 0.4% fetal calf serum for 48 h, and stimulated with 5 ng/ml wild type and mutant FGF-1s for 24 h in the presence and absence of 5 μg/ml heparin. BrdU (10 μg/ml) was added to the medium for the last 6 h of the incubation. Cells were then fixed with 70% ethanol and incubated with 2N HCI. After the medium was neutralized with 0.1 M borate buffer (pH 8.5), the cells were incubated with anti-BrdU antibody (BD PharMingen, San Diego, Calif.). BrdU incorporated cells were stained with HRP conjugated secondary antibody (Biorad) and metal enhanced diaminobenzidine substrate kit (Pierce, Rockford, Ill.). Diaminobenzidine positive and negative cells were counted from the digital images of three independent fields.
Example 9
MAP Kinase Activation
[0166] Balb3T3 cells were grown to confluence and serum starved in DMEM supplemented with 0.4% fetal calf serum for 24 h, and stimulated with wild type and mutant FGF-1 (5 ng/ml) in the presence or absence of 5 μg/ml heparin for 10 min at 37° C. Cells were washed twice with ice-cold PBS and lysed with the lysis buffer (20 mM Tris-HCI pH 8.0, 120 mM NaCl, 5 mM EDTA, 0.5% Triton-X100, 1 mM PMSF, 1 mM DTT, 10 mM NaF, 1 mM Na 3 VO 4 , 10 μg/ml aprotinin). Cell lysates were separated on 4-12% NuPAGE Bis-Tris Gel (invitrogen). Proteins were then transferred to PVDF membranes (Milli-pore), probed with antibodies, and bound antibodies were detected by HRP-conjugated anti-mouse IgG and chemiluminescence HRP substrate (Pierce). The antibodies used were anti-phospho-ERK1/2, anti-ERK1/2 (Cell Signaling Technology).
Example 10
Wound Scratch Assay
[0167] Balb 3T3 cells were plated into 6-well cell culture plate. Cells were allowed to grow in DMEM containing 10% fetal calf serum for overnight, and then cells were washed with serum-free medium and starved for 24 h. A scratch was made across the cell layer using a pipette tip. After washing with serum-free medium twice, DMEM containing 10 ng/ml wild type or mutant FGF-1 together with 5 μg/ml heparin were added to cells. Plates were photographed at 0, 6, 12, and 24 h.
Example 11
Chemotaxis
[0168] A polycarbonate filter of 8 μm pore size of the Transwell insert was coated with 10 μg/ml of fibronectin (Sigma) overnight at 4° C. After washing, the insert was placed into a 24-well cell culture plate, and the lower portion of the plate was filled with 600 μl of serum-free DMEM containing 5 ng/ml wild type or mutant FGF-1. Balb 3T3 cells (10 5 cells/filter) were plated on filter and incubated 37° C. for 24 h, and cells were visualized by crystal violet staining (0.5% crystal violet in 50 mM Borate, pH 9.0, and 2% ethanol). The uncoated side of each filter was wiped with a cotton swab to remove cells that had not migrated through the filter. Migrated cells were counted from the digital images of stained cells. Determining the mean number of cells counted per field. Results are expressed as means±SD of the relative cell number with non-stimulated cells set as 100).
[0000]
TABLE 1
Amino acid residues at the predicted interface between FGF-1 and integrin αvβ3.
FGF-1
αv
β3
Asn-33; GIy-34, GIy-35
Met-118
Tyr-122, Ser-123, Met-124
His-36, Arg-39, Leu-41
Ser-144, Gln-145, Asp-146
Lys-125, Asp-126; Asp-127
Asp-43, Thr-45, Val-46
IIe-147, Asp-148, AIa-149
Trp-129
Asp-47, GIy-48, Thr-49
Asp-150, GIy-151
Tyr-166
Arg-50, Asp-51, Arg-52
Tyr-178
Asp-179, Met-180, Lys-181
Ser-53, Asp-54
Thr-212, Gln-214, Ala-215
Thr-182, Arg-214, Asn-215
Lys-127, Lys-128, Asn-129
Ile-216, Asp-218, Asp-219
Arg-216, Ala-218, Asp-251
Gly-130, Ser-131, Cys-132
Arg-248
Ala-252, Lys-253
Lys-133, Arg-134, Arg-137
Thr-138, GIy-141, GIn-142
Lys-143, Ala-144
[0000]
TABLE 2
Phenotype of FGF-1 mutants used in this study
αvβ3
Heparin
FGFR
DNA
ERK1/2
Wound
binding
binding
binding
synthesis
activation
healing
Chemotaxis
Wild
Normal
Normal
Normal
Normal
Normal
Normal
Normal
type
R50E
Low
Normal
Normal
Low
Low
Low
Low
4xE
Low
Low
Normal
Low
Low
Low
Low
3xA
Normal
Normal
Low
Low
Low
Low
Low
Example 12
A. FRS2 Phosphorylation
[0169] This experiment tested how the FGF1 mutations affect phosphorylation of FRS2α. It was found that wt FGF1 induced, but the R50E, 4xE, and 3xA mutations of FGF1 abolished, FGF1-induced FRS2αphosphorylation ( FIG. 8 ). These results suggest that these FGF1 mutations do not induce FGFR activation and subsequent phosphorylation of its downstream target FRS2α.
[0170] Similar results were obtained with Balb3T3 cells.
Example 13
B. Tube Formation
[0171] Wells of 96-well FluoroNunc black plates were coated with 50 μl of matrigel basement membrane matrix (BD Bioscience) and allowed to gel at 37° C. for 30 min. Endothelial cells growing on the tissue culture plastic were trypsinized, washed, and added to the matrix-coated wells at 2×104 cells/well. Plating was performed in medium M-131 plus 0.1% hydrocortisone and 0.1% FBS for Human microvascular endothelial (HMVE) cells. Cells were incubated for 24 h in the presence of wt or mutant FGF. To enhance images, calcein AM (Invitrogen) was added to the medium (10 μg/ml) and incubated for 15 min at 37° C. Digital images were taken by using a fluorescent microscope and analyzed by using ImageJ. ( FIGS. 9A and 9B ).
Example 15
C. Chemoresistance
[0172] Cells were plated on well of 96-well tissue culture plates and serum-starved for 48-72 h in DMEM supplemented with 0-1% FBS. Then cells were treated with etoposide (up to 100 μM) and wt or mutant FGF for additional 24-48 h. Cell viability was determined using CellTiter 96 MTS assay (Promega) and caspases 3/7 activity was determined by using Caspase-Glo 3/7 assay kit (Promega). FIGS. 10 and 11 . | The invention relates to an isolated amino acid that can act as an antagonist to FGF signaling, comprising at least a portion of the FGF protein amino acid sequence, and including a mutation in either a) the integrin αvβ3 binding region of FGF-1; or b) the FGFR binding region of FGF-1. | 0 |
PRIORITY
Priority is claimed to European Patent Application No. 11 160 512.7, filed Mar. 30, 2011, the disclosure of which is incorporated herein by reference in its entirety
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the present invention relates to a mobile classifier (deduster) with docking devices, flushing devices and control for the dedusting of granules, in particular polymer granules, with preference polycarbonate granules. Such a mobile classifier can be set up at different locations underneath silos. To perform its function, the mobile classifier is technically connected to stationary pipelines, filters and fans.
2. Background
The granular product occurring in the reactor during the production of thermoplastics is plasticated in an extruder and formed into individual strands, which are cut into granules by means of a knife rotating in the granulating die. The granulation may be performed, for example, in a stream of liquid. Subsequently, the granules are dried and screened, in order to separate out agglomerates formed in spite of cooling. After that, the product is pneumatically conveyed to a mixing silo, from which the product is then filled and packaged. On account of the silo design and the filling strategy, mixing (homogenization) of the product inevitably takes place when it is removed from the mixing silo.
In order to separate out abraded material in dust form and further materials in dust form that are formed during the pneumatic conveyance or during mixing, depending on the proportion of dust, the granules are subjected prior to the filling or packaging process to a dedusting operation performed by air classification by means of a classifier (deduster).
Classifiers are known per se and are described, for example, in U.S. Pat. No. 5,035,331, U.S. Pat. No. 6,595,369, U.S. Pat. No. 7,380,670 and U.S. Pat. No. 7,621,975. However, these disclosures are merely concerned with increasing the efficiency of stationary classifiers (better dedusting) and ignore the handling of the classifier itself, and possibly the suitability thereof for being washed down to avoid contamination by dust and granules from an earlier dedusting operation involving different granules, which contaminate the present product during the dedusting in the classifier.
SUMMARY OF THE INVENTION
The problem addressed here has been solved by providing a device, comprising a classifier with an integrated working platform, possibly a fully automatic control and a stationary part of the plant substantially comprising pipelines and filter and fan systems, which includes a base frame with an integrated working platform provided with a travelling mechanism, in order to accommodate all the required components for a working dedusting process, in order thereby to set up a classification efficiently at different silo locations. The travelling frame accommodates several dedusting components.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, wherein like reference numerals refer to similar components:
FIG. 1 is a mobile classifier in side view
FIG. 2 shows the use of a small tractor (mover) on the mobile classifier.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
On the basis of the prior art, there was the problem of providing a classifier with the aid of which granules can be dedusted, the classifier not being stationarily located in one place, but able to be used mobily in a plant for different operations. At the same time, the device should be designed in such a way that ergonomic docking of the device onto the silo outlets is possible. A further goal is to make the procedure for operating the device such that the setting of the individual operating parameters on the basis of the numerous different classifier locations is performed in a reliable and user-friendly manner.
A further problem addressed is that of providing a classifier which, after completion of the dedusting process, is largely free from residual amounts of the granules previously conveyed therein and can be cleaned easily and reliably of any remains of granules possibly still present in the classifier by flushing, for example with water and/or compressed air, so that contamination with following portions of granules can be ruled out with certainty.
As used herein, contamination refers to a very wide range of foreign powdered materials, such as comminuted granules and the granules left behind after a change of product. The introduction of such foreign materials into polymers, in particular into high-value polycarbonates, can have a devastating influence on the end product, which are distinguished, for example, by conforming to very narrowly defined specifications with regard to optical or mechanical properties.
The problem addressed here has been solved by providing a device, as shown in FIG. 1 , comprising a classifier with an integrated working platform, possibly a fully automatic control and a stationary part of the plant substantially comprising pipelines and filter and fan systems, which includes the following features:
a base frame ( 1 ) with an integrated working platform ( 2 ) is provided with a travelling mechanism, in order to accommodate all the required components for a working dedusting process, in order thereby to set up a classification efficiently at different silo locations. The travelling frame accommodates at least the following dedusting components:
a conical docking flange ( 3 ), free from any dead space, with quick-clamping devices ( 4 ) and an associated inlet funnel ( 5 ) with a shut-off flap ( 6 ) to the classifier a wind classifier, for example a gravity classifier from the company Pelletron ( 7 ) an intermediate container ( 8 ) as a recipient vessel a telescopic pipe ( 9 ) with an initiator ( 10 ) at the conical outlet flange ( 11 ) an intake filter ( 12 ) with a supply-air fan ( 13 ) an exhaust-air pipe docking means with a lifting device ( 14 ) and an initiator ( 15 ) possibly the local control unit ( 16 ) for regulating the rate of the air supplied and allowing the classifier to operate.
The working platform ( 2 ) with the climbing ladder serves for docking onto the silo outlet ( 17 ), for connecting the exhaust-air line ( 14 ), plugging in the coded connector ( 18 ) and also for carrying out cleaning work on the classifier.
All the valves, filters, fans and classifiers that are used can be obtained as standard on the market.
The different locations of the mobile classifier result in different routes and lengths of the lines of exhaust-air pipes to the exhaust-air fan, which calls for an adapted volumetric flow of the air exhausted by regulating the exhaust-air fan. Similarly, the volumetric flow of the air supplied must be adapted to these different lengths of extraction pipes by regulating the supply-air fan ( 13 ). Furthermore, the volumetric flows of the air supplied and the air exhausted must be regulated according to the type of product to obtain optimum classification. Automatic setting of the classifier parameters is therefore helpful for the operator.
Therefore, in a preferred embodiment, an automatic location identification on the basis of a coded E-type connector ( 18 ) is made possible for each silo, fitted from the silo outlet to the classifier inlet when docking the classifier. With the connector coding, the silo is identified and, together with a table of parameters stored in the program, the control determines the required fan parameters when the type of granules is manually preselected. In order that no product can leave the silo unintentionally, this silo location identification and the assignment of the initiators ( 19 ) at the silo outlet ( 17 ) and at the telescopic pipe outlet ( 10 / 11 ) are used for monitoring allowance of the classifying process with granules.
The data transfer between the local control and the higher-level central control takes place with preference via a wireless network (WLAN). This offers the additional advantage of significantly reduced cabling for the numerous locations of the mobile classifier.
With particular preference, all the component parts that come into contact with product are structurally designed to be free from dead space. As a result, cross-contamination is avoided.
With preference, the cleaning of the plant is carried out by flushing operations with water and compressed air. The basis for effective cleaning is the structural implementation of components that are free from dead space and also of flushing water outlets.
In a preferred embodiment, the flap ( 20 ) in the supply-air pipe is closed during the flushing, so that no foreign granules can be deposited there. The flap is preferably monitored in the closed state by an initiator. Only in the opened state of the flap can the classifier then be switched on. This ensures that the supply air for a functioning classifier process is present.
With preference, the drying process is carried out by dry blasting with compressed air.
For the classifier to function optimally, the amount of granules supplied may possibly be stopped by a shut-off flap ( 6 ), in order to avoid excessive rates of flow through the classifier, or possibly accumulated amounts of granules in the classifier. For example, if the rate of granules flowing out in the filling process is too low, the inflow metering to the classifier is controlled by closing the shut-off flap ( 6 ) by means of the filling-rate monitor in the recipient vessel ( 8 ). Only when there is a sufficient amount of outflow is the flap opened and the inflow to the classifier released again.
Electrical drives, possibly locationally movable drives, are preferably used as an aid for moving the mobile classifier around. Locationally movable drives, i.e. drives which can be moved around independently and can be uncoupled from the material transported, have the advantage that they can be used for different transporting tasks. This so-called small tractor or mover ( 21 ) can be connected by a lifting mechanism, including two adaptation arms ( 22 ), with interlocking and frictional engagement onto the frame of the classifier. This allows the operator to accelerate, brake and steer the classifier by way of a driven steerable third wheel of the mover, as represented in FIG. 2 .
Thus, an improved mobile classifier is disclosed. While embodiments of this invention have been shown and described, it will be apparent to those skilled in the art that many more modifications are possible without departing from the inventive concepts herein. The invention, therefore, is not to be restricted except in the spirit of the following claims. | A mobile classifier (deduster) has docking devices, flushing devices and control for the dedusting of granules, in particular polymer granules, with preference polycarbonate granules. The mobile classifier can be set up at different locations underneath silos. To perform its function, the mobile classifier is technically connected to stationary pipelines, filters and fans. | 1 |
CROSS REFERENCE TO RELATED APPLICATION DATA
This application is a continuation application of U.S. patent application Ser. No. 13/885,157, filed on Jan. 6, 2014, and patented as U.S. Pat. No. 9,364,660 on Jun. 14, 2016, which is the U.S. National Stage of International Application PCT/US2011/060462, filed on Nov. 11, 2011, which claims the benefit of U.S. Provisional Application No. 61/412,651, filed Nov. 11, 2010; the full discloses of which are incorporated herein by reference in their entirety for all purposes.
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates generally to medical devices and methods. More particularly, the present invention relates to electrode structures and systems for delivering electrical pulses directly to the spinal cord of a patient to block pain and for other purposes.
The use of spinal cord stimulation (SCS) to relieve intractable pain symptoms originated in the 1960's along with emerging theories of the neural basis of pain perception and the pathophysiology of chronic pain disorders. Results from experimental animal studies demonstrated the existence of neural pathways that originate within the brain and project axons through the spinal cord that eventually terminate at spinal cord levels where pain signals from the peripheral nervous system enter the central nervous system. These pathways are postulated to play a role in the ‘top-down’ modulation of pain perception. Human SCS studies were initiated based on the theory that by using electrical stimulation to artificially activate descending pathways within the dorsal column of the spinal cord, the processing of pain related signals below the stimulation site could be attenuated, blocked or otherwise modulated.
Although the specific neural mechanisms that underlie the clinical efficacy of this treatment remain poorly understood, there is now abundant clinical evidence that SCS is capable of providing sustained pain relief to select patients with intractable chronic pain. The most important limitation of this treatment method is that a high percentage of patients implanted with an SCS system or device may experience only marginal improvement, or no improvement, in their pain symptoms. Treatment success rates of 50% or less are frequently reported with known SCS systems.
The neural mechanisms that mediate the clinical effects of SCS are complex and likely involve activation of multiple ascending and descending neural pathways within the spinal cord. Based on empiric clinical evidence, a number of treatment concepts have emerged to guide SCS strategies. In general, electrical stimulation will evoke sensory perceptions in the painful area of the body in order for the treatment to be effective. To accomplish this, the region within the dorsal column of the spinal cord that contains axons that are functionally related to the painful body area must be activated. Dorsal column axons are somatotopically organized, meaning that the axons that are functionally related to a particular body area are positioned in close proximity to each other, and there is an orderly anatomical pattern of organization within the spinal cord for the different groups of axons linked to different body areas. In the cervical spinal cord, for example, dorsal column axons functionally linked to the back region may be relatively close to the midline of the spinal cord, and axons linked to the arms are positioned relatively more laterally.
Adverse effects of electrical stimulation can result from unintended activation of non-targeted neural structures. When the dorsal nerve rootlets are activated, for example, discomfort can result. The effectiveness of SCS treatment is generally dependent on the capacity of the device to selectively activate targeted axons within a specific sub-region of the dorsal column, without activating the nearby dorsal rootlets. This concept is incorporated into researchers use of the term therapeutic range to describe the range of stimulus intensities that are above perceptual threshold (i.e. effectiveness threshold) but below the discomfort threshold, beyond which stimulation effects are no longer tolerated by the patient. The ideal SCS device will be capable of efficiently and safely delivering highly focused electrical stimuli to the targeted sub-region of the dorsal column without activating nearby structures. The electrode contact should be positioned as close to the targeted-axons as possible and the resulting volumetric pattern of tissue activation should tightly conform to the anatomy of the targeted neural pathway.
The spinal cord is cylindrically shaped and positioned centrally within the spinal canal. The spinal canal is lined by a dural membrane and contains cerebrospinal fluid (CSF) that surrounds the spinal cord and fills the region between the outside surface of the spinal cord and the inside surface of the dural membrane. This CSF-filled space plays a critical role in normal spinal cord biomechanics and is an important factor that should be considered when performing spinal surgery. During normal movements, such as flexion and extension of the body, the spinal cord moves within the spinal canal, altering its position relative to the dural lining of the spinal canal. The volume of CSF surrounding the spinal cord serves as a frictionless buffer during these movements. In some pathological conditions (e.g. tethered cord syndrome) this normal motion of the spinal cord is impeded by tissue attachments bridging the space between the spinal cord and the dural lining, resulting in dysfunction of the spinal cord. In other pathological conditions, a tissue barrier forms within the spinal canal (e.g. following trauma or infection) that disrupts the normal flow of CSF over the surface of the spinal cord. In this setting CSF may accumulate within the substance of the spinal cord to form a syrinx and cause neurological dysfunction.
The dural listing of the spinal canal should be managed with particular care during spinal surgery. If a detect is created in this lining, a CSF fistula may develop which increases the risk of a wound complication (infection or dehiscence) and may cause the patient to experience disabling positional headaches. In order to access the spinal cord itself, the dural membrane should be opened surgically and this is performed in a manner that allows the surgeon to achieve a ‘water-tight’ closure at the completion of the operation. Typically this involves sharply incising the dura over the dorsal aspect of the spinal canal, a location that is readily accessible and well visualized during surgery. Later the dura is re-approximated by suturing together the well defined cut margins of the fibrous membrane. This closure technique is performed in a manner that preserves the CSF filled space separating the dura from the spinal cord, thus preventing mechanical constriction, or tethering, at the surgical site.
These anatomical and surgical considerations have impacted the evolution of a wide range of operative procedures, including spinal cord stimulator surgery. When the design intent is to minimize the risk of surgical complications, the optimal strategy is to entirely avoid opening the dural membrane and place the implant outside of the dura (extra-dural procedure). If the spinal cord must be accessed directly (intra-dural procedure) the operation should be designed in a manner that prevents CSF fistula formation, mechanical tethering of the spinal cord to the dura, or physical obstruction of the CSF filled space surrounding the spinal cord.
There are limitations in the performance characteristics of the prior art. One such limitation is the following. Existing SCS devices deliver electrical stimuli through electrodes placed outside of the fibrous lining of the spinal canal (dura). This results in inefficient and poorly localized patterns of spinal cord activation due to the electrical shunting effect of cerebrospinal fluid that fills the space separating the dural lining and the spinal cord. This inability to selectively activate targeted regions of the spinal cord is thought to be an important contributing factor to the significant incidence of sub-optimal or poor treatment outcomes with existing SCS devices. Despite these limitations large numbers of patients are implanted. The size of the SCS market attests to the large scope of this public health problem and the fact that under certain circumstances, electrical activation of the spinal cord provides pain relief for patients who have failed all other treatment modalities.
A further limitation of the prior art arises in the nature of certain tethered forms of spinal cord stimulators. When SCS electrodes were first placed in human subjects, most were implanted on the surface of the dura, but in some instances the dura was opened and electrodes were placed directly on the surface (intradural) of the spinal cord (Gildenberg 2006, Long 1977, Long 1998, Shealy et al. 1970). The wires from electrodes placed directly on the spinal cord passed through the dura, thus mechanically tethering the electrode to the dura. The electrodes were constructed of conventional conductive and insulting materials, were bulky, and had a limited number of contacts through which stimuli could be delivered. The locations of the contacts relative to targeted and near-targeted neural structures were difficult to control and could not be adjusted following the implantation surgery. Because of these factors, and the increased risks associated with opening the dura, at the time there was no obvious therapeutic advantage to the intradural approach. The use of intradural stimulating electrodes was eventually discontinued and currently all SCS devices use extradural stimulating electrodes.
Still another limitation of the prior art arises in terms of the treatment efficacy. There are two broad classes of extradural stimulation electrodes. One type can be placed percutaneously through a needle into the epidural space. These electrodes have small cylindrically shaped contacts positioned along the shaft of a flexible linear electrode array. They are used either for minimally invasive testing of stimulation effects prior to implantation surgery, or as the device that is permanently implanted. The other type of extradural electrode is placed during an open surgical procedure and consists of a flat array of multiple electrode contacts positioned over the exposed dural surface. An experienced practitioner is capable of implanting these extradural electrodes with a high degree of safety. However, the current SCS devices have suboptimal treatment efficacy. We hypothesize that this shortcoming is due in large part to the inability of extradural electrodes to selectively activate the targeted sub-region of the dorsal column of the spinal cord. By placing devices outside of the dura because of safety considerations, an intrinsic disadvantage is incurred in terms of therapeutic efficacy. The presence of a CSF filled space between an extradural stimulating electrode and the spinal cord profoundly degrades the ability of the device to create a volume of electrical activation that selectively encompasses the targeted sub-region of the spinal cord. This results from the conductive properties of CSF. CSF is a far more efficient electrical conductor than any other tissue in the spine (Holsheimer 1998). When an electrical stimulus delivered by an extradural electrode traverses the dura and enters the CSF-filled space between the dura and the spinal cord, a large fraction of the stimulus is electrically ‘shunted’ diffusely within this CSF filled space. Researchers estimate that extradural stimulation results in the spinal cord receiving less than 10% of the delivered stimulus. The stimulus effect penetrates the spinal cord to a distance of 0.25 mm or less and the broad volumetric pattern encompasses both targeted (i.e. dorsal column) and non-targeted (i.e. dorsal rootlets) neural structures (He et al. 1994, Holsheimer 1998, Holsheimer 2002, Holsheimer et al. 2007).
The clinical importance of these limitations of the prior art are reflected in the numerous efforts made by device manufactures to mitigate the problems. These include the development of spatially distributed multi-contact extradural arrays and stimulation protocols that enable delivery of electrical charge distributions over widely variable anatomical patterns. This strategy allows the physician to adjust the anatomical location of maximal stimulation on the dural surface, but the presence of CSF shunting continues to markedly attenuate the stimulation effects within the spinal cord. Clinicians have also used a strategy of placing multiple cylindrical electrodes within the extradural space tor the purpose of mechanically reducing the size of the CSF-filled space and displacing the electrode contacts to a position closer to the spinal cord (Holsheimer et al. 2007). A device modification recently introduced by one of the largest manufacturer of SCS devices seeks to address problems associated with movement of the spinal cord within the CSF-filled spinal canal that occurs when patients change position. These positional changes after the spatial relationship between an extradural electrical source and the spinal cord, and the pattern of tissue activation. The new device senses patient position and automatically adjusts stimulus parameters for the purpose of achieving stable therapeutic effects. As with all other SCS design changes introduced to-date, the addition of a position sensor does not address the fundamental problem of CSF shunting of the electrical stimulus.
BRIEF SUMMARY Of THE INVENTION
The present invention addresses a major public health problem: medically intractable chronic pain. Specifically, embodiments of the invention provide devices and methods for providing effective symptomatic relief for patients suffering from chronic pain syndromes resulting from injury or disease affecting musculoskeletal, peripheral nerve, and other organ systems of the body. More specifically, embodiments of the invention provide surgically implanted devices adapted for electrical stimulation of tissues of the nervous system. Still more specifically, some exemplary embodiments of the present invention provide devices and methods for direct electrical stimulation of the spinal cord, optionally by wireless inductive coupling of signals from an electrical signal generator which may be located on the dura surrounding the spinal cord to an electrode assembly adapted to be implanted directly on the surface of the spinal cord, thus obviating the need for wires, leads or other such connections disposed through the dura. Many embodiments of the spinal cord stimulation devices described herein may be supported in engagement with the spinal cord by attaching features of the device to dentate ligaments extending laterally between the spinal cord and the surrounding dura, with either wireless or wired coupling to a signal generator disposed outside the dura. Most embodiments of the devices and methods of the present invention will electrically stimulate well defined, circumscribed sub-regions of the spinal cord with both a degree of spatial precision and a therapeutic level of electrical intensity that cannot be achieved using existing spinal cord stimulation (SCS) devices. In specific embodiments, the electrode assemblies comprise flexible electronic microcircuitry, optionally with thin-film electrode arrays, at least the latter of which are configured to be in direct physical contact with the surface of the spinal cord. The implanted electrode assemblies may be remotely powered and controlled (with no physical connections to or through the dural lining of the spinal canal), or may have a plurality of conductors extending through the dura, to selectively activate targeted regions of the spinal cord with extreme precision and the requisite electrical intensity.
The devices and methods of the subject invention address the most important deficiencies of current SCS devices in the prior art by incorporating the following design features into the device:
1) the electrical stimuli are delivered directly to the spinal cord;
2) a dense array of electrode contacts enables delivery of highly localized, spatio-temporally synchronized (could also multi-plex, alternating stimuli between various electrode montages), and positionally selective electrical stimuli to any targeted sub-region of the spinal cord;
3) the device does not mechanically tether or form a physical connection between the spinal cord and dura that significantly alters the natural support and flexibility provided by the dentate ligaments;
4) the implantable electrode assembly has as ultra-thin physical profile that does not obstruct or alter CSF flow patients around the spinal cord;
5) the contact forces between the device and the spinal cord are stable and unvarying, and hence patient movement does not affect these contact properties, which results in optimal electrical coupling between electrode contacts and spinal cord tissue;
6) the compliant nature of the device materials accommodates pulsations of the spinal cord without any harmful reactive or dissipative counter-forces;
7) the materials used to construct the device are highly resistant to electronic or structural failure with break rates that may be lower than (or similar to) existing devices, optionally using materials that are already included in stimulation implant devices or novel proprietary materials;
8) the surgical procedure (laminectomy) used to implant the device is well established and safe, and when performed by skilled practitioners, the risk of CSF fistula formation with this procedure will not differ significantly from complication rates associated with current surgical implantation procedures used to implant extradural electrode arrays;
9) the increased duration of implantation surgery, compared to current procedure times for surgical implantation of extradural SCS devices, will not exceed 30 minutes; and
10) the manufacturing cost of the new device may (in at least some embodiments) be less than that for existing devices (particularly for the ‘wired’ I-Patch).
The electrode assembly, hereinafter referred to as the Iowa-Patch (I-Patch) fulfills at least some of these design criteria, and is composed of advanced flexible electronics technologies. The electronic elements of the I-Patch are imbedded in (optionally being between layers of) a flexible polymeric or elastomeric “patch” or substrate. Electrical stimuli are delivered via an array of contacts that, when in position, can provide axial and circumferential coverage directly onto the lateral and/or dorsal surfaces of the spinal cord. Precisely localized patterns of spinal cord stimuli are achieved by selectively activating the preferred combinations of electrode contacts in any desired, programmable spatio-temporal sequences. In one embodiment, flexible polymer ‘arms’ of the device are optionally contoured to provide a continuous, gentle inward “capture” force that insures an optimal electrical interface between the device contacts and spinal cord tissue, while avoiding mechanical constriction of the spinal cord.
In one embodiment, the dorsal (outer) surface of the I-Patch contains embedded microcircuitry that implements stimulus delivery algorithms. Circuit elements may include an RF antenna that receives power and control commands from an intra- or extradural device described below, as well as other circuit elements that generate and route electrical stimuli to the appropriate electrode contacts. The self-contained I-Patch may have no mechanical or other physical connection with any other element of the SCS system. Alternatively, small gauge, flexible conductors may extend between the dura and the spinal cord along a dentate ligament, to which said conductors may be affixed, said ligaments being the structures of the body that support the spinal cord within the dura. Hence, when the device is in place there is no substantive spinal cord tethering or disruption of CSF flow dynamics around the spinal cord. All the device surfaces, with the exception of the electrode contacts, are either composed of or coated with a biocompatible insulating material, such as medical grade silicone, and the finished intradural device is very thin, on the order of (and typically being) 0.5 mm or less.
In one embodiment, the I-Patch is Inserted surgically by performing a laminectomy, creating a mid-line dorsal durotomy, inserting the device onto the spinal cords and then suturing the dura closed. Because, after implantation of some embodiments, no portion of the device penetrates the dura, and the dura is opened and closed in an optimally controlled manner, the risk of CSF fistula formation will be low.
A power and control signal transfer circuit assembly, constructed within a thin, hermetic encapsulation, is positioned either in the extradural space (over an exterior surface of the dura) or on the inside surface of the dural membrane, in either case overlying the I-Patch implant. This transfer circuit assembly generates power and command signals that are transmitted across the CSF filled space surrounding the spinal cord, and am received by the I-Patch, either wirelessly or along a conductor. The power and/or signal circuit assembly (or components thereof) may be incorporated in the main power supply battery and control circuit assembly in wired embodiments of the I-Patch. The extradural device is secured in place using sutures and includes flexible electrical leads that are connected to a power supply battery and control circuit assembly that is implanted in the subcutaneous tissue of the patient's abdominal wall. The entire system can be controlled via wireless commands that employ technologies similar to those used in standard SCS devices. The flexible microelectronics materials used are extremely robust and resistant to breakage. Such circuits have been used extensively in harsh conditions ranging from deep space (rockets and satellites) to consumer use of folding hand-held cell phones.
The I-Patch system specifically targets one aspect of SCS device performance and value: treatment efficacy. Because of improvements In the ability to precisely activate targeted sub-regions of the spinal cord, the I-Patch system will significantly improve the treatment efficacy when compared to current devices.
The I-Patch system can be used for all spinal cord stimulation applications, including treatment of patients with Parkinson's disease. Spinal Cord Injury, and Congestive Heart Failure. While usually employing surface contact electrodes, the system can also be modified to incorporate penetrating microelectrodes that emanate from the I-Patch platform and enable delivery of electrical stimuli to sub-surface neural targets. Such a system can be used not only in the spinal cord, but also in the brain and other organ systems.
One skilled in the art can see that many other embodiments of means and methods for non-contact spinal cord stimulation according to the technique of the invention, and other details of construction and use thereof, constitute non-inventive variations of the novel and insightful conceptual means system, and technique which underlie the presets invention.
Thus, in a first specific aspect of the present invention a method for treating pain in a patient comprises conformably postponing an electrode array over a surface of the patient's spinal cord so that a plurality of individual electrodes in the array directly contact selected locations on the spinal cord. Electrical stimulation energy is then delivered in a controlled spatio-temporal sequence to a targeted sub-region of the spinal cord to relieve pain without stimulating dorsal nerve rootlets. Typically, conformably positioning the electrode array comprises circumscribing a structure of the array around the spinal cord, with some embodiments circumscribing more than 180° but less than all (360°) of the spinal cord circumference. Conveniently, the circumscribing array structure can have an elastic C-shaped geometry which can be opened and elastically closed over the spinal cord to hold the electrode array in place while accommodating spinal cord pulsation and other motions. In this way, the electrode array structure when implanted to circumscribe the spinal cord will not substantially obstruct CSF flow, thus reducing the risk of syrinx formation. Alternative embodiments may circumscribe less than 180° of the spinal cord, with the electrodes of the array optionally being disposed primarily or even entirely over the dorsal surface of the spinal cord between left and right dentate ligaments.
In preferred aspects of the method of the present invention, the individual electrodes will be distributed over at least points on the dorsal surfaces of the spinal cord, and optionally over the lateral and ventral surfaces, so that sufficient regions of the spinal cord surface are contacted to permit selective actuation of the electrodes and targeted stimulation of a variety of spinal cord anatomical sites as described in more detail below. As described above, stimulation of the implanted electrode structure on the spinal cord will optionally be achieved by wirelessly transmitting energy to the electrode array from a signal generator disposed remotely from the array. Usually, the signal generator will be implanted to lie either directly on the external surface of the dura or just underneath the internal surface of the dura, preferably directly over the implanted location of the spinal cord electrode array. Alternatively, however, the signal generator in some cases could be more remotely located and provide for transcutaneous or other remote transmission of power and signal to the implanted spinal cord electrode array. Embodiments may include one or more flexible conductors (such as a flex-circuit, conductor wires, or conductor cables) extending between the array structure and an implanted generator system, with the conductors traversing through the dura and often extending along and being affixed to a dentate ligament.
In still further aspects of the present invention, an electrode array adapted to conform to an exterior surface of a patient's spinal cord comprises a compliant backing having an interior surface and an exterior surface, where the interior surface is adapted to lie in contact directly over the exterior surface of the spinal cord. A plurality of electrodes are formed over at least a portion of the interior surface, and transceiver and control circuits are disposed on or immediately beneath the exterior surface of the compliant backing. The transceiver's antenna may be adapted to receive power and signals from a remote signal generator, as described above, while the circuitry will be able to accept and process power and information signals from the antenna and convert the resulting currents to nerve stimulating pulses to be delivered by the electrodes to the spinal cord. The electrode array may include a C-clamp structure adapted to resiliently circumscribe at least a portion of the spinal cord, preferably circumscribing over 180° of the circumference while not completely enclosing the entire circumference.
In some preferred embodiments, the electrode circuitry carried by the electrode array will be adapted to selectively stimulate individual electrodes in response to the external signals received by the transceiver's antenna in order to deliver spatio-temporally selected stimuli to targeted regions of the spinal cord. Hence, a signal generator or other external circuitry may be programmed to treat particular conditions by stimulating targeted regions of the spinal cord, and such targeted stimulation will be achieved by selectively energizing particular ones of the individual electrodes which are part of the electrode array. Preferred anatomical target regions within the spinal card will be chosen by the neurosurgeon and consulting neurologists and might include the thoracic, lumbar and sacral regions.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a cross-sectional diagram of selected anatomical elements of the spinal cord.
FIG. 1A shows a cross-sectional view of the spinal cord with specific anatomical locations identified.
FIG. 2 shows a cross-sectional diagram of the results of extradural stimulation of the spinal cord.
FIG. 3 shows an illustration of the principal electronic subsystems resident on a wireless embodiment of the I-Patch receiver element or array structure.
FIG. 4 shows an illustration of the underside of the I-Patch receiver element of FIG. 3 , which would be in contact with the surface of the spinal cord.
FIG. 5 shows the deployment of the I-Patch receiver device on the surface of the spinal cord.
FIG. 6 shows a lateral view of the relative positions of the wireless I-Patch transmitter and receiver devices, on the surfaces of the dura and spinal cord, respectively.
FIG. 7 shows a cross-sectional view of the relative positions of the I-Patch transmitter and receiver devices, on the surfaces of the dura and spinal cord, respectively.
FIG. 8 shows a schematic representation of the inductive coupling action taking place between the I-Patch transmitter and receiver devices.
FIG. 9 illustrates a I-Patch having penetrating electrodes for accessing internal target regions within the spinal cord.
FIGS. 10-13 illustrate a full-circumference pliable electrode structure and method of implantation, intended to fully circumscribe the spinal cord to provide access to additional targeted regions therein.
FIGS. 14, 15, and 15A illustrate spiral and staggered electrode patch variations according to the present invention.
FIGS. 16 and 17 illustrate an insertion device for implanting the electrode assembly of the present invention on a spinal cord.
FIGS. 18 through 21 illustrate an intra-dural relay device for delivering power and signals to the implanted I-Patch when implanted on the spinal cord.
FIGS. 22 and 23 show exemplary schematic diagrams of one embodiment of the circuitry that might be incorporated onto the I-Patch implant
FIG. 24 shows the postulated somatotopic organization of the dorsal spinal column axons.
FIGS. 23 and 25A show a perspective view and an axial view of the anatomical arrangement of the spinal cord tissues, including the presence of the dentate ligaments which support of the spinal cord within the spinal canal.
FIGS. 26 and 26A show a top down or dorsal view of an alternative embodiment of an I-Patch supported on a dorsal surface of a spinal cord by fixation to a dentate ligament so as to support the I-Patch, respectively.
FIGS. 27 and 27A show a perspective view and a plan view of yet another alternative embodiment of an I-Patch configured to be supported by arms that clamp to dentate ligaments on either side of the spinal cord.
FIGS. 28-28F illustrate a still further ‘wired’ alternative embodiment of an I-Patch secured to dentate ligaments, along with implantation of the device so that a lead extends along (and is attached to) one of the dentate ligaments arm is sealed where it extends through the dura.
FIG. 29 schematically illustrates en electrode extending from an interior surface of a hacking or substrate of an array structure of the I-Patch.
FIG. 30 schematically illustrates individual electrodes flexibly mounted to a backing or substrate by a soft resilient material so as to allow the electrode to float and inhibit sliding movement of the electrode against a surface of the spinal cord during pulsation.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a cross-sectional diagram of selected anatomical elements of the spinal cord. These include the layer of dura mater 10 that encompasses the spinal cord SC and encloses the spinal canal, the dorsal nerve rootlets 12 , the zone of cerebrospinal fluid 14 that separates the outer surface of the spinal cord from the inner surface of the dura, and the axons 16 that would be targeted by spinal cord stimulation instrumentation.
FIG. 1A illustrates the complex anatomical arrangement of the postulated human spinal cord pathways. In the large dorsal column pathways (f. gracilis, f. cuneatus) activation of large numbers of axons that are located greater than 0.5 mm deep below pial surface will likely result in broader somatotopic coverage of painful areas of the body and an increased magnitude of pain attenuation effects. Activation of axons within deeply positioned dorsal mid-line structures (e.g. septomarginal f., posterior proper f.) may result in complete relief of visceral pain. Pathways positioned within the lateral and anterior regions of the spinal cord are not activated by current SCS devices. There are many potential stimulation targets in these regions, including the posterior and anterior spinothalamic tracts which conduct pain and temperature signals to the brain.
Spinal cord stimulation may also be effective in treating patients with movement disorders (e.g. Parkinson's Disease). There are a large number of potential motor and motor-modulation pathways throughout the human spinal cord that may represent optimal targets for this novel clinical application, e.g. lateral cerebrospinal f., rubrospinal, tectospinal f., dorsal spinocerebellar f., ventro spinocerebellar f., all of which are beyond the range of current SCS devices. The I-Patch system (surface and penetrating electrode variants) will be capable of selectively activating any spinal cord pathway, in any location, in a patient with a functionally intact spinal cord. Stimulation of these sites will likely result in markedly improved spinal cord stimulation clinical efficacy.
FIG. 2 shows a cross-sectional diagram of the results of extradural stimulation of the spinal cord. The standard epidural stimulating electrode 20 is placed on the outside of the dura, and the field it produces is attenuated significantly by the presence of the CSF 14 . The resulting field within the spinal cord is very weak, having little effect on the targeted dorsal column axons, but instead causing discomfort tor the patient via parasitic activation of the dorsal rootlets 12 .
FIG. 3 shows a conceptual illustration of the principal electronic subsystems resident on a wireless embodiment of the I-Patch receiver or array structure element 28 . Seen there (on the left) are the turns of a microfabricated coil 30 that is configured to serve as an RF receiver that couples inductively to the counterpart coil on a paired transmitter element, this enabling the I-Patch to receive power, information, and control signals. Also shown (on the right) are the circuits 32 constituting the control elements that regulate the size, timing and distribution of the stimuli that act on the electrodes 34 (center). Flexible attachment arms 36 extend from either side of a central body of the I-Patch, with the attachment arms typically being formed at least in part of the substrate or backing material on which circuit components 32 are mounted or formed.
FIG. 4 shows an illustration of the underside of the I-Patch receiver element, which would be in contact with the surface of the spinal cord. The electrodes 34 (center) are positioned by the neurosurgeon over the region of spinal cord to be stimulated. The underside of the biocompatible I-Patch is in contact with the surface of the spinal cord, and held to it by the gentle clamping action of the extension arms 36 shown in the figure.
FIG. 5 shows the deployment of the I-Patch receiver device 28 on the surface of the spinal cord SC. The extension arms 36 of the receiver device 28 partially encircle the body of the spinal cord SC, thus gently clamping the I-Patch to it. The extension arms are positioned to reside between the dorsal rootlets 12 , and not be in contact with them. Under some circumstances a number of dorsal rootlets may be sectioned to accommodate placement of the I-Patch.
FIG. 6 shows a lateral view of the relative positions of the I-Patch transmitter 40 and receiver 28 devices, on the surfaces of the dura 10 and spinal cord SC, respectively. The transmitter 40 and receiver 28 patches are inductively coupled to each other by electromagnetic fields established through current flows in the windings on their respective surfaces. The strength of the coupling can be adjusted by regulation of the strength of the current flow. In this way, power, information, and control signals can span the zone of CSF resident between the inside surface of the dura and the outer surface of the spinal cord.
FIG. 7 shows a cross-sectional view of the relative positions of the I-Patch transmitter 40 and receiver 28 devices, on the surface of the dura 10 and surface S of the spinal cord SC, respectively. By positioning the very thin I-Patch receiver directly on the surface S of the spinal cord SC, it is possible to drive the electrodes such that the stimuli fields penetrate through the whole treatment zone of interest and are not attenuated by the CSF. Also, this type of stimulus field concentration insures that there is no parasitic excitation of the dorsal rootlets, with the resulting associated pain. To a rough approximation, the instantaneous electric field, E, within the stimulation stone will be given by E=σ/2κ∈ 0 where σ is the surface charge density created at the electrode's surface, κ∈ 0 is the product of the dielectric constant of the spinal cord substrate and the permittivity of free space. End effects associated with the geometry of each individual stimulus electrode will modify this simple model, as will superposition of the fields due to the simultaneous activation of one or more neighboring electrodes.
FIG. 8 shows a schematic representation of the inductive coupling action taking place between the I-Patch transmitter 40 and receiver 28 devices. As seen there, the power, information, and control signals generated by the transmitter device on the dura side of the system are inductively coupled across the CSF fluid to the receiver device, where they are operated on by the on-board controller, and stimuli signals are distributed to the electrodes. The inductive coupling action is governed by the mutual inductance between the two sets of windings.
The optional ‘wireless’ design of the I-Patch system is a very important design aspect of some embodiments. However, alternative embodiments employ ‘wired’ versions of I-Patch devices that are safe and effective, as described below. Embodiments of these wired devices may have higher rates of mechanical failure and be associated with increased risks of complications compared to a wireless I-Patch version, but would function and potentially be useful for certain applications.
The I-Patch can deliver electrical stimuli to regions of the spinal cord that are targeted by current SCS devices. This is accomplished by positioning electrodes on the pial surface of the spinal cord. It is highly likely that therapeutic effects can also be achieved by selectively stimulating circumscribed sub-regions of the spinal cord positioned deep to the pial surface. In fact, the spatio-temporally selected electrical stimulation of certain structures within the central regions of the spinal cord may result in therapeutic benefits that cannot be achieved with surface stimulation. A broad range of clinical applications, beyond the currently targeted chronic pain treatments, will likely be available via placement of chronic penetrating I-Patch electrodes (e.g. activation of motor pathways to treat patients with movement disorders or paralysis).
The penetrating electrode I-Patch 50 is illustrated in FIG. 9 . Multi-contact penetrating electrodes 52 extend from the I-Patch main assembly 54 . The interface between the main assembly and penetrating electrode shaft may be held rigid (at least during implantation), allowing the surgeon to insert the penetrating electrode into the spinal cord by advancing the I-Patch device toward the dorsal spinal cord surface using the I-Patch Applier. Once the main assembly is in contact with the surface of the spinal cord, the flexible I-Patch attachment arms are optionally released restating in a stable attachment between the spinal cord and the electrode assembly. In some embodiments, the electrodes may, after implantation, be supported relative to each other and the substrate or backing of the I-Patch with resiliently flexible materials, thereby allowing the overall array of electrodes to accommodate pulsation and the like. Suitable resilient flexible support of the electrodes may be provided using a flexible material spanning between the electrode and walls of an aperture through the substrate, with the flexible material optionally comprising a separate layer bonded to the substrate, material insert molded within apertures through the substrate, or the like. Electrical stimuli are delivered through select penetrating electrode contacts using control circuitry embedded in the I-Patch main assembly. The geometric contour of electrical stimulation effects surrounding a given penetrating electrode contact is shaped by the selection of other I-Patch surface and penetrating electrode contacts that are incorporated into bi-polar, or multi-polar stimulation montages.
Clinical applications that target neural pathways on ventrally located surface structures of the spinal cord that may be targeted with a malleable full-circumference I-Patch prototype as illustrated in FIG. 10 .
In contrast to the I-Patch designs with elastic C-clamps, as described above, the device 60 of FIG. 10 is fully pliable and has no ‘memory’ of the curvature of the spinal cord. A dense array of electrode contacts 62 is imbedded in a flexible band 64 extending from a body of the device and capable of fully circumscribing the spinal cord. This flexible band 64 is inserted in the space between the dura and the spinal cord and gently advanced until the leading edge is visible on the opposite side of the spinal cord ( FIGS. 11 and 12 ). The leading edge of the electrode hand is then crimped, pinned or otherwise seemed to the main assembly of the I-Patch device ( FIG. 13 ) by a crimping device 66 or the like.
The pliable band achieves the objective of positioning electrode contacts in an un-interrupted linear array covering the entire circumference of the spinal cord. The drawbacks of this design are that the insertion technique is more difficult and associated with increased risks compared to the standard I-Patch. When advancing the electrode band around the circumference of the spinal cord there will be a small risk of injuring nerve roots or causing a hemorrhage. Also, the mechanical contact, and thus electrical coupling, achieved between the electrodes and spinal cord surface will be less optimal than with the standard I-Patch prototype. The full-circumference band cannot be attached so tightly that it impedes spinal cord pulsation; this would result in injury to the neural tissue. Conversely, a ‘loose fitting’ circumferential band will not exert the optimal inward forces on the electrode contact and thus allow spinal fluid to flow between the electrode contact and the pial surface resulting its sub-optimal electrical coupling. One potential design variant would involve having the electrode contacts protrude from the flexible band, allowing tor firm contact between electrodes and the pial surface, but also gaps between the pial surface and the non-electrode bearing portions of the flexible arm. These gaps would accommodate pulsatile spinal cord expansion and contraction.
Alternative patch designs with reduced spinal cord compression and improved accommodation of spinal cord pulsations are illustrated in FIGS. 14 and 15 . The devices of FIGS. 14, 15, and 15A have incomplete ring configuration and elastic properties that enable the devices to gently expand and contract along with the spinal cord. The I-Patch variant 70 of FIG. 14 has spiral attachment arms 72 , and the staggered I Patch variant 80 of FIGS. 15 and 15A has staggered arms 82 .
The devices of FIGS. 14 and 15 further reduce the degree of mechanical constriction in a given cross-sectional portion of the spinal cord. The net effect of gently exerting inward forces on the device to maintain contact with the spinal cord is achieved by ‘staggering’ the attachment arms, or by using ‘spiral’ configured attachment arms.
An I-Patch applier (IPA) 90 is illustrated in FIGS. 16 and 17 . The IPA 90 will preferably enable the surgeon to maintain a rigid, but reversible attachment to the I-Patch main assembly of receiver 28 . While maintaining a rigid attachment of the I-Patch with a main assembly of the IPA 90 , the surgeon will have the ability to adjust the position of the I-Patch's pliable attachment arms in an incremental, precisely controlled, and reversible manner. After the I-Patch is placed on the surface of the spinal cord, and the flexible attachment arms are in their final position, the IPA allows the surgeon to safely and efficiently detach the I-Patch from the IPA.
The IPA 90 can be used as a hand-held device, or attached to an intra-operative mechanical advancer device. The surgeon controls the position of the IPA fey controlling the insertion device rod 92 ( FIG. 16 ). A stabilizing plate 94 is attached to the end of this rod 92 . The plate 94 is contoured to match the curvature of the I-Patch device 28 , which in turn is contoured to match the curvature of the spinal cord SC. The I-Patch main assembly contains the transceiver antenna and control circuitry and fits snuggly into IPA stabilizing plate 94 .
The I-Patch flexible attachment arms 36 extend away from the main assembly and are contoured to follow the curvature of the spinal cord surface S. The distal ends of these flexible arms 36 can be reversibly extended during the insertion procedure in order for the I-Patch to be placed oh the spinal cord SC. This function is achieved by securing a suture through an eyelet 96 positioned at the termination points of the flexible arms 36 . A double strand suture 98 is then passed through a series of islets 100 until secured to a suture tension adjustment rod having a knob 102 . The surgeon rotates this rod to adjust the conformation of the extension arms. When the I-Patch is being inserted onto the spinal cord, the adjustment rod is rotated into a position that achieves the desired degree of flexible arm extension. Once the I-Patch is in the desired position, the surgeon rotates the adjustment rod until the flexible arms have returned to their pre-formed position, resulting in uniform, gentle, direct contact of the entire I-Patch device with the spinal cord surface. The surgeon then disengages the IPA from the I-Patch by cutting the tension sutures. The cut sutures are gently removed, followed by removal of the IPA. The entire insertion procedure should be accomplished in approximately 15 seconds ( FIG. 17 ).
The I-Patch system will typically include a thin-film extra-dural device 40 that wirelessly transmits power and command signals to the spinal cord electrode assembly 28 This extra-dural device element 40 achieves the following design goals. Optionally, no physical connection between the power/command relay device and the spinal cord electrode (i.e. no ‘tethering’). No physical obstruction of the CSF surrounding the spinal cord (avoid risk of syrinx formation). Optionally, no device elements penetrate the dura in a manner that would result in an increased risk of CSF fistula formation. The distance, or gap, across which wireless transmission occurs can be made be as short as possible without compromising the other device design specifications.
The extradural relay device 40 , however, will be exposed to blood products/plasma serum that always accumulates in the extra-dural space following surgery. In some instances, these materials could accumulate in the space between the extra-dural device and dura, altering the spatial and electromagnetic relationships between the relay device and the spinal cord implant. While this will not usually be a concern, under certain circumstances the electromagnetic coupling between the extra-dural and spinal cord elements may be affected, as it is highly sensitive to relative spatial relationships and the dielectric properties of intervening materials.
An intra-dural relay device (IDRD) 120 as may be used an alternative to the extra-dural relay element 40 and may have superior performance characteristics under certain circumstances. The IDRD 120 includes a thin film power/command relay device body 122 that is placed on the inner surface of the dura lining the dorsal aspect of the spinal canal See FIGS. 18 through 21 . The pliable thin film device 122 contours to the curved surface of the dorsal spinal canal dura and is held in place with sutures 124 . It is placed after the spinal cord electrode array device 28 is positioned, at the beginning of the dural closure procedure. The doral closure procedure does not differ significantly from the standard closure procedure. The risk of CSF leak around the lead cable emanating from the thin film IDRD is eliminated by using a simple ‘washer’ clamping method at the lead cable exit site. Following surgery, the IDRD body 122 will lay flush with the inner surface of the dura. The IDRD's low profile will not obstruct CSF flow. The spatial relationship between the IDRD and spinal cord electrode away will not be altered by the post-operative accumulation of blood products in the extra-doral space. The surgical technique fur suturing closed the dura will not differ significantly from that used with the ‘standard’ I-Patch procedure. Only additional seconds are required to place the ‘washer’ and crimping device, such as by sliding a dual compression washer 126 along a flexible lead 128 beyond a groove 130 so as to secure the washer in position by a clamping or washer compression device 140 , with the dura clamped between the washer 126 and a flanged, flat backstop 132 of IDRD body 122 . The IDRD 120 can be secured in position under the surface of dura 10 within cut dura edges 134 with stay sutures 136 placed at proximal and distal ends of the IDRD body 122 . Dural edges 134 can be approximated by sutures 138 , and washer 126 can then be slid along lead 128 beyond groove 130 so that the crimp or washer compression device 140 engages the groove.
FIGS. 22 and 23 show one embodiment of the electronic elements that might be on-board the I-Patch spinal cord implant. FIG. 22 shows the transceiver coils that inductively couple power and information signals into the circuit. A bridge circuit converts the ac signals to de voltage levels, in order to provide power to the rest of the circuit. A reset signal is generated from the input pulses via a Schmitt trigger. FIG. 23 shows the other elements of the control and pulsing circuit. These consist of a phase-locked-loop that generates a pulse train which is operated on by a counter, and a 3-bit to 8-line decoder that, with a monostable multivibrator, converts the counter's wavetrain into signals that are distributed to selected electrodes. The above-mentioned reset signals are used to clear the circuit elements at the end of each pulsing cycle.
FIG. 24 shows the somatotopical organization of the dorsal spinal column axons. Embodiments of the devices, systems, and methods described herein may make use of such organization by selectively energizing electrodes of the array structure 28 so as to inhibit focal pain of (or otherwise treat) somototopically corresponding anatomy of the patient. Axial regions T 11 , T 12 , L 1 , and L 2 are associated with low back signals; L 3 , L 4 , and L 5 are associated with leg and foot signals 152 ; and S 1 -S 4 are associated with pelvis signals 154 ; so that stimuli applied to one of these regions may provide therapeutic effects for pain of the associated anatomy. Note that limiting lateral transmission of stimuli by employing direct contact or near field signal transmission from a discrete electrode of the array to the spinal cord may be particularly beneficial for treatment of low back pain or the like, as the axons associated with low back pain may be located in close proximity to the dorsal root entry zone DREZ, and inhibiting transmission of spurious or collateral signals to the DREZ may improve the efficacy and/or decrease deleterious effects of the therapy.
FIGS. 25 and 25A show dentate ligament structures that extend laterally between the spinal cord and surrounding dura. More specifically, FIG. 25 is a profile-view diagrammatic representation of the human spinal cord with surrounding meninges. Arachnoid mater A is closely applied to the thick outer dura 10 . An intermediate leptomeningeal layer IL lies between the arachnoid mater A and the pia mater. This layer is fenestrated and is attached to the inner aspect of this arachnoid mater. It is reflected to form the dorsal septum S. Dentate ligaments 160 are present on either side of the spinal cord SC. The collagenous core of the dentate ligaments fuses with subpial collagen medially and at intervals laterally with dural collagen, as shown on the left side of the diagram. Blood vessels V within the subarachnoid space are seen along a surface of the spinal cord SC. As cart be seen in the axial section through the spinal cord of FIG. 25A , dorsal rootlets 162 and ventral rootlets 164 may extend from spinal column SC dorsally and ventrally of denticulate ligaments 160 , with the dentate ligaments generally attaching the left and right lateral portion of the spinal cord SC to left and right regions along an internal surface of dura 10 . Additional details regarding these anatomical structures may be understood, for example, with reference to “The Fine Anatomy of dm Human Spinal Meninges” by David S. Nicholas et al.; J. Neurosurg 69:276-282 (1988); and to “The Denticulate Ligament: Anatomy and functional Significance” by R. Shane Tubbs et al.; J. Neurosurg 94:271-275 (2001).
FIGS. 26 and 26A show yet another alternative embodiment of an I-Patch 170 having an electrode array 34 supported by a body 172 including a flexible substrate or backing as described above, with the array here configured to engage a dorsal portion of the spinal cord SC. Dentate ligament attachment features such as flexible arms 174 extend laterally from left and right sides of body 172 , with the arms optionally comprising the same substrate or backing material from which the body is formed. These arms or other features are configured to be attached to left and right dentate ligaments 160 on either side of the treatment region of the spinal cord so as to support the array 34 in engagement with the surface of the spinal cord.
The dentate ligament provides a thin, but high tensile strength fibrous attachment that extends from the lateral spinal canal wall to fuse with and attach to the pia-arachnoid membrane on the lateral surface of the spinal cord, approximately at the ‘equator’ of the cord as viewed in cross-section. This location and geometry is well suited for gently exerting a desirable amount of downward/inward pressure on the I-Patch, optionally without having to resort to sutures and without using any ‘non-targeted’ parts of the spinal cord as points of attachment. The body of dentate-ligament supported I-Patch device 170 may be largely or entirely flexible and/or elastic. Electrodes 34 may be arrayed to provide coverage within the dorsal column of the spinal cord and may be embedded in a flexible silicone-type, biocompatible material. The dentate ligament attachment features such as attachment arms 174 may be more highly elastic, optionally having no electronic elements contained within them, and may extend laterally from the electrode-bearing body portion of the device. These attachment arms can be thin (optionally being thinner than the substrate adjacent the electrode array), flat, and/or floppy. The attachment arms may ‘flair’ to a larger width adjacent the ends opposite the array, and/or may have slightly raised groves or texture at or near these ends to facilitate clipping, crimping, and/or adhesively bonding the arms to the dentate ligament.
During implantation, the dentate ligament supported I-Patch device 170 may be placed and centered over the exposed dorsal column of the spinal cord. A small number of rootlets may optionally be sectioned to create room for the attachment arms (as may also be done with other I-Patch embodiments). The flared end of each attachment arm can be draped on the dentate ligaments on either side of the spinal cord. With the patient in the prone position the gravitational forces will result in a gentle fit of the electrode bearing portion of the I-Patch on the dorsal spinal cord. The amount of downward gravitational force exerted on the I-Patch will not be large enough to occlude surface blood vessels. The preferred points of contact will be between an array of slightly protruding electrode contacts and the pial surface of the dorsal columns. Microchips 176 or other types of fixation or crimping devices can be used to secure the attachment arms to the dentate ligaments. Metal microclips used in a variety of surgeries (e.g. Week Clips) may be employed, though non-metallic clips or other fasteners may have particular advantages, and are used widely for endoscopic surgical procedures. A relatively broad surface of attachment is beneficial because of the thin, almost spider web nature of the dentate ligament. An approximately 3 mm clip may, for example, be employed. Alternatively, a tissue glue could be used. With many techniques, there is no requirement for the I-Patch, or I-Patch attachment arms to be jostled or manipulated into position. The device is simply draped on the dorsal spinal cord surface and dentate ligaments, and secured in place. With these embodiments, the ‘point of attachment’ or ‘anchor point’ of the device may be on connective tissue rather than spinal cord tissue, limiting the clinical significance of any damage to the supporting tissue structure.
A variety of alternative dentate ligament-supported I-Patch embodiments may be provided, including embodiment 190 of FIGS. 27 and 27A . In general, these embodiments of the I-Patch should be highly flexible so as to avoid restricting normal spinal cord pulsations in-situ. Firm, constant mechanical contact should be achieved between the electrode surfaces and the pial surface of the spinal cord. A ‘cue size fits’ all design is desirable, whereby a standard device can accommodate almost the full range of spinal cord anatomy variants encountered in patients, and/or where a limited number of sizes (1-5) will span a significant patient population. The implantation procedure should be simple, safe, last and un-complicated. Toward that end, embodiment 190 makes use of the dentate ligaments 160 to serve as a purchase point for a malleable I-Patch electrode array. There is a simple clasp 192 at the end of each malleable or plastically deformable I-Patch attachment arm 194 . In the operating room, the surgeon secures the ends of each attachment arm 194 to the dentate ligaments 160 . These ligaments are comprised of connective tissue and have no innervation. They are firmly attached to the lateral margin of the spinal cord. The highly elastic/malleable I-Patch electrode assembly 190 is thus secured to the spinal cord surface. Advantages of this and/or other dentate ligament supported I-Patch variants may include a relatively simple electrode design. Also, these embodiments should result in excellent mechanical contact between electrodes and pial surface, as the dentate ligaments will easily withstand the chronic forces exerted on them by the I-Patch. The variability provided through deformable arms may allow a ‘one size fits all’ (or limited number of sizes) in the device, and the implantation procedure may be relatively less complicated. Penetrating electrodes may optionally be employed in place of the contact electrodes, with the body of many of the dentate ligament embodiments optionally providing a pial surface platform to which such electrodes could be mounted.
FIG. 28-28F illustrate a still further ‘wired’ alternative dentate ligament (DL) supported embodiment of an I-Patch 200 , along with implantation of that device so that a lead extends along (and is attached to) one of the dentate ligaments and is sealed where it extends through the dura. Wired DL I-Patch 200 has a flexible lead that extends through dura 10 , with the lead preferably extending along one of the DL attachment arm 174 . The lead then optionally runs laterally and dorsally, hugging the inner surface of the dura 10 , optionally using a staple, clip, suture, or stapled bracket 210 to maintain the position of the lead against the dura. The lead 202 may exit the dura 210 along the midline. By placing crimping clips 176 to secure the lead hearing I-Patch attachment arm 174 to the DL 160 , a strain relieving function will be achieved. This should prevent torquing on the I-Patch by the leads and injury to the spinal cord with spinal cord movement. As shown in FIGS. 28B-28F , a dura-traversing lead fitting 212 can help inhibit lead migration and facilitate water-tight dural closure, with the lead optionally being disposed along a re-approximated mid-line durotomy after closing most of the incision using standard techniques. A compression clip 216 can engage fitting 214 to help seal the doral leaflets to each other around fitting 214 , and tissue glue 218 can also be placed on and around the compression clip to effect closure.
FIG. 29 schematically illustrates an electrode extending from an interior surface of a backing or substrate of an array structure of the I-Patch. The therapeutic benefit of the I-Patch to the patient may be enhanced by maximizing the SCS current densities in the targeted conducting tracts of the spinal cord itself, while minimizing the current density shunted away by the CSF. This benefit may be enhanced by engaging the electrodes against the surface of the spinal cord as shown, with a stand-off column 220 extending between the exposed portion of the electrode 34 and the underside of the implant substrate body 222 . This can support the implant off the surface S of the spinal cord SC by about 100 μm to accommodate micropulsations of the spinal cord, as described above. By insulating the surface of stand-off column 220 , it is possible to minimize the shunting effect of the CSF, as the exposed portion of the electrode will be in contact only with the pial surface of the spinal cord, and not with the CSF itself. Gentle inward pressure causes slight inward “dimpling” of the pial surface by the electrode. As a result, the un-insulated (active) exposed surface of the electrode is “sealed” by spinal cord tissue enveloping the protruding portion of the contact. A small gap separates the electrically inactive portions of the I-Patch device, providing space into which the spinal cord tissue may expand and contract with cardiac pulsation cycles.
FIG. 30 schematically illustrates individual electrodes 34 flexibly mounted to a backing or substrate 230 by a soft resilient material 232 so as to allow the electrode to resiliently float or move radially and/or laterally relative to the substrate by a distance that is at least as large as the pulsations of the surface S of spinal column SC. This movement of the individual electrodes may inhibit sliding engagement of the electrodes against the surface of the spinal cord during pulsation. In some implementations of the I-Patch the only parts of the I-Patch device that directly engage the spinal cord are the electrode contacts. These may serve as mechanical anchoring points for the device. They should exert just enough pressure to maintain good electrical contact with the surface of the spinal cord. The pressure exerted on the spinal cord by the contacts should be generally even for all of the contacts. Some embodiments achieve this by having electrodes protruding slightly from contoured attachments arms. These contoured attachment arms position all contacts in the desired position relative to the surface of the spinal cord. Outward and inward movements of the contacts (e.g. with pulsations and respirations) are accommodated by movements of the semi-rigid attachment arms. Unfortunately, this makes significant demands on the mechanical characteristics of the attachment arms. The arms may benefit from being contoured to a spinal cord of individual patients, and they should be constructed of materials that both bold this contour for a decade or more, yet expand and contract to accommodate spinal cord expansion/contraction.
The mobile electrode approach facilitates design and material performance goals of the attachment arms. Each contact is mobile and attached to the I-Patch via an elastic/spring-like interface. The degree to which each contact extends out from the attachment arm is determined by the distance separating the attachment arm from the spinal cord surface at each contact location. The elastic nature of the connection between each contact and the attachment arm/body cause each contact to independently protrude out from the device until the desired tissue contact/force interface is achieved. In this way desirable mechanical; interfaces are achieved between some, most, or all electrode contacts and the spinal cord, even if the attachment arms/body do not conform perfectly to the shape of the spinal cord. Also, the elastic interface allows the contacts to slide in and out with expansion/contraction of the spinal cord without attachment arm movement. With mobile contacts, the attachment arms can be more rigid and will not be required to perfectly follow the contour of each patient's spinal cord.
In the embodiment of FIG. 30 , electrode bodies 234 extend through apertures 238 in substrate 230 , with the substrate being pliable and having elasticity appropriate to supporting thin film circuit components. A soft elastomeric material 236 spans the apertures from substrate 230 to the electrode bodies, with the elastomeric material here comprising a sheet of material adhered to the outer surface of the substrate. In other embodiments, the electrodes may be supported relative to each other and the substrate with a soft elastomeric material spanning directly between the electrode and walls of the aperture (such as by insert molding the material into the apertures with the electrode bodies positioned therein). In still further alternative embodiments, the resilient material may form column 220 or the like. Flexible conductors (not shown) may extend between the substrate and electrode bodies within or outside the elastic material with these conductors optionally being serpentine, having loops, or the like to accommodate movement of each electrode body relative to the substrate.
As can generally be understood from the description and the parent provisional application, embodiments of the invention provide an implantable electronic system including and/or consisting of a signal generator means and a signal transceiver means. The transceiver means conforms to a surface structure of a region of spinal cord in a patient. The transceiver means is able to receive signals wirelessly from said signal generator means, and to process said signals according to an algorithm. The algorithm is then able to cause said transceiver means to generate electrical stimuli according to said algorithm. Said stimuli can be applied by electrodes of said transceiver means to selected points on the surface of said spinal cord in said patient.
Optionally, the transceiver means may include and/or consists of an electronic circuit, a pliable substrate containing said electronic circuit, a plurality of contact points that apply said stimuli from said circuit to said spinal cord, and attachment arms that hold said pliable substrate in non-damaging contact with said spinal cord.
In some embodiments, said generator of said wireless signals consists of a signal production means and an inductive coupling means such as a planar coil prepared on the surface of a pliable substrate. In some embodiments, said planar coil of said signal generator means is configured and positioned so as to conform to the inner or outer surface of a region of the dura mater surrounding the spinal cord. In some embodiments, said planar coil of said signal generator means deployed on a region of said dura mater of said spinal cord and said transceiver means deployed on the actual surface of said region of said spinal cord are positioned in proximity to each other and separated only by the thickness of said dura mater itself and/or by the layer of cerebrospinal fluid filling the gap between said inside surface of said dura mater and said outer surface of said transceiver means which is in intimate contact with said region of spinal cord.
In some embodiments, said planar coil of said signal generator means communicates inductively with an opposing coil that is part of said electronic circuit means on said transceiver means in order to transfer electrical power and electrical control signals from said generator means to said transceiver means, as in an electromagnetic transformer. In some embodiments, said electronic circuit on said transceiver means further consists of circuit elements that may include an information processing means, a memory means, a bus means, a signal distribution means and other means for executing the function of the device according to the method of the invention. In some embodiments, said information processing means of said transceiver means is able to execute one of a plurality of algorithms that are resident either within said memory means of said transceiver or within said generator, with said algorithm being chosen in response to the physiological and anatomical needs of said patient.
The electrical stimuli produced by said transceiver means in response to the action of said algorithm means can be applied to selected points on said region of spinal cord of said patient in response to the physiological and anatomical needs of said patient The electrical stimuli produced by said transceiver means arc generated as desired for the treatment of intractable pain as might be caused by musculo-skeletal disorders, neoplasms, arthritic degenerations, neurodegenerative disorders, trauma and/or the like.
The circuit of said transceiver may include an assembly of discrete or integrated analog and digital components. The analog circuit elements within said transceiver may include active and passive components. The digital circuit elements within said transceiver may operate on electronic pulses, analog or digitized waveforms, dc voltage levels, and/or combinations thereof. The electronic circuit for said transceiver may incorporate a signal multiplexer that is able to distribute a plurality of stimulus signals to a plurality of electrodes in contact with a spinal cord of a patient. The electronic circuit for said transceiver may incorporate a phase-locked-loop system for detecting, synthesizing or processing a plurality of electronic waveforms, pulses and combinations thereof, for subsequent use in generating and distributing stimulus signals to a plurality of electrodes in contact with a spinal cord of a patient. The electronic circuit for said transceiver may incorporate frequency-shift keying and/or pulse-width modulation means for detecting, synthesizing or processing a plurality of electronic waveforms, pulses and combinations thereof for subsequent use in generating and distributing stimulus signals to a plurality of electrodes in contact with a spinal cord of a patient. The electronic circuit for said transceiver may contain subcircuits to prevent accidental delivery of excess voltages to the spinal cord of a patient during the normal application of stimulus signals. The electronic circuit for said transceiver may contain ferrite elements to prevent the propagation within the circuit of parasitic or spurious radio-frequency signal components. The electronic circuit for said transceiver means may contain miniature solid-state fuses, fusible links or other such current interrupters, as well as back-up circuits, to protect said transceiver and said spinal cord of said patient from short circuits or other modes of failure. The electronic circuit for said transceiver may contain capacitive or inductive energy storage to allow for uninterrupted synthesis and application of stimulus signals in the event of interruption of the power transfer process.
While exemplary embodiments of the devices, systems, and methods have been described in some detail for clarity of understanding and by way of example, a variety of changes, modifications, and adaptations will be obvious to those of skill in the art. Hence, the scope of the invention is limited solely by the appended claims. | A method for treating intractable pain via electrical stimulation of the spinal cord. Remote, non-contact stimulation of a selected region of spinal cord is achieved by placement of a transceiver patch directly on the surface of that region of spinal cord, with said patch optionally being inductively coupled to a transmitter patch of similar size on either the outer or inner wall of the dura surrounding that region of the spinal cord. By inductively exchanging electrical power and signals between said transmitter and transceiver patches, and by carrying out the necessary electronic and stimulus signal distribution functions on the transceiver patch, the targeted dorsal column axons can be stimulated without the unintended stray stimulation of nearby dorsal rootlets. Novel configurations of a pliable surface-sheath and clamp or dentate ligament attachment features which realize undamaging attachment of the patch to the spinal cord are described. | 0 |
RELATED APPLICATIONS
[0001] This application claims the benefit of the U.S. provisional application 60/462,575 filed Apr. 11, 2003 entitled “Vehicle Conversion Assembly and Method of Converting a Vehicle” which is incorporated herein in its entirety by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to a conversion assembly and method for a vehicle, and more particularly, but not exclusively, to a conversion assembly and method for a front-wheel-drive vehicle for enabling or improving wheelchair accessibility to the vehicle.
[0004] 2. Description of the Related Art
[0005] It has been previously proposed to modify a standard production motor vehicle to enable access to the vehicle by a person in a wheelchair. The converted vehicle must have an interior with sufficient distance between the floor and the roof to provide for headroom for the occupant of the wheelchair, and a sufficient width to accommodate the width of the wheelchair. Owing to such limitations of internal space and the necessity for a large door (usually in the form of a rear tailgate or a side sliding door), motor vehicles of the kind known as “people movers” or “vans” are popular for such conversions.
[0006] It is usually necessary to rearrange the interior of the vehicle to provide access for the wheelchair, for example by altering the standard seating arrangement of the vehicle to provide a space in the vehicle in which the wheelchair is able to be located during driving of the vehicle, and by lowering the floorpan of the vehicle in conjunction with raising the roof of the vehicle to provide sufficient headroom for an occupant of the wheelchair. The lowered portion of the floorpan provides a surface on which the wheelchair can roll from an entry means (typically in the form of a ramp or a lift) to the space in which the wheelchair is located during driving.
[0007] Conversions of this type have been performed on a motor vehicle in which the conventional suspension existing in the vehicle is of the kind having a rear beam axle configuration. In this conversion the floor is lowered in part, however as the ability to lower the floor is limited by the presence of the rear beam axle, previously proposed conversions profile the floorpan to accommodate the rear beam axle. This results in a hump or raised portion of the floorpan over the rear beam axle. As this previously proposed conversion is a rear-access conversion in which the wheelchair with occupant is loaded into the vehicle through a rear tailgate of the vehicle and is wheeled forwardly into the space in which the wheelchair is located during driving of the vehicle, the presence of the hump is problematic as it must be traversed during entry and exit to/from the vehicle. Furthermore, the presence of the hump also results in the headroom available for the wheelchair occupant being limited. In some cases, a wheelchair occupant in a converted vehicle of this kind has been known to hit his or her head on the roof of the vehicle when traversing the hump. The roof of the vehicle may be raised to improve headroom available to the occupant of the wheelchair, however this is typically undesirable for a number of reasons including that it results in the modifications to the vehicle being conspicuous.
[0008] One type of previously proposed conversion of a vehicle for enabling or improving wheelchair accessibility to the vehicle enables an occupant of a wheelchair to be seated as a passenger of the vehicle. Another type of previously proposed conversion of a vehicle enables an occupant of a wheelchair to drive the vehicle by providing a driver's seat which is movable to a position adjacent the wheelchair. The occupant of the wheelchair is able to transfer from the wheelchair to the driver's seat from where he or she is able to drive the vehicle. However, such a conversion is disadvantageous as it can be difficult, awkward, inconvenient and time-consuming for the occupant of the wheelchair to have to transfer from the wheelchair to the driver's seat to drive the vehicle and then to transfer back again to the wheelchair when he or she is to exit the vehicle.
SUMMARY OF THE INVENTION
[0009] Preferred embodiments of the present invention seek to overcome or at least alleviate one or more of the above disadvantages associated with previous conversions of vehicles for enabling or improving wheelchair accessibility.
[0010] Preferred embodiments of the present invention seek to provide a conversion assembly for a front-wheel-drive motor vehicle for enabling or improving wheelchair access to the vehicle, wherein the conversion assembly enables a portion of a floorpan of the vehicle to be lowered, the lowered portion of the floorpan being sufficiently lowered to provide sufficient interior height to accommodate a wheelchair with occupant therein, the lowered portion of the floorpan being sufficiently wide to accommodate the width of a wheelchair, and the lowered portion being substantially flat to facilitate rolling of the wheelchair along said portion of the floorpan.
[0011] In accordance with one aspect of the invention, there is provided a conversion assembly for enabling or improving wheelchair accessibility to a front-wheel-drive vehicle, wherein said assembly comprises rear suspension mountings for fixing to the structure of the vehicle in place of an existing rear suspension such that a portion of a floorpan of the vehicle of sufficient width to accommodate the width of a wheelchair can be lowered between said rear suspension mountings.
[0012] In one embodiment of the invention, the occupant of the wheelchair is a passenger of the vehicle. In one particular form of the invention, the space in which the wheelchair is to be located during driving of the vehicle is in a second row and/or a rear row of seats of the vehicle. Preferably, at least one of the standard passenger seats of the vehicle is retained next to said space, said at least one of the standard passenger seats being narrowed to accommodate the wheelchair.
[0013] In another embodiment of the invention, the vehicle is a self-drive vehicle wherein the occupant of the wheelchair is the driver of the vehicle. In this embodiment, the space in which the wheelchair is to be located during driving of the vehicle is in a second row and/or a rear row (of seats) of the vehicle, and a movable carriage is provided, the movable carriage being movable between a rear position in which the movable carriage is adjacent to said space such that the occupant can transfer between the wheelchair and the carriage and a front position in which the occupant on the carriage is in a driver's position for driving the vehicle.
[0014] Preferably, the conversion assembly is such that the lowered portion of the floorpan can extend forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a driver's position to enable the occupant of the wheelchair to drive the vehicle from the wheelchair.
[0015] Alternatively, the conversion assembly is such that the lowered portion of the floorpan can extend forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a front row passenger position of the vehicle where the wheelchair is restrained during driving of the vehicle to enable the occupant of the wheelchair to occupy the wheelchair in the front row passenger position during driving of the vehicle.
[0016] In accordance with another aspect of the present invention, there is provided a front-wheel-drive vehicle when converted for enabling or improving wheelchair accessibility to the vehicle using one of the above conversion assemblies.
[0017] Preferably, the lowered portion of the floorpan extends forwardly from the rear entrance of the vehicle to include the driver's position of the vehicle.
[0018] Preferably, the conversion assembly is for enabling or improving wheelchair accessibility to the vehicle from the rear of the vehicle through a doorway at the rear of the vehicle. More preferably, the conversion assembly is for enabling or improving wheelchair accessibility to the vehicle from the rear of the vehicle through a tailgate of the vehicle.
[0019] Preferably, the pair of rear suspension mountings is a pair of independent rear suspension mountings.
[0020] In embodiments in which the vehicle is provided with a chassis, the independent rear suspension mountings are preferably fixed to opposite sides of the chassis. Preferably, an additional chassis frame is fastened to an existing chassis of the vehicle, the additional chassis frame being adapted for mounting said rear suspension mountings thereon.
[0021] Typically, the existing rear suspension is in the form of a rear beam axle configuration. However, the present invention is equally applicable to vehicles having existing rear suspension of other kinds. For example, the invention is also applicable to vehicles having existing rear suspension of the kind which extends inwardly of the vehicle and inhibit the floorpan from being lowered to a width sufficient to accommodate a wheelchair.
[0022] Preferably, the lowered portion of the floorpan is at least 760 mm wide. More preferably, the lowered portion of the floorpan is at least 840 mm wide. In one preferred embodiment of the invention, the lowered portion of the floorpan is 850 mm wide. Preferably, the lowered portion of the floorpan is substantially flat. In a preferred embodiment, the lowered portion of the floorpan is substantially level.
[0023] Preferably, each of the rear suspension mountings includes an independent rear trailing arm suspension component comprising an elongated arm having a pivotal coupling at a front end thereof for enabling the elongated arm to pivot with respect to the structure of the vehicle about an axis substantially transverse to the longitudinal axis of the elongated arm, a wheel mounting for mounting a wheel of the vehicle longitudinally spaced from the axis of rotation of the elongated arm, a spring mounting for mounting a spring between the elongated arm and the structure of the vehicle, and a shock absorber mounting for mounting a shock absorber between the elongated arm and the structure of the vehicle.
[0024] Preferably, the pivotal coupling is a bearing arrangement at the front end of the elongated arm. Preferably, the shock absorber mounting is a shock absorber mounting bracket at a rear end of the elongated arm. Preferably, the spring is a coil spring or an air spring, and the spring mounting is a seating in an upper surface of the elongated arm for receiving a lower end of the coil spring or air spring. Preferably, the wheel mounting is a wheel mounting bracket mounted to an outer side of the elongated arm.
[0025] Preferably, the vehicle is provided with a restraining belt, the restraining belt being anchored to the vehicle at either side of a space in which the wheelchair is to be located during driving of the vehicle, for restraining the occupant of the wheelchair. Preferably, the belt is anchored to the vehicle on one side of the space in which the wheelchair is to be located during driving of the vehicle, by way of a belt mounting frame fixed to the structure of the vehicle.
[0026] Preferably, the vehicle is provided with locking restraints for locking the wheelchair in place during driving of the vehicle.
[0027] In accordance with another aspect of the present invention, there is provided a method of converting a front-wheel-drive vehicle to enable or improve wheelchair accessibility to the vehicle, the method including the steps of:
[0028] removing an existing rear suspension from the vehicle;
[0029] installing rear suspension mountings to the vehicle, one at each side of the structure of the vehicle; and
[0030] lowering a portion of the floorpan of the vehicle between said rear suspension mountings.
[0031] Preferably, the lowered portion of the floorpan extends forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a driver's position where the wheelchair is restrained during driving of the vehicle to enable the occupant of the wheelchair to drive the vehicle from the wheelchair.
[0032] Alternatively, the lowered portion of the floorpan extends forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a front row passenger position of the vehicle where the wheelchair is restrained during driving of the vehicle to enable the occupant of the wheelchair to occupy the wheelchair in the front row passenger position during driving of the vehicle.
[0033] Preferably, the method includes the step of lowering the portion of the floorpan of the vehicle between said rear suspension mountings such that the lowered portion of the floorpan extends forwardly from the rear entrance of the vehicle to include the driver's position of the vehicle.
[0034] Preferably, the rear suspension mountings are independent rear suspension mountings.
[0035] Preferably, the method further includes the step of attaching an additional chassis frame to an existing chassis of the vehicle, the additional chassis frame being adapted for mounting said independent rear suspension mountings thereon.
[0036] Preferably, the step of lowering the portion of the floorpan of the vehicle includes lowering the portion of the floorpan such that the lowered portion of the floorpan is at least 760 mm wide. In one preferred embodiment, the step of lowering the portion of the floorpan of the vehicle includes lowering the portion of the floorpan such that the lowered portion of the floorpan is at least 840 mm wide. In one particular embodiment, the step of lowering the portion of the floorpan of the vehicle includes lowering the portion of the floorpan such that the lowered portion of the floorpan is 850 mm wide. Preferably, the step of lowering the portion of the floorpan of the vehicle includes lowering the portion of the floorpan such that the lowered portion of the floorpan is substantially flat. In a preferred embodiment, the step of lowering the portion of the floorpan of the vehicle includes lowering the portion of the floorpan such that the lowered portion of the floorpan is substantially level.
[0037] Preferably, the method further includes the step of installing a restraining belt, the restraining belt being anchored to the vehicle at either side of a space in which the wheelchair is to be located during driving of the vehicle, for restraining the occupant of the wheelchair. Preferably, the method further includes the step of fixing a belt mounting frame to the structure of the vehicle on one side of said space, the belt mounting frame being for mounting the restraining belt.
[0038] In accordance with another aspect of the present invention, there is provided a front-wheel-drive vehicle when converted for enabling or improving wheelchair accessibility to the vehicle using the method described above.
[0039] In accordance with yet another aspect of the present invention, there is provided a front-wheel-drive vehicle converted to enable or improve wheelchair accessibility to the vehicle, wherein said vehicle includes rear suspension mountings fixed to the structure of the vehicle, a portion of a floorpan of the vehicle of sufficient width to accommodate the width of a wheelchair, said portion being located between said rear suspension mountings and extending forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a driver's position where the wheelchair is restrained during driving of the vehicle to enable the occupant of the wheelchair to drive the vehicle from the wheelchair.
[0040] In accordance with still another aspect of the present invention, there is provided a front-wheel-drive vehicle converted to enable or improve wheelchair accessibility to the vehicle, wherein said vehicle includes rear suspension mountings fixed to the structure of the vehicle, a portion of a floorpan of the vehicle of sufficient width to accommodate the width of a wheelchair, said portion being located between said rear suspension mountings and extending forwardly from a rear entrance of the vehicle such that a wheelchair is able to be driven from the rear entrance to a front row passenger position where the wheelchair is restrained during driving of the vehicle to enable the occupant of the wheelchair to occupy the wheelchair in the front row passenger position during driving of the vehicle.
[0041] In accordance with another aspect of the invention, there is provided an independent rear trailing arm suspension component for a front-wheel-drive vehicle requiring wheelchair access comprising an elongated arm having a pivotal coupling at a front end thereof for enabling the elongated arm to pivot with respect to a structure of the vehicle about an axis substantially transverse to the longitudinal axis of the elongated arm, a wheel mounting for mounting a wheel of the vehicle longitudinally spaced from the axis of rotation of the elongated arm, a spring mounting for mounting a spring between the elongated arm and the structure of the vehicle, and a shock absorber mounting for mounting a shock absorber between the elongated arm and the structure of the vehicle.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] The invention is described, by way of non-limiting example only, with reference to the accompanying drawings in which:
[0043] [0043]FIG. 1 is a top perspective view of an independent rear trailing arm suspension component;
[0044] [0044]FIG. 2 is a side perspective view of the independent rear trailing arm suspension component of FIG. 1;
[0045] [0045]FIG. 3 is a detailed side perspective view of a front portion of the independent rear trailing arm suspension component of FIG. 1, also showing separate elements used in the manufacture of the independent rear trailing arm suspension component;
[0046] [0046]FIG. 4 is a rear perspective view of a left-hand independent rear trailing arm suspension component similar to that shown in FIG. 1, the left-hand independent rear trailing arm suspension component being fitted to a vehicle;
[0047] [0047]FIG. 5 is a rear view of the undercarriage of the vehicle shown in FIG. 4, showing both left-hand and right-hand independent rear trailing arm suspension components fitted to the vehicle;
[0048] [0048]FIG. 6 is a rear perspective view of the right-hand independent rear trailing arm suspension component shown in FIG. 5;
[0049] [0049]FIG. 7 is a top perspective view of a rear portion of a lowered floorpan of a vehicle partially converted for self-drive rear-entry wheelchair access;
[0050] [0050]FIG. 8 is a right side perspective view of a centre portion of the lowered floorpan shown in FIG. 7;
[0051] [0051]FIG. 9 is a right side perspective view of a front portion of the lowered floorpan shown in FIG. 7;
[0052] [0052]FIG. 10 is a rear perspective view of the lowered floorpan shown in FIGS. 7, 8 and 9 ;
[0053] [0053]FIG. 10 a is a rear perspective view of the lowered floorpan shown in FIGS. 7 to 10 ;
[0054] [0054]FIG. 10 b is a seating diagram of a vehicle using the floorpan shown in FIGS. 7 to 10 a;
[0055] [0055]FIG. 11 is a left side perspective view of a wheelchair with occupant in the vehicle shown in FIGS. 7 to 10 a , the wheelchair being located at the driver's position of the vehicle such that the occupant is able to drive the vehicle from the wheelchair;
[0056] [0056]FIG. 12 is a rear perspective view of a restraining belt anchored to a vehicle, for restraining an occupant of a wheelchair during driving of the vehicle;
[0057] [0057]FIG. 13 is a rear perspective view of the restraining belt shown in FIG. 12;
[0058] [0058]FIG. 14 is a rear perspective view of a rear, right-hand corner of the vehicle shown in FIGS. 12 and 13;
[0059] [0059]FIG. 15 is a front perspective view of a seat of the vehicle shown in FIGS. 12 to 14 , the seat being narrowed to accommodate the wheelchair;
[0060] [0060]FIG. 16 is a rear perspective view of a spare wheel of the vehicle shown in FIGS. 12 to 15 , the spare wheel being a “space-saving” spare wheel mounted to one side of the lowered portion of the floorpan;
[0061] [0061]FIG. 17 is a rear view of the vehicle shown in FIGS. 12 to 16 , the vehicle being shown with a ramp of the vehicle in a stowed configuration and with a tailgate of the vehicle in an open configuration;
[0062] [0062]FIG. 18 is a rear view of the vehicle shown in FIGS. 12 to 17 , the vehicle being shown with the tailgate in a closed configuration;
[0063] [0063]FIG. 19 is a rear view of a vehicle, the vehicle being shown with a ramp of the vehicle in a deployed configuration;
[0064] [0064]FIG. 20 is a side view of the vehicle shown in FIG. 19, the vehicle being shown with the ramp in the deployed configuration;
[0065] [0065]FIG. 21 is a general seating diagram of the vehicles shown in FIGS. 4 to 6 and in FIGS. 12 to 20 ;
[0066] [0066]FIG. 22 is a rear perspective view of a front portion of a lowered portion of a floorpan of the vehicle shown in FIGS. 19 and 20;
[0067] [0067]FIG. 23 is a front perspective view of a rear portion of the lowered portion of the floorpan of the vehicle shown in FIG. 22, the ramp of the vehicle being shown in a stowed configuration;
[0068] [0068]FIG. 24 is a front perspective view of a movable carriage of a vehicle, the movable carriage being in the form of a seat on rails; and
[0069] [0069]FIG. 25 is a view of an underside of an additional chassis frame prior to mounting of same to an existing chassis of a vehicle for converting the vehicle for wheelchair access.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0070] A left-hand independent rear trailing arm suspension component 10 is shown in FIGS. 1 to 3 , and comprises an elongated arm 12 having a pivotal chassis coupling in the form of a bearing arrangement 14 at a front end thereof. The rear trailing arm suspension component 10 also comprises a wheel mounting bracket 16 mounted to an outer side of the elongated arm 12 , and longitudinally spaced from the bearing arrangement 14 . A shock absorber mounting bracket 18 is mounted at a rear end of the elongated arm 12 . Intermediate the bearing arrangement 14 and the shock absorber mounting bracket 18 , a spring mounting in the form of a coil spring seating 20 is formed in an upper surface of the elongated arm 12 . The independent rear trailing arm suspension component 10 shown in the accompanying drawings is manufactured by welding and machining processes. The independent rear trailing arm suspension component 10 is reinforced internally of its outer surfaces by additional struts and ties (not shown) to ensure that the component 10 is able to withstand forces, such as torsional and axial forces, to which it may be subjected during its working life.
[0071] [0071]FIG. 3 shows detail of bearing arrangement 14 at the front end of the independent rear trailing arm suspension component 10 , together with separated elements 22 , 24 from which the independent rear trailing arm suspension component 10 is manufactured. In particular, FIG. 3 shows a housing 22 of the bearing arrangement 14 , and an inner core shaft 24 of the bearing arrangement 14 . As can be seen from the side view of the formed bearing arrangement 14 in this Figure, bearings 26 are inserted between the inner core shaft 24 and the housing 22 to enable rotation of the inner core shaft 24 within the housing 22 . In use, independent rear trailing arm suspension component 10 is mounted to a vehicle requiring wheelchair access by bolting the inner core shaft 24 at either end thereof to a chassis 38 of the vehicle (and more particularly to an additional chassis frame 38 a of the vehicle), as can be seen in FIGS. 4 to 6 .
[0072] [0072]FIG. 4 shows the left-hand independent rear trailing arm suspension component 10 mounted to a motor vehicle requiring wheelchair access. A left-hand rear wheel 30 is mounted to the wheel mounting bracket 16 by way of a drum brake 32 of the left-hand rear wheel 30 being bolted to the wheel mounting bracket 16 . An original standard shock absorber 34 and original standard coil spring 36 from the original rear beam axle configuration of the standard production vehicle as it existed prior to being modified for wheelchair access are retained in the conversion. A lower end of the shock absorber 34 is bolted to the shock absorber mounting bracket 18 , and the coil spring 36 is mounted between the independent rear trailing arm suspension component 10 and the structure of the vehicle such that a lower end of the coil spring 36 sits in the seating 20 formed in the upper surface of the elongated arm 12 of the independent rear trailing arm suspension component 10 . The suspension operates by the independent rear trailing arm suspension component 10 being able to pivot about the inner core shaft 24 which forms an axis, substantially transverse to the longitudinal axis of the elongated arm 12 , for such pivotal movement. The coil spring 36 operates resiliently to oppose upward movement of the independent rear trailing arm suspension component 10 toward the chassis 38 of the vehicle 28 , and the shock absorber 34 acts to dampen pivotal movement of the independent rear trailing arm suspension component 10 with respect to the chassis 38 of the vehicle 28 . A deformable stopper 39 is provided, mounted on the additional chassis frame 38 a , to inhibit excessive upward movement of the independent rear trailing arm suspension component 10 with respect to the chassis 38 by bearing against a rear plate 41 of the independent rear trailing arm suspension component 10 . The standard braking system from the original standard production vehicle is retained in the conversion.
[0073] In alternative embodiments, other forms of spring may be used in place of the coil spring 36 . In one particular alternative embodiment (not shown), an air spring is used in place of the coil spring 36 .
[0074] As can be seen in FIG. 5, the rear beam axle configuration rear suspension which was present in the original standard production vehicle prior to conversion for wheel chair access has been removed, and in its place independent rear trailing arm suspension components 10 have been mounted to either side of the chassis 38 of the vehicle 28 . A portion of the floorpan 40 between the independent rear trailing arm suspension components 10 has been lowered to facilitate the wheelchair access to the cabin of the vehicle 28 . To enable this portion of the floorpan 40 to be lowered, an additional chassis frame 38 a is fastened to an existing chassis 38 b of the vehicle by conventional chassis-forming techniques such as welding, fastening with bolts and/or adhesives. The relative narrowness of the independent rear trailing arm suspension components 10 enables the floorpan to be lowered by approximately 0.45 m from its original height, and in a sufficient width to accommodate the width of a wheelchair. The floorpan is lowered by cutting out the original floorpan with angle grinders or the like and by installing the replacement lowered floorpan on the additional chassis frame 38 a . Owing to the lowering of the floorpan taking up space which was previously used for a fuel tank and a spare wheel, a replacement fuel tank 42 is installed toward the front of the vehicle 28 and a “space-saver” spare wheel 44 is installed inside the cabin of the vehicle 28 , as shown in FIG. 16.
[0075] [0075]FIG. 25 shows a separate chassis frame 38 a shown prior to mounting of same to an existing chassis of a vehicle for conversion of that vehicle for wheelchair access.
[0076] The vehicle 28 shown in FIGS. 4 to 6 is configured such that a space 46 in which a wheelchair is located during driving of the vehicle 28 is in a centre row 48 of seats 50 of the vehicle, as shown in FIG. 21. In this diagram, the lowered portion of the floorpan is indicated by the broken line 52 . The rear of the vehicle is indicated by reference numeral 54 .
[0077] In the embodiment shown in FIGS. 4 to 6 wherein the occupant of the wheelchair remains seated in the wheelchair (the wheelchair being locked into the space 46 ) during driving of the vehicle, a restraining belt 62 (see FIGS. 12 and 13) is provided in order to provide upper body support to the occupant in case of an accident or abrupt deceleration. The restraining belt 62 is anchored securely to a belt mounting frame 64 fixed to the structure of the vehicle such that the belt 62 is able to provide high restraining forces if the need arises. In the embodiment depicted in FIGS. 12 and 13, the belt mounting frame 64 is made from metal bars fixed to the structure of the vehicle on one side of the space 46 in which the wheelchair is to be located during driving of the vehicle. In use, the belt extends about the front of the upper body of the occupant of the wheelchair and a buckle of the belt is fastened to a buckle receptacle on the opposite side of said space. A safety belt system of this kind is of great benefit, as a conventional belt mounted to the wheelchair is known to fail in accidents, particularly as in previously proposed wheelchair access vehicles the wheelchair itself is prone to breaking free of its lockings to the vehicle when excessive forces are experienced.
[0078] The actual method of entry to the vehicle 28 by a wheelchair and occupant is best seen with reference to FIGS. 17 to 23 . With particular regard to FIGS. 19 and 20, a rear tailgate 66 of the vehicle 28 is opened such that a rear folding aluminium ramp 68 is able to be moved from its stowed configuration in which it resides substantially upright at the rear of the vehicle (see FIG. 17) to its deployed configuration in which it extends downwardly from the rear of the vehicle to the ground (see FIGS. 19 and 20). The ramp 68 is provided with a non-slip coating 70 to provide grip such that the wheelchair is able to drive up the ramp 68 (or be pushed up the ramp in the case of a non-motorized wheelchair) and onto the lowered portion of the floorpan 40 . Once on the lowered portion of the floorpan 40 , the wheelchair is driven or pushed to the space 46 where it is to be located during driving of the vehicle 28 . The ramp 68 is then returned to its stowed configuration as shown in FIGS. 17 and 23. In its stowed configuration, the ramp 68 is arranged so as not to interfere with vision from the cabin, and in particular, with the driver's rear vision through a rear window 70 of the tailgate 66 when the tailgate 66 is closed (as seen in FIG. 18). Moreover, the ramp 68 is arranged in its stowed configuration to be as discreet as possible when viewed from outside the vehicle 28 with the tailgate 66 closed, so that the vehicle is able to blend into traffic and does not attract unwanted attention. For example, the external appearance of the vehicle may particularly be of importance where the occupant of the wheelchair is a child being dropped off at school and does not want to draw attention to his or her own self.
[0079] To accommodate the wheelchair in the space 46 in which it is to be located during driving of the vehicle 28 , in the embodiment shown in FIG. 15 the neighbouring passenger seat 72 has been narrowed slightly and reupholstered. A neighbouring passenger seat on the opposite side of space 46 may also be narrowed to accommodate the wheelchair. Also, in the embodiment shown in FIG. 13, it is possible to accommodate two wheelchairs in the lowered portion of the floorpan by removing the central seat 74 , such that one wheelchair is able to be accommodated in space 46 , and by locating a second wheelchair in a space 76 behind space 46 . The vehicle is provided with locking restraints for locking each of the wheelchairs in place during driving of the vehicle, and these locking restraints may be in automatic, electric form or manual form. When the vehicle is to be used without a wheelchair in space 46 , the central seat 74 is able to be mounted in space 46 for seating a passenger.
[0080] With reference to FIGS. 14 and 21, when a wheelchair is to be moved between the outside of the vehicle and space 46 , or when a wheelchair is to be located in space 76 behind space 46 , a rear passenger bench seat 78 is able to be folded to its stowed configuration (see FIG. 14) in which it rests substantially upright against a side wall of the vehicle 28 .
[0081] Although in the above-discussed conversions the occupant of the wheelchair is a passenger of the vehicle, sitting in the wheelchair during driving of the vehicle, the wheelchair being suitably locked into the space 46 (or 76 ) by way of electric restraints or the like, an alternative conversion provides a self-drive version of the vehicle in which the wheelchair is locked into the same space 46 during driving of the vehicle. Such a conversion uses a movable carriage in the form of a movable driver's seat 60 on rails (see FIG. 24) which is movable between a rear position (as seen in FIG. 24) in which the driver's seat 60 is adjacent to the space 46 such that the occupant of the wheelchair can transfer from the wheelchair to the driver's seat 60 by simply sliding across laterally, to a front position in which the occupant is able to reach the driving controls of the vehicle from the driver's seat 60 . The occupant is able to control the position of the driver's seat 60 between the front and rear positions, for example by way of electric controls or the like. In order to return to the wheelchair from the driver's seat, for example after parking the vehicle, the occupant moves the driver's seat to the rear position and slides across laterally to the wheelchair.
[0082] FIGS. 7 to 11 show another form of self-drive vehicle according to an embodiment of the present invention. In the embodiment depicted in these Figures, there is provided a vehicle 28 partially converted to enable access to the vehicle 28 by a wheelchair, and more particularly to enable rear-entry self-drive wheelchair access to the vehicle, wherein the lowered portion 40 of the floorpan extends to a front row driver's position 80 of the vehicle 28 such that an occupant 56 of the wheelchair 58 is able to drive the vehicle 28 from being seated in the wheelchair 58 . Although in the embodiment depicted the lowered portion 40 of the floorpan extends forwardly from the rear entrance of the vehicle to include the front row driver's position 80 of the vehicle 28 , it is foreseen that in an alternative embodiment, in a vehicle already having a portion of floorpan at the driver's position which is sufficiently low in relation to driving controls and a ceiling of the vehicle prior to conversion, it would not be necessary for that portion of floorpan to be lowered further. Accordingly, in such an embodiment, the lowered portion of the floorpan would only need to extend far enough to enable the wheelchair with occupant to drive from the rear entrance to the driver's position.
[0083] In order to accommodate the lowered portion 40 of the floorpan, a fuel tank of the standard vehicle is removed and is replaced by a customised fuel tank located under the floorpan opposite the side of the vehicle to which the lowered portion of the floorpan extends. Similarly, the standard exhaust system from the vehicle post catalytic converter is removed and is replaced with a custom exhaust routed along the same side of the vehicle to which the lowered portion of the floorpan extends. The lowered floorpan is formed by a network of cross-members forming framework to which sheet metal is bonded. The network of cross-members enhances rigidity in the lowered portion of the floorpan to inhibit unwanted flexure during use.
[0084] The specific controls provided to enable the occupant to drive the vehicle may differ from case to case, depending on the ability of the occupant to use his or her arms and legs. Such controls are already well-established and will not be described in detail herein. This vehicle uses a similar configuration of the independent rear trailing arm suspension components 10 as is used in the vehicle shown in FIGS. 4 to 6 , however instead of the lowered portion 40 of the floorpan extending from the rear 54 of the vehicle to just behind the front row of seats as shown in FIG. 21, the lowered portion 40 of the floorpan of the embodiment shown in FIGS. 7 to 11 extends from the rear 54 of the vehicle to the driver's position 80 . Similarly to the previously-described embodiment, the wheelchair 58 is locked into the driver's position 80 by an electric restraint or the like to secure the wheelchair during driving of the vehicle.
[0085] As shown in the seating diagram in FIG. 10 b , in a proposed drive-from-wheelchair embodiment of the present invention, a front row passenger seat 50 , centre row passenger seat 50 , and two-person rear passenger bench seat 78 are also provided, with the bench seat 78 being a two-person seat which is stowable in a position in which it rests substantially upright against a side wall of the vehicle. The centre row passenger seat 50 is narrowed to fit in the space available adjacent the lowered portion of the floorpan, and is mounted on a releasable mounting to enable removal of the seat from the vehicle when it is not required. Preferably, the releasable mounting is retained from the standard vehicle as it existed prior to conversion.
[0086] In an alternative conversion (not shown), a vehicle is converted to have rear-entry wheelchair access wherein the lowered portion of the floorpan extends to the front of the cabin to include a front row passenger position of the vehicle in which position the wheelchair is to be located during driving of the vehicle such that the wheelchair occupant is able to ride in the wheelchair and next to the driver of the vehicle.
[0087] One or more of the vehicle conversions described above provide advantages over previously proposed wheelchair accessible vehicles. In particular, the lowered and substantially flat floor enables wheelchair occupants in the vehicle to have improved headroom, improved mobility as the widened lowered floorpan portion enables front trolley wheels of a wheelchair to rotate freely when changing direction, and improved visibility as the wheelchair occupant's head height is brought closer to the standard head height for which the vehicle is designed.
[0088] One particular model of vehicle suitable for conversion in accordance with the present invention, by way of example only, is the Kia Sedona, also known as the Kia Carnival in some markets.
[0089] The above embodiments have been described by way of example only and modifications are possible within the scope of the invention. In particular, although in the embodiments described the original suspension removed from the vehicle to be replaced by the independent rear trailing arm components is of the type having a rear beam axle configuration, it is also foreseen that other suspension systems which do not enable sufficient wheelchair access to a vehicle may be successfully converted in accordance with the present invention.
[0090] Although the vehicle depicted in the drawings is a right-hand drive vehicle, the invention is of course also applicable to left-hand drive vehicles, in which case the general layout of the lowered portion of the floorpan is mirrored from right to left to suit. | A conversion assembly for enabling or improving wheelchair accessibility to a front-wheel-drive vehicle, wherein said assembly comprises rear suspension mountings for fixing to the structure of the vehicle in place of an existing rear suspension such that a portion of a floorpan of the vehicle of sufficient width to accommodate the width of a wheelchair can be lowered between said rear suspension mountings. A method of converting a front-wheel-drive vehicle to enable or improve wheelchair accessibility to the vehicle, the method including the steps of removing an existing rear suspension from the vehicle, installing rear suspension mountings to the vehicle, one at each side of the structure of the vehicle, and lowering a portion of the floorpan of the vehicle between said rear suspension mountings. | 1 |
BACKGROUND OF THE INVENTION
[0001] The invention relates to a chopping aid device for use in chopping of firewood, the chopping aid device comprising a frame to prevent pieces of wood to spread into the surroundings outside the chopping aid device during chopping.
[0002] Such a chopping aid device is known from patent publication EP 1886779 B1. This known device in the form of a basket-like closed ring frame is designed to be mounted onto a chopping block and designed to prevent chopped wood to fall to the ground from the chopping block. By having this function, the chopping aid device provides at the same time for the user, and for people nearby the chopping aid device, safety in that chopped wood does not fly and hit the user or the people nearby. However, if the basket-like frame is not filled enough with chopping woods, the risk remains that the chopped wood flies over the ring frame. Further, the logs will easily turn to a position not being upright as a result of an incorrect hit with the axe. Still further, there is a risk of the axe bouncing pass the chopping block and hitting on the ground or on the knee/leg/foot of the person who is chopping.
[0003] Woods to be chopped shall be placed upright on the chopping block. This is not always easy. Especially if the wood to be chopped has a cut surface which is at an oblique angle in relation to the longitudinal axis of the wood to be chopped, the wood cannot be placed on the chopping block so that it remains upright without support. This problem, also present with the known chopping aid device of EP 1886779 B1, can be—provided the chopping block has an even planar upper surface and is not worn—solved by cutting off the inclined surface from the wood to be chopped and replacing the inclined surface with a surface which is perpendicular to the longitudinal axis of the wood to be chopped. Such a procedure is, however, time consuming and creates wood debris. Neither does it give the desired result if the chopping block has worn so that the upper surface thereof shows a concave form. Sometimes the problem with an oblique support area is solved by keeping the wood by hand in upright position and taking quickly the hand off the wood before hitting the wood with the axe. The wood must be hit immediately after the hand has been taken off the wood, because otherwise the wood turns horizontal making the chopping impossible. Such chopping is dangerous, difficult and time consuming. If the hand is not taken off the wood, there is an imminent possibility for injury. If the wood to be chopped is not split with one hit and the ring frame has not been fully filled with woods to be chopped, the wood will typically move within the ring frame in such a position that one must correct its position to enable a successful next hit with the axe. This is time consuming.
BRIEF DESCRIPTION OF THE INVENTION
[0004] An object of the invention is to provide a new chopping aid device, to be used for chopping firewood, which device generally makes chopping and splitting of logs easier, faster and safer. Justifiably the device could also be called a safety device.
[0005] The chopping aid device of the invention is characterized by a support comprising a plurality of flexible spikes to keep the firewood in an upright position within the cuff frame.
[0006] An essential idea of the invention is to use a plurality of flexible spikes, or the like, to keep the wood to be chopped upright within the frame of the device, the spikes (or the like) being adapted to support the wood laterally from its periphery and to keep the wood in place within the frame of the device. With the term “spike” is meant any type of longitudinal element, e.g. bristles providing the desired function.
[0007] Preferably the frame is a basket-like cuff frame comprising an upper edge whose distance from the bottom of the cuff frame is smaller at the front side or user side than the distance from the bottom at a side which differs from the front side. This prevents the handle of the axe from hitting the cuff frame when chopping.
[0008] Preferably the first ends of the spikes which are opposite to free ends of the spikes are attached to the cuff frame, whereby the spikes preferably are directed at least substantially horizontal within the cuff frame and preferably at an obtuse angle with respect a front-rear-line of the chopping aid device. Such arrangement of the spikes provides a good support for the woods and positively keeps the woods within the cuff frame. In such an arrangement
[0009] preferably further the cuff frame is flexible and made of elastomeric material and the collar is made of harder material than the cuff frame. Such a selection of materials makes the chopping aid device durable: the collar prevents the blade of the axe to cut into the cuff frame, and the cuff frame prevents, by providing dampening properties, the collar from being damaged by the impact of the axe.
[0010] Preferably the spikes are detachably fastened to the collar. This makes replacement of worn or broken spikes easy.
[0011] In order to very effectively support plenty of woods, i.e. within the major area of the cuff frame, the spikes cover at least 70% of the cross-sectional area of the cuff frame.
[0012] Preferred embodiments of the chopping aid device according to the invention are disclosed in the attached claims.
[0013] The most important advantages of the chopping aid device according to the invention are that it makes chopping of wood easy, fast and safe. The chopping aid device allows to keep all sizes and shapes of woods upright all the time for more continuous splitting. The chopping aid device avoids the need for constant and cumbersome resetting of woods. Several woods or, if desired, only one wood, can be put into the chopping aid device at a time. The chopping aid device collects small debris from cutting making the splitting work less strenuous. The chopping aid device prevents the axe from bouncing astray during splitting and prevents woods from flying away.
BRIEF DESCRIPTION OF THE FIGURES
[0014] In the following the invention will be described in closer detail by means of two embodiments and with reference to the accompanying drawing in which:
[0015] FIG. 1 shows the first embodiment of the chopping aid device mounted on a chopping block,
[0016] FIG. 2 shows the chopping aid device of FIG. 1 in an exploded view,
[0017] FIG. 3 shows the second embodiment of the chopping aid device, and
[0018] FIG. 4 shows a detail of the chopping aid device of FIG. 3 .
DETAILED DESCRIPTION OF THE INVENTION
[0019] In FIG. 1 the chopping aid device is shown mounted on top of a chopping block 10 drawn with broken line. The chopping aid device has been tightened around the chopping block with a buckle or straining strap 9 . The chopping aid device lies with a bead 27 on the upper surface of the chopping block 10 . The bead 27 prevents wood debris from being accumulated in possible gaps between the chopping block 10 and the chopping aid device. It is, however, possible to lower the chopping aid device from the position shown in FIG. 1 to a position where the bead 27 encircles the chopping block 10 by first moving it downwards in the vertical direction and thereafter tightening the straining strap 9 using the tightening and locking device 14 of the straining strap. Such lowering may be desirable in order to provide good support for very short logs to be chopped. For reasons of simplicity, in the figure only one wood 11 to be chopped has been drafted.
[0020] As illustrated in FIG. 1 , the woods are placed vertically within the chopping aid device. A plurality of flexible spikes 3 support the wood 11 to be chopped. The spikes have a diameter of e.g. 1 to 2 mm, but the diameter can vary much depending on the material of the spikes, the size of the logs to be split, etc. If very thin spikes 3 are used (diameter 1 mm or less), the spikes can be called bristles. When the wood 11 is positioned within the chopping aid device, the spikes 3 adjacent the wood bend downwards thus providing a lateral force on the wood. By bending downwards, the risk of cutting or damaging in another way the spikes with an axe, is also reduced. The lateral force of the spikes 3 supports the wood and ensures that the wood 11 is positively kept upright within the chopping aid device even if the cross-section of the wood supporting the wood from below does not, as such, provide adequate support owing to the reason that it is not at right angles to the longitudinal axis of the wood. Thanks to the spikes 3 , the wood 11 is positively kept upright before it is hit with an axe (not shown) and also after it has been split with the axe. The next hit with the axe can immediately be carried out without an intermediate need to touch the wood.
[0021] The chopping aid device comprises a basket-like cylindrical cuff frame 1 made of flexible elastomeric material, e.g. rubber, Thermo Plastic Elastomer (TPE), Polypropylene (PP) or Polyethylene (PE). The bottom 5 of the cuff frame 1 is arranged around the upper end of the chopping block 10 . The cuff frame 1 is circumferentially open having a peripheral wall 26 which is non-continuous by comprising a slot 8 at the front side or user side. The slot 8 enables to easily adjust the diameter of the bottom of the cuff frame 1 making it easy to position the cuff frame around chopping blocks 10 of different size. By tightening the straining strap 9 , the cuff frame 1 will steadily be fastened to the chopping block 10 . The diameter of the cuff frame 1 is preferably about 400 mm. Such a cuff frame can easily be fastened to chopping blocks 10 having diameters between 300 to 500 mm.
[0022] Because the cuff frame 1 is resilient, it will dampen the impact on the chopping aid device if the device is accidentally hit on by the axe. To protect the cuff frame 1 form being damaged by an accidental hit, a cylindrical collar 7 has been mounted on top of the cuff frame 1 . The collar 7 is made of a harder material than the cuff frame 1 , e.g. from polyamide (nailon) Glassfiber reinforced Polyamide (PA) or Glassfiber reinforced Polybutylene terephthalate (PBT). The collar 7 distributes the force of the accidental hit to a large area of the cuff frame 1 thus preventing the blade of the axe to cut into the cuff frame 1 . Even a relatively strong hit on the collar 7 will not damage the collar, because the cuff frame 1 under the collar dampens effectively the hit.
[0023] FIG. 2 shows the components of the chopping aid device of FIG. 1 . The device comprises a cylindrical collar 7 to be mounted on top of the cuff frame 1 . The spikes 3 are detachably attached to the collar 7 in order to make replacement of worn and damaged spikes easy. Thus the spikes 3 are indirectly, by means of the collar 7 fastened to the cuff frame 1 . The spikes 3 and the collar 7 together form a support 2 to keep the wood 11 to be chopped upright and also to keep the chopped firewood upright. The collar 7 is made of flexible material. The spikes 3 are horizontal with respect to the collar 7 and the cuff frame 1 .
[0024] The distance from the bottom 5 of the cuff frame 1 to the upper edge 4 of the frame varies in such a way that the distance L 1 at the front side or user side of the chopping aid device is much smaller than the distance L 2 at the rear side of the chopping aid device, or at any other direction which differs from the front side. In this way the cuff frame 1 is open at the front side. The opening at the front side of the cuff frame 1 gives space for the handle of the ax (not shown) when firewood is chopped and makes it easy to clean the upper surface of the chopping block 10 from wood debris. The distance L 2 is preferably about 200 mm. The distance L 1 can be e.g. 20-50 mm.
[0025] The collar 7 has a peripheral wall 12 which is non-continuous so that it comprises a peripheral opening 15 . When the collar 7 is put on top of the cuff frame 1 , the opening 15 of the collar 7 is aligned with the front side of the cuff frame 1 . The opening 15 (like the opening of the cuff frame 1 ) gives space for the handle of the axe when firewood is chopped.
[0026] The collar 7 is detachably fastened to the cuff frame 1 . For this purpose the upper edge 13 of the collar 7 comprises a groove 16 to receive the upper edge 4 of the cuff frame 1 . The height L 3 of the collar 7 must be less than the height L 2 of the cuff frame 1 because the collar 7 must not hit the upper end of the chopping block 10 if the axe accidentally hits on the collar. If the distance L 2 , i.e. the maximum height of the cuff frame 1 is about 200 mm, the height L 3 of the collar 7 is preferably 150-180 mm. In normal use of the chopping aid device, the collar 7 is fastened to the cuff frame 1 in such a way that the opening 15 thereof faces the user, c.f. FIG. 1 . However, the collar 7 can alternatively be positioned on the cuff frame 1 in such a way that the opening 15 thereof is diametrically opposite to the opening of the cuff frame 1 .
[0027] Such a positioning of the collar 7 gives as result a chopping aid device having fully closed walls and no opening facing the user. Fully closed walls and detached spikes 3 allow to easily fill up the whole cross-section of the chopping aid device with woods. Because the collar 7 can be rotated 0 to 180 degrees with respect to the cuff frame 1 , it can be positioned on top of the cuff frame 1 so that the opening 15 thereof points at any desired direction.
[0028] The spikes 3 have been fastened at two arcs 17 , 18 which, in turn, are detachably fastened to the collar 7 , e.g. by snap-fasteners, which can be of pin-hole type.
[0029] As can be seen from FIGS. 1 and 2 , the spikes 3 are directed horizontally to a longitudinal axis X-X of the cuff frame 1 . The spikes 3 are fastened at opposite sides of the collar 7 so that two rows of spikes 3 are formed. The spikes 3 of one row are directed against the spikes 3 in the other row leaving between the free ends, i.e. between the tips of the spikes of respective row, a narrow slot-like zone 6 which is free of spikes. The width of the zone 6 , against which the free ends of the spikes 3 are directed, is 10 to 50 mm. The zone 6 is directed against the user and the spikes 3 are at right angles to the user.
[0030] Thanks to said arrangement of the spikes 3 , the spikes 3 effectively prevent the wood from moving against the user when the wood is chopped and they also prevent the wood from collapsing within the cuff frame 1 . Also, the spikes 3 are short enough (shorter than the height of the chopping aid device) so that the tips thereof do not reach the upper surface of the chopping block 10 when they are bent downwards. Owing to this, the spikes cannot be cut by being pinched between the axe and the upper surface of the chopping block 10 The angle of the spikes 3 in relation axis X-X and to the front side of the chopping aid device, and the user, does not have to be a right angle; however, an obtuse angle with respect to the front-rear-line of the chopping aid device is preferred.
[0031] To make the chopping aid device easier to manufacture and also to avoid charging of logs too close to the margins of the chopping aid device, in which case the risk of mishits including hits on the edge of the chopping aid device increases, there is also at the rear side of the chopping aid device a segment 19 free of spikes as seen from FIG. 1 . The front side of the chopping aid device has a similar segment (however, not shown by reference numeral) free of spikes. The spikes 3 cover at least 70% of the cross-sectional area of the cuff frame 1 . In said figure of 70% not only the total projection area of the individual spikes 3 but also the areas of the gaps between adjacent spikes are included.
[0032] The chopping aid device comprises handles 20 , 21 in order to make it easy to lift and move. The handles 20 , 21 are formed of holes 22 , 23 and 24 , 25 made in the cuff frame 1 and collar 7 , respectively. The holes 22 and 23 , like the holes 24 and 25 are preferably spaced 180 degrees apart. The holes 23 to 25 are not, however, indispensable as the chopping aid device is not heavy.
[0033] FIG. 3 shows another embodiment of the chopping aid device. In FIG. 3 has been used similar reference numerals as in FIG. 1 for corresponding components. For the sake of simplicity only one spike 3 ′ has been separately drafted in FIG. 3 although the number of spikes in the support 2 ′ is large, like in the embodiment of FIG. 1 .
[0034] The embodiment of FIG. 3 differs from the embodiment of FIG. 1 in that the spikes 3 ′ are arranged in four levels 3 a ′, 3 b ′, 3 c ′, 3 d ′. The length of the spikes 3 ′ in the different levels 3 a ′, 3 b ′, 3 c ′, 3 d ′ diminishes in the direction downwards so that the average length of the spikes in a lower level, e.g. level 3 c ′, is shorter than the average length of the spikes in an upper level, 3 b ′ or 3 a ′. Such an arrangement of the spikes 3 ′ has the advantage that it provides better support for the woods to be chopped by adding more progressive support force when more wood is added and prevents the creeping and permanent deflection of longer spikes by supporting them from underneath with shorter spikes which are less prone to creepage and deflection caused by gravity.
[0035] The embodiment of FIG. 3 differs from the embodiment of FIG. 1 further in that the spikes 3 ′ are fastened to arcs in the form of holders 17 ′, 18 ′ which are fastened to the collar 7 ′ by means of grooves 17 a ′, 18 a ′. The holders 17 ′, 18 ′ also comprise branches 17 b ′, 18 b ′ the lower edge of which press against the cuff frame 1 and the collar 7 . From FIG. 4 , which shows the holder 18 ′ separately from the support 2 ′, the groove 18 a ′ is clearly seen. In FIG. 3 the groove 18 a ′ receives the upper edge 13 ′ of the collar 7 ′. The advantage of the groove 18 a ′ is that the holder 18 ′ is easy to position in place on the collar 7 ′ and remove from the collar 7 ′. The holders 17 ′, 18 ′ of the embodiment of FIG. 3 also make it very easy to position the spikes 3 of two holders 17 ′, 18 ′ in such a way that the spikes 3 ′ are in line regardless variations in diameter of the chopping block.
[0036] Still further the embodiment of FIG. 3 differs from the embodiment of FIG. 1 in that the width of the zone 6 ′ free of spikes is negligible small.
[0037] The invention has been described above only by two examples. It shall be understood that the invention can be implemented in many ways within the scope of the attached claims. Hence, it is for instance possible that the frame of the chopping aid device is not a basket-like cuff frame but a frame which is formed of e.g. two oppositely positioned walls and having two major openings between the walls. If a basket-like cuff frame is used, the cuff frame can have a geometrical form which is not cylindrical: the cross-section of the device can be elliptic or square. However, a cylindrical form is preferable, because a cylindrical cuff frame is easy to position on top of a chopping block. The bead in the inner wall of the cuff frame 1 is not indispensable, but is highly preferable, because it gives stability to the chopping aid device. The chopping aid device, however, can be used without an ordinary chopping block: it can be positioned on a firm base which provides the required support for chopping woods. In such a situation the cross-section of the chopping aid device can very well be for instance rectangular, in which case no straining strap is needed. The zone 6 in the central area of the cross-section of the cuff frame 1 need not have the form of a slot; it can e.g. have the form of a circle or some other form. Further, deviating from what has been disclosed in the two embodiments, it is possible to implement the chopping aid device by integrating the support (c.f. support 2 , 2 ′) with the cuff frame (c.f. cuff frame 1 , 1 ′). This can e.g. be carried out by two component molding. The support is injection molded of a material providing a support durable against cuts, and the cuff frame is, in the same injection molding machine, injection molded of a material providing a cuff frame which is flexible and resilient. | A chopping aid device for use in chopping of firewood includes a frame to pre-vent pieces of wood from spreading into the surroundings outside the chopping aid device during chopping. In order to make chopping of wood easy, fast and safe, the chopping aid device has a support with flexible spikes to keep the firewood in an upright position within the frame. | 1 |
BACKGROUND OF THE INVENTION
1. Technical Field
This invention relates to a method for treating severe chronic inflammatory disease, such as demyeliniating diseases, uveitis, or graft-versus-host disease, by administrating tumor necrosis factor or "TNF" in an effective antisevere chronic inflammatory disease amount to a patient suffering from the disease.
2. Background Art
Severe chronic inflammatory disease is a generic name of a category of diseases which have no fundamental remedy because the mechanism of incidence has not been elucidated and is characterized by its regional and generalized chronic inflammatory symptoms. Severe chronic inflammatory disease consists of demyelinating disease, uveitis, graft-versus-host disease and the like.
The main morbific cause of demyelinating disease is a destruction of the myelin sheath of a nerve or nerves. It is generally classified into multiple sclerosis and acute disseminated encephalomyelitis. Demyelinating disease also includes disseminated sclerosis, leukodystrophy and the like. It has been considered that allergic reactions to the myelin sheath are related to the incidence of demyelinating disease. However, the cause of these reactions has not yet been elucidated. Multiple sclerosis is different from acute disseminated encephalomyelitis and other demyelinating diseases, because multiple sclerosis is characterized by remissions and persistently recurring exacerbations. Acute disseminated encephalomyelitis can be transformed into multiple sclerosis.
The presenting symptoms of demyelinating disease are neurologic disorders which mainly consist of ataxia and paresthesias. Demyelinating disease is sometimes fatal in the acute period. In spite of such severity, no efficient therapeutic method exists. As therapeutic methods for multiple sclerosis, adrenocortical hormone-like agents are used for the exacerbation period. For the remission period medical rehabilitation and medical preventive treatment against infection are utilized. But, demyelinating disease cannot be healed by these treatments. As therapeutic methods for acute disseminated encephalomyelitis, the use of adrenocortical hormone-like agents are effective in some cases. However, after the treatment, some problems remain such as neurologic disorders and transference into multiple sclerosis.
Uveitis is an inflammation of the eye which is caused by various diseases as an original disease, such as Behcet's disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis or toxoplasmosis. The symptoms of anterior uveitis are iridocyclitis and hypopyon. The symptoms of posterior uveitis are opacity of the vitreousbody, hemorrhage and extravasation on the eyeground, edema and opacification on the retina and neuritis optica. Posterior uveitis leads to a reduction or a loss of visual activity through complicated cataract or glaucoma. The mechanism of incidence of uveitis and the relation to the original diseases have not been elucidated. Neither have the cause or causes of Behcet's disease, Vogt-Koyanagi-Harada syndrome, sarcoidosis or toxoplasmosis been elucidated.
As therapeutic methods for uveitis, the instillation of mydriatic agents and steroidal agents and the general administration of steroidal agents have been conventionally utilized. The use of steroidal agents and immunosuppressive agents for a long-term administration has been utilized with the aim of prophylaxis and mitigation of uveitis, because uveitis is often recurs and tends to be chronic. However, steroidal agents and immunosuppressive agents such as cyclosporine are known for their strong side effects, and it is known that long-term administration can be life-threatening. Moreover, the effects of these agents have not been justified. The reduction in the dose and the interruption of the administration in cases where there is no improvement often causes the disease to become chronic.
Graft-versus-host disease (hereinafter "GVHD") is often observed in patients with foreign bone marrow transplantations. The major symptoms are fever, lesion, diarrhea and liver disorders. GVHD is a life-threatening disease. The bone marrow transplantation is performed on patients who are deficient in or lack hematopoietic stem cells and immunity-charging cells in cases such as aplastic anemia, severe immune difficiency and leukemia. It is also performed on patients whose myelopoietic function has been destroyed by radiation therapy and chemotherapy. However, there are many problems to be solved in the use of bone marrow transplantation, including the occurrence of such disorders as GVHD, interstitial pneumonia, reoccurrence and infection. GVHD sometimes causes interstitial pneumonia. The ratio of incidence of GVHD is very high when the bone marrow transplantation is utilized, making GVHD one of the major obstacles to bone marrow transplantation.
GVHD is classified into acute GVHD and chronic GVHD depending on the onset of GVHD. Also, there are differences between acute GVHD and chronic GVHD in clinical aspects. Acute GVHD occurs within 100 days after grafting. The main targets of acute GVHD are the skin, the liver and the gastrointestinal tract. The clinical symptoms of acute GVHD are erythema, bulla and erosion on the skin, icterus and diarrhea which are caused by the disorders of the organs mentioned above. Chronic GVHD occurs after 100 days following grafting. The targets of chronic GVHD are wider than those of acute GVHD. Therefore, the symptoms of chronic GVHD take various forms. Chronic GVHD is classified into localized GVHD and generalized GVHD according to the clinical findings. The main symptom of localized GVHD are lesions which include drying, lichen planus-like change, pigmentation, depigmentation and erythema accompanied with detachment. It sometimes accompanies with liver disorders. The syndrome of generalized GVHD consists of affections of the mucous membrane of the salivary gland, the mouth and the esophagus, the iachrymals, the lung, the bronchus, muscle and the joint. These symptoms lead to a reversion of autoantibodies and are similar to the symptoms of autoimmune disease.
As therapeutic methods for GVHD, general administration of immunosuppressive agents, such as methotrexate, steroids, azathioprine and cyclosporine A has been conventionally utilized. However, they have problems with side effects which have yet to be solved.
Tumor necrosis factor, or "TNF", was discovered originally in mouse serum after intravenous injection of bacterial endotoxin into mice primed with viable Mycobacterium bovis, strain Bacillus Calmette-Guerin (BCG). See, Proc. Nat. Acad. Sci. U.S.A., 72(9), 3666-70 (1975). TNF-containing serum from mice is cytotoxic or cytostatic to a number of mouse and human transformed cell lines, but less so to normal cells in vitro. It causes necrosis of transplantable tumors in mice. TNF also occurs in the sera of the rat, rabbit and guinea pig. Further, it is also known that TNF can be produced by mononuclear phagocytes, fibroblasts, B-cells, and the like derived from a mammal under certain conditions. In this connection, there are many reports in the literature which have been summarized by Lloyd J. Old in Scientific American, 258(5), 59-75 May, 1988).
TNF is now being developed under clinical trials for use as an anti-tumor agent. It is also reported that TNF has an anti-inflammatory effect and an anodzne effect [Japanese Patent Application laid-open No. 62-292727]. It is also reported that TNF has a suppressive effect against autoimmune disease defined as immune complex-disease [European Patent 254647] and a therapeutic effect against inflammatory skin disease such as atopic dermatitis [WO 90/05532]. However, there is no disclosure that TNF is effective against severe chronic inflammatory disease, such as demyelinating disease, uveitis, or graft-versus-host disease. On the contrary, it is reported that TNF may be one of the substances related to the destruction of the myelin sheath in demyelinating disease [Hofman et al., J. Exp. Med. 170, 607-612 (1989)]. It is also reported that an intravitreous administration of TNF causes an inflammatory reaction in the anterior eye [Rosembaum et al., Am. J. Pathol. 133. 47-53 (1988)]. It is also reported that TNF may be one of the substances related to skin and gastrointestinal tract disorders in acute GVHD [Piguet et al., J. Exp. Med. 166, 1280-1289 (1987)].
Considering the description of the above-mentioned reports, it was expected that TNF would not be useful for the purpose of treating demyelinating disease, uveitis, or graft-versus-host disease.
However, unexpectedly, our experimental data, i.e. in vivo data and data on the different condition of the dosage from those in the above-mentioned reports, show that TNF would be useful for the purpose of treating demyelinating disease, uveitis, or graft-versus-host disease.
Based on these novel findings, the present invention has been completed.
Accordingly, it is an object of the present invention to provide a novel therapeutic method effective for treating demyelinating disease.
Another object is to provide a novel therapeutic method effective for treating uveitis.
Another object is to provide a novel therapeutic method effective for treating graft-versus-host disease.
These and other objects of the invention as well as the advantages thereof can be had by reference to the following description and claims.
SUMMARY OF THE INVENTION
The foregoing objects are achieved according to the present invention by the inventors, discovery of a new type of pharmaceutical composition and method for its use in the treatment of demyelinating disease, uveitis or graft-versus-host disease, which are free from the above-mentioned drawbacks inevitably accompanying the conventional therapeutic compositions and methods. More particularly, it has been found that when tumor necrosis factor or "TNF" is administrated to animal models of demyelinating disease, uveitis or graft-versus-host disease, the symptoms of the disease are suppressed. These results are based on a new type of activity of TNF different from any known activities mentioned above.
According to the present invention, a new method for treating demyelinating disease is provided which comprises administrating an effective anti-demyelinating disease amount of TNF to a patient having demyelinating disease. A new pharmaceutical composition for the treatment of demyelinating disease comprises TNF and at least one pharmaceutically acceptable carrier, diluent or excipient.
A new method for treating uveitis is also provided which comprises administrating an effective anti-uveitic amount of TNF to a patient having uveitis. A new pharmaceutical composition for the treatment of uveitis comprises TNF and at least one pharmaceutically acceptable carrier, diluent or excipient.
A new method for treating graft-versus-host disease is also provided which comprises administrating an effective anti-graft-versus-host disease amount of TNF to a patient having graft-versus-host disease. A new pharmaceutical composition for the treatment of graft-versus-host disease comprises TNF and at least one pharmaceutically acceptable carrier, diluent or excipient.
In the present invention, TNF obtained from serum or cells derived from a mammal can be used as an active ingredient. However, for purposes of utilizing the present invention on human patients, it is preferred to use pharmaceutical compositions containing human TNF from the standpoint of immunological compatibility.
Human TNF suitable for use in the present invention can be produced by recombinant DNA techniques. Alternatively, human TNF can also be produced by culturing cells derived from humans.
Suitable methods for producing human TNF by recombinant DNA techniques are described, for example, in Shirai T. et al., Nature, 313, 803-6 (1985) and Japanese Patent Application Laid-Open Specification No. 60-252496 (corresponds to European Patent Application Publication No. 0 158 286). By way of illustration, human TNF can be obtained by culturing E. coli to homogeneity.
The activity of human TNF during purification is monitored by mouse L-cell killing activity using a modification of the method of Williamson et al. employing L-M cells (American Type Culture Collection, CCL 1.2). See, Moss B., Proc. Nat. Acad. Sci. U.S.A., 80, 5397-401 (1983). The number of surviving cells is determined by the photometric method of Ruff and Gifford, published in J. Immun., 125, 1671-7 (1980).
The human TNF can also be produced by other known methods, including these described in Diane Pennica et al., Nature, 312, 20-7 (December, 1984); EP-A-168214; EP-A-155549; and the like.
The number of amino acid units constituting human TNF varies depending upon the production method used to obtain the TNF. For example, human TNF produced by recombinant DNA techniques described in EP-A-0158286 consists of 155 amino acid, units whereas human TNF produced by the method of Pennica et al., supra, consists of 157 amino acid units in the same sequence as in the TNF having 155 amino acid units and in addition having attached to its N-terminus, 2 amino acids.
The human TNF produced by recombinant DNA technique also includes a polypeptide having a methionine moiety attached to the N-terminus of the above-mentioned amino acid sequence and an intermediate having a partial or entire signal peptide for human TNF attached to the N-terminus of the above-mentioned amino acid sequence. It is possible to change a portion of the structure of a DNA coding for a polypeptide by natural or artificial mutation without significant change in the activity of the polypeptide.
The human TNF which can be used in the present invention includes a polypeptide having a structure corresponding to homologous variant(s) of the polypeptide having the above-mentioned amino acid sequence. Examples of homologous variants include polypeptides described in U.S. Pat. Nos. 4,677,063 and 4,677,064, the disclosures in which are incorporated herein by reference. All such physiologically active polypeptides are also hereinafter referred to as "human TNF".
Natural human TNF is likely to undergo biochemical modification or chemical modification, and is also likely to aggregate to form a multimer, such as a dimer or a trimer. These TNF polypeptides produced in nature are also hereinafter referred to as "human TNF", and can be used as an active ingredient in the pharmaceutical compositions of the present invention.
The pharmaceutical compositions of the present invention can be formulated into various preparations adapted, for example, to intravenous, intramuscular, subcutaneous, and intradermal injection, oral or rectal administration, external application and instillation. It is advantageous that the preparations are adapted for the administration of a polypeptide composition.
In preparing the pharmaceutical compositions of the present invention, various additives can be included as may be appropriate, such as one or more carriers, diluents, excipients, fluidizing agents, binding agents, stabilizers, thickeners, pH adjusting agents and the like.
Suitable carriers, diluents and excipients include starches and derivatives thereof, such as potato starch, corn starch, dextrin and wheat starch and hydrxypropyl starch; sugars, such as lactose, glucose, sucrose, mannitol and sorbitol; celluloses, such as methylcellulose, carboxylmethylcellulose and hydroxypropylcellulose; inorganic compounds, such as sodium chloride, boric acid, calcium sulfate, calcium phosphate and precipitated calcium carbonate; and the like.
Suitable fluidizing agents include magnesium oxide, synthetic aluminum silicate, metasilicic acid, magnesium aluminum oxide, hydrous silicic acid, anhydrous silicic acid, talc, magnesium stearate, kaolin and the like.
Suitable binding agents include polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, gum arabic, tragacanth, sodium alginate, gelatin, gluten, and the like.
Suitable stabilizers include proteins, such as albumin, protamine, gelatin and globulin; amino acids and salts thereof, and the like.
Suitable pH adjusting agents include hydrochloric acid, sodium hydroxide, phosphates, citrates, carbonates, and the like.
The pharmaceutical compositions of the present invention can be administered to a patient in an amount such that the daily dose of TNF for an adult is generally in the range of from about 50 to 100,000,000 units, and preferably from about 50 to 500,000 units in the case of local administration, from about 1,000 to 10,000,000 units in the case of general injection such as intravenous injection and intramuscular injection, and from about 10,000 to 100,000,000 units in the case of oral administration.
The term "unit" as used above means a quantity of TNF by which 50% of 1×10 5 cells/ml of L-M cells (American Type Culture Collection CCL 1.2) are killed. This quantity is measured as follows: As culture vessels, there are employed 96-well microtiter plates produced by Flow Laboratories, Inc. (U.S.A.). L-M cells are cultured in Eagle's minimum essential medium containing 1 v/v % of fetal calf serum [the composition of this medium is described, for example, in Tissue Culture, edited by Junnosuke Nakai et al., Asakura Shoten, Japan (1967)]. A sample (0.1 ml), serially diluted with the medium, and the L-M cell suspension (0.1 ml, 1×10 5 cells/ml) are mixed into each well of the plates and the plates are incubated at 37° C. for 48 hours in air containing 5% carbon dioxide. At the end of the culture period, 20 μl of glutaraldehyde is added to fix the cells. After fixation, the plates are washed with distilled water and allowed to dry, and 0.05% methylene blue (0.1 ml) is added to stain the viable cells. The plates are thoroughly washed with distilled water to remove excess dye and allowed to dry. Hydrochloric acid (0.36N) is added to each well to extract the dye from stained cells. Absorbance of each well at 665 nm is measured with Titertek Multiskan produced by Flow Laboratories, Inc. (U.S.A.). The absorbance is proportional to the number of viable cells. The above-mentioned quantity of the physiologically active polypeptide of the present invention by which 50% of 1×10 5 cells/ml of L-M are killed is obtained by a plotting of the dilution versus the absorbance.
The dosage regimen for treating a patient with the pharmaceutical composition of the present invention varies according to the age and symptoms of the patient. As mentioned above, the composition can generally be administered over several days to several weeks in a daily dose of 50 to 10 8 units. The daily dose can be administered to a patient all at once or in several applications. The administration of the present pharmaceutical composition can be conducted each day, or alternatively, the administration can be conducted at intervals. Representative examples of the dosage regimen are as follows:
(a) daily administration for 1 to 4 weeks;
(b) daily administration for 1 to 6 days, alternatively with a pause for one day to several weeks;
(c) administration for one day per week; and
(d) daily administration for 5 days, alternately with a pause of one month.
DESCRIPTION OF PREFERRED EMBODIMENTS
EXAMPLE 1
Experimental allergic encephalomyelitis(EAE) has been studied for many years as an animal model for demyelinating disease [Tahira et al., Experimental Allergic Encephalomyelitis(EAE). [Multiple Sclerosis -basic and clinical-] Shiokoigakushuppansha 241 (1985)]. A quantity (0.1 ml) of emulsion of bovine myelin basic protein and Freund's complete adjuvant is subcutaneously injected to the footpad of a 5 week-old female Hartley guinea pig to induce EAE. After the injection, 300,000 units/guinea pig of human TNF obtained by the recombinant technique according to the method described in European Patent Application Publication No. 0 158 286 is intraperitoneally injected to the each of 8 guinea pigs every day until day 12. 0.1% gelatin containing-phosphate buffer solution which is used to dilute human TNF is injected to the each of 8 guinea pigs in a control group by the same schedule and method as those in the TNF-injection group. The neurological signs are observed and recorded every day to determine the onset of the disease. And findings are confirmed by the histologic examination of the brain and the spinal cord 21 days after the injection.
The observation period is set for 21 days after the injection. The number of guinea pigs which show severe clinical signs during the recorded period is statistically compared. As shown in Table 1, statistically significant suppression of EAE incidence based on Wilcoxon's rank sumtest is observed in the TNF-injection group. Moreover, 2 out of 8 guinea pigs in the control group die by acute encephalomyelitis. By contrast, there is no guinea pig dead in the TNF-injection group.
TABLE 1______________________________________ No. scored/No. tested - + ++ +++ ++++______________________________________CONTROL 1/8 1/8 2/8 2/8 2/8TNF 3/8 3/8 0/8 2/8 0/8______________________________________
The difference between the control group and the TNF-injected group is significant by Wilcoxon's rank sum test (p<0.05).
Individual animals are scored as follows;
-: normal
+: weakness of limbs
++: ataxia
+++: paralysis, tremor
++++: death
These results indicate the suppressive effect of TNF against demyelinating disease.
EXAMPLE 2
Endotoxine-induced rabbit uveitis is examined as an animal model for anterior uveitis according to a general method by Rosenbaum et al., [Am. J. Pathol. 133, 47-53 (1988)]. New Zealand white female rabbits are anesthetized intramuscularly with a combination of ketamine(30 mg/kg) and xylazine(5 mg/ml). A quantity (1 ng) of Escherichia coli endotoxin is injected by a 30-gauge needle into the vitreous body to induce anterior uveitis. Incidence of the disease is determined by the histologic examination of paraffin embedded sections of the bulbus oculi, leakage protein quantification in aqueous humor and extravasated celi numbers in aqueous humor, when the rabbits are killed 24 hours after the injection. Protein is quantitated according to the binding of brilliant blue as described by Bradford. Cell numbers are counted with a hemocytometer. 24 hours and 1 hour before the injection, 300,000 units/kg of human TNF obtained by the method described in Example 1 is intravenously injected via the ear vein of each of 4 rabbits. A 0.1% gelatin containing-phosphate buffer solution which is used to dilute human TNF is injected to each of 4 rabbits in the control group by the same schedule and method as those in the TNF-injection group.
According to the histological examination, infiltration of many monocytes and neutrophils in the iris and the ciliary epithelium is observed in the control group. By contrast, TNF treatment results in a significantly decreased number of infiltrated cells. As shown in Table 2, the amount of leakage protein and the number of extravasated cells in aqueous humor as an index of anterior inflammation in the TNF-injection group are decreased compared to those of the control group.
TABLE 2______________________________________ Protein (mg/ml) Cell (× 10.sup.6 /ml)______________________________________TNF 14.9 ± 5.8 1.52 ± 0.63CONTROL 2.0 ± 1.1 0.21 ± 0.14______________________________________ N = 4 for each group.
Average are expressed as mean ± standard error.
These results indicate the suppressive effect of TNF against endotoxine-induced uveitis.
EXAMPLE 3
Rat experimental autoimmune uveoretinitis(EAU) is examined as an animal model for uveitis including posterior uveitis according to a general method by Nussenblatt et al., [Arch. Ophtaimol, 100, 1146-1149 (1982)]. A quantity (0.05) ml of mixed emulsion with bovine S-antigen(20 μg/rat) prepared by Dorey et al., [Ophthalmic res. 14, 249 (1982)] and Freund's complete adjuvant is administrated to a female Lewis rat (5 week-old) by the rear-footpad route to induce EAU. Incidence of the disease is determined by the histologic examination of paraffin embedded sections of the bulbus oculi, when the rats are killed 14 days after the administration. A quantity (100,000 units/kg) of human TNF obtained by the method described in Example 1 is intraperitoneally injected into the each of 4 rats every day after the S-antigen administration until day 14. A 0.1% gelatin containing-phosphate buffer solution which is used to dilute human TNF is injected to the each of 4 rats in the control group by the same schedule and method as those in the TNF-injection group.
According to histologic examination, infiltration of many monocytes and neutrophils in the whole area of the retina and the choroid is observed in the control group. By contrast, TNF treatment results in a significantly decreased number of infiltrated cells.
The results in Examples 2 and 3 indicate the suppressive effect of TNF against uveitis.
EXAMPLE 4
Mouse acute GVHD is examined as an animal model for GVHD according to a method by Piguet et al. [J. Exp. Med. 166, 1280-1289 (1987)]. A 3 month-old Fl mouse(B10×CBA) is irradiated(800 rad) and intravenously injected from tail vein with 2×10 6 lymphocytes prepared from the inguinal and axiliary lymph nodes of C57BL/10 mice and 2×10 6 bone marrow cells derived from C57BL/10 mice from which T lymphocytes are depleted by using anti-Thyl-antibodies and complements. After the irradiation, the mice are housed with neomycin(0.5 mg/ml)-containing water. After the next day of the transplantation 10,000 units/mouse of human TNF obtained by the method described in Example 1 is intravenously injected every two days until day 41. A quantity of 0.1% gelatin containing-phosphate buffer solution which is used for diluting human TNF is injected to each of 4 mice in the control group by the same schedule and method as those in the TNF-injection group. Incidence of the disease is determined by the number of mice surviving 84 days after the transplantation, and histologic examination of the skin and the duodenum 21 days after the transplantation.
According to the survival ratio as shown in Table 3, a dead mouse is observed 21 days after the transplantation in the control group. The death ratio is increased after day 21 and all mice are dead 12 weeks after the transplantation. By contrast, in the TNF-injection group, no mouse is dead during the injection period and only 2 out of 8 mice are dead even 12 weeks after the transplantation.
According to the histological examination, in the control group, flattening of villi, cellular necrosis in crypts and lymphocyte infiltration into the submucosa are observed in addition to epidermal thickening, cellular infiltration and necrosis of epidermal cells. In the TNF-injection group, such changes are supressed.
TABLE 3______________________________________ Survival Ratio Day After Transplantation 21 day 42 day 63 day 84 day______________________________________CONTROL 7/8 3/8 1/8 0/8TNF 8/8 8/8 7/8 6/8______________________________________
These results indicate the suppressive effect of TNF against GVHD.
EXAMPLE 5
Human TNF is produced by recombinant DNA technique by the method described in Example 1. Using the thus-produced recombinant human TNF, a lyophilized preparation for injection having the following composition is formulated.
______________________________________Formulation______________________________________Human TNF 5 × 10.sup.5 unitsD-Mannitol 30 mgNormal serum albumin (human) 10 mgSodium chloride 2.0 mgSodium dihydrogen phosphate dihydrate 3.9 mg(adjusted at pH 8.0 by sodium hydroxide)______________________________________
The foregoing description is intended to illustrate the invention, and it is understood that changes and variations can be made in the foregoing embodiments without departing from the spirit and scope of the invention which is defined in the following claims. | A pharmaceutical composition and a method for its use in the treatment of severe chronic inflammatory diseases, such as demyelinating disease, uveitis and graft-versus-host disease are provided. The composition comprises tumor necrosis factor as an active ingredient and at least one pharmaceutically acceptable carrier, diluent or excipient. | 0 |
FIELD OF THE INVENTION
[0001] As recent events such as the disastrous failure of levees during Hurricane Katrina show, there is a modern need for concretes and other composites of greater strength. In particular, it would be desirable to increase the strength of the concrete in both tension as well as in compression. While steel rebar has been used for many years to increase the strength of concrete, there is a need for better composite materials.
[0002] Among those which have been discovered are glass fiber reinforced concrete (GFRC). GFRCs employ thin layers of a synthetic glass fiber material more commonly known as Fiberglass to reduce the size of the reinforcement members without reducing their individual tensile strength. In addition, steel fiber reinforced concrete is known. For these materials, small threads or even woven sheets of stainless steel are used for reinforcement.
[0003] Carbon nanotubes are relatively new materials and have garnered much recent attention. There are two basic types of nanotubes. The first are single-wall nanotubes, or SWCNTs. Also known are multi-wall nanotubes or MWCNTs. which are known to have at least two different sub-types. For the purpose of this invention, the term “CNT” is defined as including both types, namely SWCNTs, and MWCNTs.
[0004] Regardless of their specific structure, all nanotubes share a great deal of interesting and unique properties. Perhaps first among these is their remarkable strength. Due to their molecular construction, each bond in a nanotube is an SP 2 orbital bond, which results from the hybridization of an s oribital with two p orbitals and which is among the strongest possible chemical bonds. Because of this fact, the carbon nanotube is among the strongest substances known to man in terms of tensile strength. A nanotube was measured to have a tensile strength of 63 GPa. This can be compared to high carbon steel which has a tensile strength of around 3.1 GPa.
PRIOR ART
[0005] Researchers in Canada have published a study regarding the possible use of carbon nanotubes in cement composites. See, Carbon Nanotubes/Cement Composites—Early Results And Potential Applications, Jon Makar, Jim Margeson and Geanne Luh, National Research Council, Canada. These researchers used CNT/Cement in a ratio of about 0.02% by weight. CNT's were added directly to Portland cement, apparently without additional aggregate. Mixes were made at various water/cement ratios and with and without superplasticizer. The Canadian researchers concluded from their testing and SEM imaging that particles of powdered hydrated cement were being held together by CNT bundles. The group apparently did not test, nor suggest, the use of specific amounts of CNTs or plasticizers in connection with a cement composite that includes both an aggregate, such as sand, the CNTs and Portland cement.
SUMMARY OF THE INVENTION
Summary of the Invention
[0006] CNT reinforced concrete formed with the aid of plasticizers has been discovered to have increased strength properties. It has been found through experimental studies that use of at least about 0.2% by weight CNT in combination with relatively low amounts of plasticizer in otherwise conventional mixtures of cement and aggregate produces concrete with increased strength as measured by compression and modulus of rupture testing. The percentage by weight of CNT referred to throughout this disclosure is calculated on a mass basis by dividing the mass of the CNT by the total amount of cement, aggregate and water. This discovery can be implemented by, for example, preparing additive products comprising CNT and plasticizer in appropriate weight ratios for addition to conventional ready-mix concrete that contains cement and aggregate. Depending on the plasticizer chosen, it is possible to use as little as about 2% plasticizer by weight and 0.2% CNT by weight to obtain measurable strength enhancement of the cured composites.
[0007] Preferred examples of the CNT reinforced concretes of the invention include composites formed from admixture of about 0.2% by weight CNT, and about 2% by weight of a superplasticizer with a standard mixture of dried sand and Portland cement. The mixtures were prepared by adding the CNT material to the water used to hydrate the mixture, then adding the cement and the dry sand, and finally adding the superplasticizer after the other materials are at least partially admixed. Testing of samples cured under standard conditions indicated an increase in both compressive strength and modulus of rupture.
[0008] Thus, while use of CNT with cement has been previously reported, we have discovered that conventional cement/aggregate (concrete) composites (as compared to pure cement CNT mixtures previously studied) can be structurally improved providing that at least a minimum amount of CNT is used in combination with efficient plasticizers. Experiments demonstrated that the disruption in cement bonding that occurred when CNT alone was added to cement/sand mixtures could actually cause a reduction in strength compared to non CNT control samples. On the other hand, once even relatively low amounts of effective plasticizer material were added, the addition of CNT was shown to increase both the compressive strength and the modulus of rupture of the samples.
DETAILED DESCRIPTION
[0009] This invention arose from participation of the inventors in a school sponsored science contest. The hypothesis for testing was whether or not increasing the percent by mass of CNT would increase the failure pressures both in tension and compression. To test this hypothesis a first set of experiments was designed using amounts of CNT material ranging from 0.0% to 0.3% CNT. The results of strength testing on these samples indicated no significant increases in strength and, in some instances, indications of decrease in strength. Microscopic evaluation of the samples revealed that significant amounts of voids had developed in the CNT containing samples. It was hypothesized that the presence of such voids was responsible for lack of improved strength and may also have accounted for an indication of strength reductions. It was concluded that the use of CNT alone was disrupting the hydration and cement bonding that is required to form strong cement/aggregate composites. Whatever possible value the strength and geometry of the CNT material might provide, it was apparently being negated by this disruption of cement bonding. A complete summary of the materials, procedures results and data analysis of this first set of tests is set forth below.
Initial Testing
[0010] In the initial set of experiments, samples were prepared in accordance with ASTMC305 for the production of 1.5 liters of material. The initial samples were prepared as follows: distilled water in the amount of 391.1 milliliters was added to a mixing bowl. For the control group the next addition of material was cement. For the four (4) test groups, amorphous carbon and varying amounts of CNT's were added. In particular, a sample using 10.2452 grams of amorphous carbon added to the water was prepared. Then groups of samples at weight amounts of 0.1% CNT (3.4151 grams of carbon nanotubes), 0.2% CNTs (6.830 grams of carbon nanotubes) and 0.3% CNTs (10.2452 grams of carbon nanotubes) were added to the distilled water.
[0011] Then 806.4 grams of cement powder was added to the water and mixed at low speeds for approximately thirty seconds. Finally, 2,217.6 grams of dry sand was gradually added over thirty seconds while mixing at low speeds. The mixer was then set at medium speed for thirty seconds. After allowing the mix to sit for ninety seconds, and scraping the excess from the sides of the bowl, the mixer was again turned on to medium speed and mixed for sixty seconds.
[0012] As expeditiously as possible, molds for flexure samples were produced by distributing the cement into six (6) 40 by 40 by 160 millimeter molds. Compression samples were then produced by distributing cement into six (6) 50.8 by 50.8 by 50.8 millimeter cubes.
[0013] All the samples were allowed to set overnight at room conditions. They were then removed from the molds and cured in lime-saturated water for twenty-eight days.
[0014] In this initial experiment, the resulting data was erratic in both sets of strength testing. The control group (no additive) was measured to have an average compressional strength of 7,673 psi. The carbon control group (amorphous carbon) was slightly weaker averaging only 7,183 psi, a decrease of 6.39%. The 0.1% CNT group was slightly weaker as well, averaging 7,237 psi, a decrease of 5.69% over the control. The 0.2% CNT group was the weakest of all, averaging only 5,744 psi, a decrease of 25.14%. The 0.3% CNT sample broke the apparent trend made by the first two nanotube groups and the control, still decreasing the cement strength, but only to 6,135 psi, or by 20.05%. Variance for the results were 5.17%.
[0015] modulus of rupture tests showed a similar lack of conclusiveness. The control group was measured to have an average MOR of 1.330. The carbon control group was slightly weaker, averaging only 1.270 psi, a decrease of 4.75%. The 0.1% CNT group was slightly weaker also, though barely, averaging 1,320 psi, a decrease of 0.75% over the control. The 0.2% CNT group averaged only 1,310 psi, a decrease of 1.75%. In this test, the 0.3% CNT group continued the apparent trend made by the first two nanotube groups and the control, decreasing the cement strength more than both of the previous nanotube groups, to 1,300 psi or by 2.5%. Percent variance for this test was 7.75%.
Revised Testing
[0016] Visual observation of these samples showed numerous voids and cracks. It was postulated that strong capillary forces of the nanotubes caused water to be drawn into them, effectively sequestering the water from the rest of the mixture and therefore causing workability to decrease. This, in turn, caused the fluid cement to not completely fill its respective mold, resulting in large bubbles of gas being trapped in the cement while curing. These bubbles and voids produced samples with uneven sides and surfaces which significantly reduced the compressive and tensile strengths.
[0017] The visual analysis of the samples from the initial testing led the inventors to set up and run a second set of tests that would address the void problem. In this second set of testing a superplasticizer was used to enhance the mixability and flow of the samples. Relatively low amounts of a super plasticizer, sold under the tradename Glenium 3400 NV, when combined with at least about 0.2% by weight CNT resulted in samples that demonstrated increased strength properties.
[0018] The general procedures outlined above for the initial set of experiments were repeated, this time using a small amount of plasticizer. The plasticizer was added after the CNT's, cement and dried sand, approximately halfway to completion of the mixing time. In this set of 1.5 liter samples, 3.18 millimeters of Glenium plasticizer was employed.
[0019] This is equal to approximately 2.3 grams/liter, based on a reported density of 1,100 grams/liter for the plasticizer. On a weight basis, the plasticizer was used in approximately 0.1% by weight, calculated on the basis of the amount of plasticizer divided by the total of the plasticizer, cement, aggregate and CNT. In this group of samples, the control group (no additions) was measured to have an average compressional strength of 8,730 psi. The carbon control group (amorphous carbon) was slightly weaker, averaging only 7,990 psi, a decrease of 8.53%. The 0.1 CNT group was slightly weaker as well, averaging 7,800 psi, a decrease of 10.63% relative to the control. However, the 0.2% CNT group increased the strength relative to the control, averaging 9,179 psi, an increase of 5.05%. The percent variance of the results as a whole was only 3.33%.
[0020] The modulus of rupture tests showed the following. The control group was measured to have an average MOR of 1,480 psi. The carbon control (amorphous carbon) group was slightly weaker, averaging only 1,460 psi, a decrease of 1.35%. The 0.1 CNT group was considerably stronger, averaging 1,580 psi, an increase of 7.22% over the control. The 0.2% CNT group also increased the MOR, but only to 1,520 psi, or by 2.93%. Percent variance for these tests was 5.17%.
[0021] The above data confirms that the tensile strength of carbon nanotubes can be used to improve strength properties of concrete. The results of the above tests show that by adding as little as 0.1% CNT by mass, can increase the tensile strength of Portland cement composites, but that same amount can reduce compressive strength. When at least about 0.2% CNT was added, there was a small amount of increase in both compressive and tensile strength capabilities of the samples. It was further recognized that the workability of the concrete that contained the CNT additives could be greatly enhanced through the use of small amounts of super plasticizers. It is believed that the combination of the enhanced workability supplied by the super plasticizers greatly aids the transmission of the inherent tensile strength of the CNTs to the composite as a whole. | Carbon nanotubes (CNTs) are combined with cement, aggregate and plasticizers to form composites with increased strength. CNT reinforced concretes comprising cement, plasticizer, aggregate, and nanotubes, hydrated with water are disclosed. A mixture of CNTs, cement, and plasticizer can be prepared for later admixture with aggregates and water to form composites having improved strength characteristics. A method for increasing the strength of concrete comprising the steps of admixing CNTs and plasticizer's with cement, aggregate, and water for hydration is also disclosed. | 2 |
BACKGROUND
[0001] The present invention relates generally to welding helmets and, more particularly, to the control methods by which the user adjusts settings of functions within a welding helmet.
[0002] Welding operations are generally performed with certain precautions due to the potential exposure of the welding operator to high heat, flames, weld spatter and ultraviolet light. For example, in arc welding, an arc may provide extremely bright emissions in the weld area that may lead to a condition known as “eye arc” in which ultraviolet light causes the inflammation of the cornea and can burn the retina of the eyes if they are unprotected. To prevent such a condition, goggles and helmets are worn by welders. These helmets generally include a face plate (or lens) that is darkened to prevent or limit exposure to the arc light. In some helmets, the lens is constantly dark with the user flipping down the helmet during welding. In other helmets, the lens may change from a clear state to a darkened state. For example, a user may “turn on” the lens to a constant darkened state, or the lens may automatically darken when it detects bright light that is in excess of a threshold value. Further, such welding helmets may provide for adjustment of the threshold value to trigger the lens change, as well as adjustment of a time delay for transitioning between darkened and clear states. For example, the user may remove the helmet and adjust a dial to provide for a threshold light limit, shade level, or delay from the time the arc is extinguished until the lens returns to a clear state.
[0003] In certain welding applications, it may be desirable for the welder to frequently change the state of the lens from a light state to a dark state or vice versa, or to adjust the settings of the helmet. For example, during welding, the welder may frequently need a clear state between welds to inspect the weld, or a welder may need to modify the settings to darken the helmet to avoid exposure to light generated by another nearby welder. In these instances, it may be time consuming and laborsome for the welder to manually adjust the settings of the lens. Accordingly, it may be desirable that a welding helmet include features that allow simpler and more flexible command of helmet settings and functions.
BRIEF DESCRIPTION
[0004] In accordance with one aspect of the present invention, a welding helmet includes a helmet shell; an electronically controllable lens mounted to the shell; a microphone configured to receive an audible input and to generate a signal in response to the audible input received. An electronic control module is coupled to the lens and to the microphone and configured to control the electronically controllable lens based upon the signal.
[0005] In accordance with another aspect of the present invention, a control system for a welding helmet includes an electronically controllable lens configured to be mounted in a welding helmet shell; a microphone configured to receive an audible input and to generate a signal in response to the audible input received. An electronic control module is again coupled to the lens and to the microphone and configured to control the electronically controllable lens based upon the signal.
[0006] A method is also provided for manufacturing a welding helmet. The method includes mounting an electronically controllable lens assembly in a helmet shell; and mounting a microphone in the helmet shell. The microphone is configured to receive an audible input and to generate a signal indicative of the audible input. A control module is mounted to the helmet shell, and is coupled to the electronically controllable lens and configured to control the electronically controllable lens based upon the signal.
DRAWINGS
[0007] These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:
[0008] FIG. 1 is an illustration of an exemplary arc welding system including a welding helmet in accordance with aspects of the present technique;
[0009] FIG. 2 is an illustration of an exemplary embodiment of the welding helmet of FIG. 1 including a microphone in accordance with aspects of the present technique;
[0010] FIG. 3 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 2 in accordance with aspects of the present technique;
[0011] FIG. 4 is an illustration of an alternate exemplary embodiment of the welding helmet of FIG. 1 including arc sensors in accordance with aspects of the present technique;
[0012] FIG. 5 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 4 in accordance with aspects of the present technique;
[0013] FIG. 6 is an illustration of yet another exemplary embodiment of the welding helmet of FIG. 1 including a manual input in accordance with aspects of the present technique;
[0014] FIG. 7 is an illustration of an exemplary embodiment of the welding helmet of claim 6 including a remote control manual input in accordance with aspects of the present technique;
[0015] FIG. 8 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIGS. 6 and 7 in accordance with aspects of the present technique;
[0016] FIG. 9 is an illustration of yet another alternate exemplary embodiment of the welding helmet of FIG. 1 including a heads-up display in accordance with aspects of the present technique;
[0017] FIG. 10 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 9 in accordance with aspects of the present technique;
[0018] FIG. 11 is an illustration of yet another alternate exemplary embodiment of the welding helmet of FIG. 1 including a fan in accordance with aspects of the present technique;
[0019] FIG. 12 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 11 in accordance with aspects of the present technique;
[0020] FIG. 13 is an illustration of yet another alternate exemplary embodiment of the welding helmet of FIG. 1 including a secondary control module accordance with aspects of the present technique;
[0021] FIG. 14 is a diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 13 in accordance with aspects of the present technique; and
[0022] FIG. 15 is another diagrammatical illustration of the exemplary embodiment of the welding helmet of FIG. 13 configured to provide a modular lens assembly in accordance with aspects of the present technique.
DETAILED DESCRIPTION
[0023] The present invention may have uses in a variety of welding applications. For example, FIG. 1 illustrates an arc welding system 10 . As depicted, the arc welding system 10 may include a power supply 12 that generates and supplies a current to an electrode 16 via a conduit 14 . In the arc welding system 10 , a direct current (DC) or alternating current (AC) may be used along with a consumable or non-consumable electrode 16 to deliver the current to the point of welding. In such a welding system 10 , an operator 18 may control the location and operation of the electrode 16 by positioning the electrode 16 and triggering the starting and stopping of the current flow.
[0024] In welding operations employing welding system 10 depicted in FIG. 1 , welding is generally performed with certain precautions due to the generation of heat, and bright light in visible and non-visible spectra. To avoid overexposure to such light, a helmet assembly 20 is worn by the welding operator 18 . The helmet assembly 20 includes a helmet shell 22 and a lens assembly 24 that may be darkened to prevent or limit exposure to the light generated by the welding arc, as discussed below.
[0025] When the operator 18 applies current from the power supply 12 to electrode, and begins the welding operation, an arc 26 is developed between the electrode and a work piece. The conduit 14 and the electrode 16 thus deliver current and voltage sufficient to create the electric arc 26 between the electrode 16 and the work piece. The arc 26 melts the metal (the base material and any filler material added) at the point of welding between electrode 16 and the work piece, thereby providing a joint when the metal cools. The welding systems 10 may be configured to form a weld joint by any known technique, including shielded metal arc welding (i.e., stick welding), metal inert gas welding (MIG), tungsten inert gas welding (TIG), gas welding (e.g., oxyacetylene welding), and/or resistance welding.
[0026] As described below, helmet assemblies in accordance with the present invention include a lens assembly that may include functionality to transition a lens 28 from a clear state to a darkened state. Generally, a lens assembly that transitions from a clear to darkened state may include a lens including a LCD layer that darkens when a voltage is applied across the layer. For example, a user may “turn on” the lens to provide a voltage across the lens and cause the lens to transition from a light or relatively clear state to a darkened state.
[0027] As described below, in particular embodiments, the lens assembly may include a lens 28 and associated electronic components to cause the lens to automatically darken when sensors detect bright light that is in excess of a threshold value, triggering circuitry of the lens assembly to provide a voltage across the lens. In addition to darkening the lens, helmets in accordance with the invention may provide for adjustment of the threshold value of sensed light that triggers the lens to transition between light and dark states. For example, the circuitry of the helmet assembly may include a circuit designed to allow for adjustment of the sensitivity of the helmet sensors and circuitry to light, and thereby set the level of external light that triggers the transition of the lens between states. Further, a time delay for transitioning between the darkened and clear states may be set by the user. Such a setting may govern the time delay between detecting that the arc is extinguished and transition of the state of the lens from its dark state to its clear state.
[0028] To simplify the use of welding helmet assembly 20 , the present invention allows for a voice control feature that may provide for audible selection and adjust of common features of the welding helmet assembly. Embodiments of this invention, including those discussed in detail below, may provide for adjusting settings in real-time while welding, and may also provide for adjusting settings without removing the helmet assembly 20 . For example, as depicted in FIG. 2 , a welding helmet assembly 20 will include, in addition to a helmet shell 22 and lens assembly 24 , a microphone 30 , and a lens control module 32 . The microphone 30 may be incorporated into the lens control module 32 , or may be separate from it.
[0029] Certain of the settings of the welding helmet assembly 20 may be pre-set at the time of manufacture, and may be re-adjusted by the operator 18 . In particular, functions of the helmet assembly 20 may have adjustable settings controlled by manually adjusting analog or digital knobs, sliders, switches, buttons, and so forth. Accordingly, to make adjustments to the settings, an operator 18 may adjust the settings prior to welding, and/or re-adjust the settings once welding has begun.
[0030] As depicted by FIG. 2 , the helmet shell 22 may constitute the general frame and support for the components of the welding helmet assembly. For example, the helmet shell 22 provides a partial enclosure about the face of the operator 18 and neck to shield the operator from exposure to the high heat and bright light produced during welding. In addition to providing general protection, the helmet shell 22 provide a location to mount a lens assembly 24 and any additional accessories or control circuitry discussed in more detail below (e.g., lens control module 32 or a secondary control module 40 of FIG. 13 ).
[0031] The lens control module 32 may include circuitry configured to monitor and control the state of the lens 28 , as well as circuitry to control other functions of the helmet assembly 20 . In one embodiment, the lens control module 32 may be provided as component of the lens assembly 24 . For example, the lens assembly 24 may be mounted to the helmet shell 22 as a single unit. In another embodiment, the lens control module 32 may be a component that is separate from the lens assembly 24 and the lens 28 . For example, where the lens control module 32 is separate from the lens assembly 24 , it may be mounted remotely in the helmet shell 22 with a connection (e.g., via wire conductors) to the lens assembly 24 sufficient to transmit control signals. As will be discussed in further detail, the lens control module 32 may acquire various inputs (e.g., microphone 30 or manual inputs 36 ), process the inputs, compare the inputs to the values stored in a memory and carry out programmed functionality to provide corresponding outputs to accessories related to the welding helmet assembly 20 , particularly to lighten and darken the lens.
[0032] As an additional component of the welding helmet assembly, the microphone 30 may be configured to receive voice commands as an input to the lens control module 32 . In one embodiment, the microphone 30 may be mounted to the helmet shell 22 in a location convenient to receive voice commands from an operator 18 . For example, as depicted in FIG. 2 , the microphone 30 may be located near the portion of the helmet shell 20 covering the mouth of the operator 18 . The proximity of the microphone 30 to the mouth of the user may provide for audible commands of the operator 18 to be sensed by the microphone 30 . As will be appreciated by those skilled in the art, the location of the microphone 30 may vary to meet requirements of specific applications. For example, the microphone 30 may be located remotely in the helmet shell 22 , within the lens control module 32 , or may be within additional circuitry of the helmet assembly 20 .
[0033] As depicted in the diagram of FIG. 3 , the microphone 30 communicates with the lens control module 32 to facilitate audible control of the lens assembly 24 . In one embodiment, the microphone 30 may sense an audible command by the operator 18 , and output a signal indicative of the command sensed. For example, the microphone 30 may detect a command and output a raw or amplified analog waveform signal representative of the command detected. The signal may then be transmitted to the lens control module 32 for processing. The lens control module 32 may then process the signals from the microphone 30 and provide an output to the lens 28 based on the result of the processing and functions stored in memory. For example, the lens control module 32 may implement voice recognition processing to interpret a signal from the microphone 30 and determine that the audible command from the operator 18 was “dark.” Accordingly, the lens control module 32 may output a signal to the lens 28 which is configured to darken the lens. As an additional example, if the sensitivity of the lens 28 is too low such that the lens has not darkened, an operator 18 may issue an audible command (e.g., “dark”) to increase the sensitivity until the lens 28 darkens. The new sensitivity setting may remain as a setting even after the arc 26 is extinguished. As will be appreciated by those skilled in the art, other commands may be sensed and processed based on the functions and settings of the helmet assembly 20 . For example, the lens control module 32 may interpret the command “sensitivity” followed by the words “more” or “less” to make adjustment to sensitivity setting of an auto-darkening helmet assembly 20 .
[0034] Although some embodiments may include voice recognition processing in the lens control module 32 , the processing may be completed separate from the lens control module 32 . In one embodiment, the microphone 30 may include voice recognition processing to interpret the audible command and output a representative signal. For example, the microphone 30 may be configured to sense a command from a user, provide voice recognition processing and transmit a corresponding digital signal to the lens control module 32 for subsequent processing. As will be appreciated by those skilled in the art, various techniques and software for voice recognition currently exists, and may be implemented in any location and manner that provides for the processed voice command to control functions related to the welding helmet assembly 20 .
[0035] In addition to using an audible command to implement functions of the helmet assembly 20 , an auto-darkening welding helmet assembly 20 may include arc sensing circuitry that is responsive to the level of light created by the arc 26 . For example, as depicted in FIG. 4 , the lens assembly 24 may include arc sensors 34 about the periphery of the lens 28 . In one embodiment, the arc sensors 34 may include photodetectors configured to sense the light of the arc 26 . In another embodiment, the arc sensors 34 may include electromagnetic sensors configured to detect the electromagnetic emissions of the arc 26 . The arc sensors 34 may determine the intensity of the light experienced at the lens 28 , and output a signal indicative of the light intensity to the lens control module 32 . Based on the signal provided by the sensors 34 , the lens control module 32 may output a signal to the lens 28 to change to a light or dark state. In one embodiment, the signals provided by the microphone 30 and the arc sensors 34 may be simultaneously monitored by the lens control module 32 (see FIG. 5 ). For example, the lens control module 32 may command a dark lens 28 if either of the microphone 30 or arc sensors 34 provide a signal to that requires the lens to be darkened (e.g., an audible command or light above a threshold value). In another embodiment, the lens control module 32 may be configured to give priority to one input over another. For example, to ensure that the lens 28 is darkened when an arc 26 is present, the lens control module 32 may darken the lens even if the last audible command to the microphone 30 was for a clear lens 28 . In another embodiment, to prevent inadvertent clearing of the lens 28 during welding, the lens control module 32 may not respond to command signals to clear the lens 28 while the arc sensors 34 detect an arc.
[0036] Although measures such as auto-darkening may be beneficial, there may be times when the operator 18 needs to override the light or dark status of the lens 28 or commands from the control circuitry. In one embodiment, the operator 18 may be able to override the darkened state. For example, during the detection of an arc 26 , and darkened state of the lens 28 , the user may be able to command “override” and “clear” to return the lens 28 to a clear state. This may be useful when the sensitivity of the lens control module 32 has been set low, and the lens 28 darkens prematurely. As will be appreciated by those skilled in the art, the priority of each function may be manipulated to provide desired functionality of the helmet assembly 20 .
[0037] In addition to providing hands-free operation of the welding helmet assembly 20 , it may also be desirable that the helmet assembly 20 includes a manual input to select and fine tune functions or settings of the welding helmet assembly 20 . As depicted in the embodiment of FIG. 6 , the manual input 36 may include a dial secured to the exterior of the helmet shell 22 that provides a signal when the dial is manipulated by the operator 18 . As will be appreciated by those skilled in the art, the manual input 36 may take any form which provides a corresponding signal in response to the input of the operator 18 . For example, the manual input 36 may include a digital encoder, a knob, a touch sensitive sensor and/or one or more buttons or keys.
[0038] In another embodiment, as depicted in FIG. 7 , the manual input 36 may include a wired or wireless remote control 37 worn by the operator 18 . For example, the remote control 37 may include buttons to adjust a variety of settings and functions including those previously and subsequently discussed (e.g., shade, sensitivity, speed of an integrated fan—see FIG. 11 , and other options). As depicted in the diagram of FIG. 8 , the remote control 37 may transmit the inputs to the lens control module 32 , wherein the lens control module 32 is configured to receive and process the inputs, and output an appropriate signal to the lens 28 , a heads-up display (HUD) 38 (see FIG. 9 ), or other helmet function 43 . In one embodiment, the remote control 37 may also receive and process signals from the lens control module 32 . For example, the lens control module 32 may output the status of helmet functions, and the remote control 37 may display the status of helmet functions (e.g., the status and settings of the lens 28 ). In yet another embodiment, a function of the remote control 37 may be provided independently or in coordination of a display on the HUD 38 . For example, a LED on the remote may indicate that the helmet assembly 20 is powered on, while a numerical indication of the current sensitivity setting is displayed via an LCD of the remote control 37 and the HUD 38 .
[0039] In operation, the manual input 36 may provide for inputs in conjunction with the microphone 30 . As depicted in the diagram of FIG. 8 , the lens control module 32 may monitor inputs from both the microphone 30 and the manual input 36 , and output an appropriate signal to the lens 28 . In one embodiment, the operator 18 may speak a command into the microphone 30 to select the functionality of the manual input 36 , followed by the user adjusting the manual input 36 . For example, the operator may speak “shade” and then adjust the digital encoder knob to select the desired shade. As will be appreciated by those skilled in the art, the design of the manual input 36 may allow for increased flexibility in adjustment of the settings. For example, a high resolution encoder may provide for very fine adjustment of settings.
[0040] In a similar embodiment, the microphone 30 and manual input 36 may provide for simultaneous adjustment of functions and settings. For example, the operator 18 may command to adjust a particular function (e.g., shade), and subsequently adjust the setting for that function with audible commands through the microphone 30 or by manual input 36 (i.e., speak a command “dark” or “light”, or adjust the manual input until the desired shade is reached). In another embodiment, the manual input 36 may be used to select a particular function to adjust, and subsequently allow commands spoken into the microphone 30 to make the setting adjustments. For example, the operator may set the manual input 36 to a “shade” position and subsequently command “darker” or “lighter” to change the shade setting. As will be appreciated, the functionality of the microphone 30 and the manual input 36 may be varied in any combination to provide the desired functionality.
[0041] In addition to providing hands-free adjustments of the welding helmet functions and settings, it may be desirable for information to be readily available to the operator 18 . In one embodiment, the welding helmet assembly 20 may include a (HUD) that provides visual information in the line-of-sight (or peripheral vision) of the operator 18 . For example, as depicted in FIG. 9 , the lens assembly 24 may include a HUD 38 on the lens 28 and in view of the operator 18 . In one embodiment, the HUD 38 may include a display of the present settings. For example, the HUD 38 may display the “shade” or “sensitivity” each followed by a corresponding number or symbol (e.g., “50%” or an icon) that indicates the present setting. In another embodiment, the HUD 38 may display the current selections of the operator 18 . For example, operator 18 may command “shade” followed by the HUD 38 displaying “shade” to indicate to the operator 18 that the manual input 36 and voice commands are now controlling the “shade” setting. As will be appreciated by those skilled in the art, the HUD 38 may also incorporate displaying information other than functions and settings of the welding helmet assembly 20 . For example, the HUD 38 may also display an indication of the status of the welding power supply 12 , a clock, the temperature, and so forth. Further, in an environment where a respirator is required, it may also be useful for the HUD 38 to display the surrounding air quality to inform the operator 18 when it may be safe to remove the respirator and welding helmet assembly 20 .
[0042] To provide for the display of information on the HUD 38 , the HUD 38 may be controlled by the lens control module 32 . In one embodiment, as depicted by the diagram of FIG. 10 , the lens control module 32 may monitor inputs from the microphone 30 , the manual input 36 , the arc sensors 34 , and/or other inputs 39 and provide corresponding outputs to the lens 28 and HUD 38 . For example, the operator 18 may command “H-U-D shade” which is received by the lens control module 32 via the microphone 30 . The lens control module 32 may then process the input from the microphone 30 and send a corresponding signal to the HUD 38 to display the current shade setting. In another embodiment, the HUD 38 may activate when the operator 18 adjusts the manual input 36 . For example, the HUD 38 may be configured to display a blank screen until an input is received (e.g., a manual input). In such an embodiment, when the operator 18 turns the knob of the manual input 36 , the lens control module 32 may detect the input and provide a signal for the HUD 38 to display the current value of the setting and update the displayed value as the manual input 36 is manipulated. In yet another embodiment, the HUD 38 may be responsive to the arc sensors 34 as depicted in the diagram of FIG. 10 . For example, in response to a signal from the arc sensor 34 indicating a light value above the a threshold limit, the lens control module 32 may provide an output to darken the lens 28 and may simultaneously output a signal for the HUD 38 to display an indication that the lens 28 has been auto-darkened (e.g., an icon representative of exceeding the threshold value). As will be appreciated by those skilled in the art, the lens control module 32 may control the lens 28 and HUD 38 based on signals from the microphone 30 , manual input 36 , arc sensors 34 , other inputs 39 , or any combination of the like.
[0043] Similar to the limitations of adjusting the lens assembly 24 , adjustment of additional helmet assembly functions may require removal of the helmet assembly 20 , which may decrease the efficiency of the operator 18 . Accordingly it may be desirable for the microphone 30 and lens control module 32 to control other functions of the welding helmet assembly 20 . In one embodiment, the helmet assembly 20 may include an additional helmet function that may be controlled by the lens control module 32 . For example, as depicted in FIG. 11 , the welding helmet assembly 20 may include a fan 42 that may run at a variety of speeds. In one embodiment, the fan 42 may be controlled by an output of the lens control module 32 as depicted by the diagram of FIG. 12 . The lens control module 32 may monitor inputs from the microphone 30 , manual input 36 , arc sensors 34 , or other inputs 39 , and send an appropriate control signal to the cooling fan 42 represented by the “other helmet functions” block 43 in the diagram of FIG. 12 . For example, the operator 18 may speak the command “fan” and “up” into the microphone 30 , wherein the lens control module 32 responds by transmitting a signal to increase the speed of the fan 42 . As will be appreciated by a person of ordinary skill in the art, the control of other helmet functions 43 may include integration of all of the variations discussed previously, including the manipulation of the HUD 38 and the integration of the manual input 36 . For example, the manual input may be coordinated with audible inputs to control the fan 42 , all while the settings are updated on the HUD 38 . As will also be appreciated by those skilled in the art, the other helmet functions 43 may include any functions desirable to implement into that helmet assembly. For example, the lens control module may control radio communication, an audio system, a helmet security system, or a respirator connection.
[0044] Previously, the discussion has focused on control of the welding helmet assembly 20 by a single lens control module 32 . Although this configuration may prove beneficial, in some cases it may be desirable for additional control circuitry to be integrated into the helmet assembly 20 . In one embodiment, the helmet assembly 20 may include the lens control module 32 as well as a secondary control module 40 , as depicted in FIG. 13 . For example, as depicted in the diagram of FIG. 14 , the lens control module 32 and the secondary control module 40 may each receive inputs (e.g., microphone 30 , manual input 36 , arc sensors 34 , or other inputs 39 ), wherein the lens control module 32 outputs control signals to the lens 28 , the HUD 38 , and other outputs 44 (e.g., power supply 12 ), while the secondary control module 40 controls other helmet functions 43 (e.g., fan speed). For example, in an embodiment, a control signal may be output to the power supply 12 to control functions of the power supply 12 , including initiating welding in coordination with darkening the shade of the lens 28 .
[0045] A secondary control module may also provide for a modular helmet assembly wherein components such as the lens assembly 24 may be implemented as add-on features. In one embodiment, in contrast to the control system of FIG. 14 , the lens control module 32 of FIG. 15 may be limited to controlling the lens 28 and the HUD 38 , while the secondary control module is configured to control the other outputs 44 and the other helmet functions 43 . For example, as depicted in the diagram of FIG. 15 , the lens control module 32 may be provided as part of the lens assembly 24 , and be configured to control functions of the lens 28 and arc sensors 34 , while a secondary control module 40 transmits and receives signals related to functions of the helmet not directly connected to the lens assembly 24 . In another embodiment, the lens control module 42 and the secondary control module 40 may share a signal to coordinate their responses. For example, the lens control module 42 may only receive inputs from the microphone 30 and arc sensors 34 , while the secondary control module 40 receives and processes signals from the additional inputs (microphone 30 , manual input 36 , and other inputs 39 ). The lens control module 32 and the secondary control module 40 may then be configured to coordinate the signals output to the lens 28 , HUD 38 , other helmet functions 43 and other outputs (e.g., power supply 12 ). For example, the operator 18 may command into the microphone 30 a particular shade for the lens which is interpreted by voice recognition processing in the secondary control module 40 . The secondary module may output the setting to an “other output” (e.g., remote control) and the lens control module 32 . In response the lens control module 32 may send a signal to the HUD 38 to display the current shade setting, and signal the lens to change to the darkened shade only when the arc sensor 34 detects light in excess of a threshold value. As will be appreciated by those skilled in the art, such a configuration may allow for a helmet design to modularize the lens assembly 24 . For example, an operator 18 may purchase a helmet assembly 20 with voice control of functions, and later add a lens assembly 24 that incorporates arc sensors 34 and a lens control module 32 to coordinate the HUD 38 and the lens 28 with the voice control processing. As will also be appreciated by those skilled in the art, the configuration of the helmet assembly 20 (inputs and outputs) may be modified and combined to provide the desired functionality and modularity within the welding system 10 .
[0046] Due to the demand for welding helmets, and the increased cost of helmets that include a range of features described above, it may also be desirable for the welding helmet assembly 20 to incorporate a security system into the control circuitry. In one embodiment, the helmet assembly 20 may include security via the voice recognition. For example, upon powering on of the helmet assembly 20 , the operator 18 may be required to speak a password to “unlock” the functionality of the helmet. The voice command sensed may then be compared to a previously recorded password, or stored audio data, to determine if the operator 18 is in fact an authorized operator 18 of the helmet assembly 20 . In another embodiment, the voice recognition software may also compare the vocal patterns to ensure that the password was spoken by the correct operator 18 .
[0047] To increase the level of flexibility for the helmet assembly 20 , it my also be desirable that the operator 18 be capable of customizing the interface. In one embodiment, an interface may be provided between the helmet assembly 20 and a processing computer (PC). For example, the helmet assembly 20 may include a standard connection (e.g., a USB cable connection) to a processing computer that allows the operator 18 to modify the commands available, the helmet assembly response to commands, and/or the menu structure. In another embodiment, this functionality may be contained within the helmet. For example, the HUD 38 in coordination with other inputs (e.g., microphone 30 , manual input 36 ) may be configured to provide for the operator 18 to modify the commands and menu structures. As would be appreciated by those skilled in the art, customizing the interface may take a multitude of forms, and include various implementations of functionality.
[0048] While only certain features of the invention have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. | Provided for is a control system for a welding helmet comprising: an electronically controllable lens configured to be mounted in a welding helmet shell, a microphone configured to receive an audible input and to generate a signal in response to the audible input received and an electronic control module coupled to the lens and to the microphone and configured to control the electronically controllable lens based upon the signal. Also provided for is a welding helmet implementing a control system and a method of manufacturing a welding helmet including a control system. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of International Patent Application No. PCT/JP99/01997, filed Apr. 14, 1999, and claims priority from Japanese Patent Application No. 10/121805, filed Apr. 14, 1998.
FIELD OF THE INVENTION
[0002] This invention relates to a novel cytokine-like protein and the encoding genie.
[0003] 1. Background of the Invention
[0004] Cytokines are multi-functional cell growth/differentiation inducing factors controlling immune and hematopoietic reactions. The series of factors composing cytokines, are mainly produced by activated T cells, macrophages, or stromal cells and connect the cells of the lymphoid system and the hematopoietic system in a network, regulating the proliferation, differentiation, and functions of these cells. So far, a number of factors have been isolated as cytokines and apart from the factors themselves, antibodies and receptor molecules of those factors, or antibodies against those receptors, have been developed as therapeutic drugs and are in actual use.
[0005] For example, G-CSF, which has a neutrophil-proliferating function, is already in use as a drug for many diseases and leukopenia resulting from the treatment of these diseases (K. Welte et al., the first 10 years Blood Sep. 15 1996; 88:1907-1929 and also refer GENDAIKAGAKU ZOUKAN no. 18, Cytokine, edited by TOSHIAKI OHSAWA, 1990, published by TOKYO KAGAKU DOUJIN). Furthermore, an antibody against the receptor of IL-6, which acts in immune functions and inflammation, is being developed as a potential therapeutic drug against rheumatism and leukemia.
[0006] 2. Summary of the Invention
[0007] The present invention provides a novel cytokine-like protein and the encoding DNA. It also provides a vector into which the DNA has been inserted, a transformant carrying the DNA, and also a method for producing a recombinant protein using the transformant. Furthermore, screening methods for a compound, which binds to the protein and regulates the activity, and the uses of the protein and the compounds regulating its function as pharmaceutical drugs, are also provided by the present invention.
[0008] Most cytokines known so far, have a conserved characteristic such as a W S Motif (Idzerda, R L et al., J Exp Med 1990 Mar 1; 171 (3) 861-873), and form a super-family of cytokine receptors. Although the cytokine itself, which is the ligand, does not have a conserved characteristic or homology compared to the receptor, some groups have an extremely weak homology, hinting of a close stereoscopic structure. EPO/TPO family and IL-6/G-CSF/MGF family can be taken as examples. The present inventors, thinking that unknown, yet unidentified genes may exist in these families, attempted to isolate an unknown cytokine belonging to these families.
[0009] Specifically, it was found that the EST (AA418955) sequence, which does not show any homology to other proteins in the Database, has a weak homology to G-SCF and constructed primers based on that sequence, and did PCR cloning from a human fetal spleen library. As a result, the present inventors succeeded in isolating a full-length cDNA corresponding to the EST (this clone was named SGRF). Also, the isolated SGRF cDNA was sequenced and the structure analyzed to find that the isolated cDNA has the typical characteristics of a factor belonging to the IL-6/G-CSF/MGF family. Furthermore, the inventors analyzed the activity of the SGRF protein to find that the culture supernatant of SGRF-transfected CHO cells has a proliferation supporting activity towards specific bone marrow cells in the presence of mouse kit ligand. The isolated SGRF protein itself may be applicable for the prevention and treatment of diseases of the lymphoid and hemiiatopoictic systems and for diseases related to defective cell growth. Also it is possible to use this protein for the screening of other factors related to the lymphoid and hematopoietic systems and as a drug candidate compound for diseases of those systems.
[0010] Namely, this invention relates to a novel cytokine-like protein SGRF and the encoding gene, their production as well as the use of the protein in the screening of drugs and drug candidate compounds. More specifically,
[0011] 1. a protein comprising the amino acid sequence of SEQ ID NO:1, or said sequence in which one or more amino acids are replaced, deleted, added, and(/or inserted,
[0012] 2. a protein encoded by a DNA hybridizing with the DNA comprising the nucleotide sequence of SEQ ID NO:2, which is functionally equivalent to the protein having the amino acid sequence of SEQ ID NO:1,
[0013] 3. a DNA encoding the protein of (1) or (2),
[0014] 4. the DNA of (3), which contains the coding region of the nucleotide sequence of SEQ ID NO:2,
[0015] 5. a vector in which the DNA of (3) or (4) is inserted,
[0016] 6. a transformant carrying, in an expressible manner, the DNA of (3) or (4),
[0017] 7. a method for producing the protein of (1) or (2), which comprises the culturing of the transformant of (6),
[0018] 8. a method for screening a compound which can bind to the protein of (1) or (2), the method comprising the steps of:
[0019] (a) exposing a test sample to the protein of (1) or (2) or its partial peptide;
[0020] (b) detecting the binding activity between the test compound and said protein or its partial peptide; and
[0021] (c) selecting a compound having a binding activity to said protein,
[0022] 9. a compound which can bind to the protein of (1) or (2),
[0023] 10. the compound of (9) which is obtainable by the method of (8),
[0024] 11. a method for screening a compound which can promote or inhibit activity of the protein of (l) or (2), the method comprising the steps of:
[0025] (a) exposing the protein of (1) or (2) and the kit ligand to mammalian bone marrow cells under the absence of a test compound;
[0026] (b) detecting the proliferation of said bone marrow cells; and
[0027] (c) selecting a compound which promotes or inhibits the proliferation of bone marrow cells in comparison with the assay under the presence of the test sample,
[0028] 12. the method of (11), wherein the bone marrow cells are Lin negative, Sca-1 positive, c-kit positive, and CD34 positive,
[0029] 13. a compound which promotes or inhibits the activity of the protein of (1) or (2),
[0030] 14. the compound of (13) which is obtainable by the method of (I 1) or (12),
[0031] 15. a pharmaceutical composition comprising the protein of (I) or (2) as an active component,
[0032] 16. a promoter or inhibitor of the protein of (1) or (2) wherein the active component is the compound of (13) or (14),
[0033] 17. an antibody which can bind to the protein of (1) or (2), and
[0034] 18. a DNA comprising at least 15 nucleotides, which can specifically hybridize with the DNA comprising the nucleotide sequence of SEQ ID NO:2.
[0035] The present invention relates to a novel cytokine-like protein. The nucleotide sequence of the cDNA encoding the protein named “SGRF”, which is included in the protein of the present invention is shown in SEQ ID NO:2; the amino-acid sequence of said protein in SEQ ID NO:1.
[0036] So far, in mammals, IL-6 and G-CSF have been reported as factors thought to belong to the IL-6/G-CSF/MGF family. The “SGRF” cDNA isolated by the present inventors, had in its 3′ non-coding region, four mRNA destabilizing sequences (Lagnando C A, Brown C Y, Goodall G J (1994) Mol. Cell. Biol. 14, 7984-7995) called ARE (AT Rich element), often seen in cytokine mRNAs. The consensus sequence preserved in the IL-6/G-CSF/MGF family was also roughly maintained (FIG. 3). From these facts, “SGRF” can be assumed to be a novel factor belonging to the IL-6/G-CSF/MGF family.
[0037] The “SGRF” expression in human normal tissue as detected by northern-blot analysis is extremely localized, and was seen in the testis, lymph nodes, and thymus, being not present in a detectable level in other tissues (FIG. 4). Even in tissues where expression was detected, the expression level was assumed to be very low. An EST (U38443), a partial fraction of “SGRF”, which is normally hardly expressed, is reportedly induced following activation in a T cell-line (Jurkat) (Yatindra Prashar, Sherman M. Weissman (1996) Proc. Natl. Acad. Sci. USA 93:659-663). From this fact and from the results of northern-blot analysis, it can be assumed that in vivo, “SGRF” is mainly expressed in activated T cells.
[0038] Furthermore, the culture supernatant of “SGRF” transfected CHO cells showed an activity, which supported the proliferation of bone marrow cells (FIG. 12), in the presence of the kit ligand.
[0039] The characteristics of “SGRF” such as those above, suggest that it is a kind of a typical interleukin. “SGRF”, as are most cytokines isolated so far, is thought to be involved in the lymphoid and hematopoietic systems. Therefore, it can be applied as a therapeutic or preventive drug in diseases of the lymphoid and hematopoietic systems, and also in diseases associated with defects in cell proliferation.
[0040] The protein of the present invention can be prepared by methods commonly known to one skilled in the art, as a recombinant protein made using genetic engineering techniques, and also as a natural protein. For example, a recombinant protein can be prepared by, inserting DNA encoding the protein of the present invention (for example, DNA comprising the nucleotide sequence in SEQ ID NO:1) into a suitable expression vector, introducing this into a host cell, and purifying the protein from the resulting transformant or the culture supernatant. The natural protein can be prepared by immobilizing( in a column, antibodies taken from immunizing a small animal with the recombinant protein, and performing affinity chromatography for extracts of tissues or cells (for example, testis, lymph nodes, thymus, etc.) expressing the protein of the present invention.
[0041] Also, this invention features a protein, which is functionally equivalent to the “SGRF” protein (SEQ ID NO:1). The method of inserting a mutation into the amino acids of a protein is a well-known method for isolating such proteins. In other words, for a person skilled in the art, the preparation of a protein functionally equivalent to the “SGRF” protein, is something which can be generally done using various methods such as the PCR-mediated, site-specific-mutation-induction system (GIBCO-BRL, Gaithersburg, Md.), oligonucleotide-mediated, site-specific-mutation-induction method (Kramer, W. and Fritz, H J (1987) Methods in Enzymol., 154:350-367) suitably replacing amino acids in the “SGRF” protein shown in SEQ ID NO:1, which do not influence the function. Mutations of amino acids can occur spontaneously as well. Therefore, the protein of the invention includes those proteins that are functionally equivalent to the “SGRF” protein, having an amino acid sequence in which one or more amino acids in the amino acid sequence of the “SGRF” protein (SEQ ID NO:1) have been replaced, deleted, added, and/or inserted. The term “functionally equivalent” as used herein, refers to a protein having a cytokine activity equivalent to that of the “SGRF” protein. The cytokine activity of the “SGRF” protein includes, for example, a proliferation-supporting activity (Example 11) towards cells which are Lin negative, Sca-1 positive and c-kit positive.
[0042] The number of amino acids that are mutated is not particularly restricted, as long as a cytokine activity equivalent to that of the “SGRF” protein is maintained. Normally, it is within 50 amino acids, preferably within 30 amino acids, more preferably within 10 amino acids and even more preferably within 5 amino acids. The site of mutation may be any site, as long as a cytokine activity equivalent to that of the “SGRF” protein is maintained.
[0043] A “conservative amino acid substitution” is one in which an amino acid residue is replaced with another residue having a chemically similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
[0044] In the present invention, the protein having numerous depletions in the amino acid sequence of the “SGRF” protein (SEQ ID NO:1) includes a partial peptide. The partial peptide includes, for example, a protein of which the signal peptide has been excluded from the “SGRF” protein of SEQ ID NO:1.
[0045] Also, a fusion protein can be given as a protein comprising the amino acid sequence of the “SGRF” protein and several amino acids added thereto. Fusion proteins are, for example, fusions of the above described proteins and other peptides or proteins, and are included in the present invention. Fusion proteins can be made by techniques commonly known to a person skilled in the art, such as linking the DNA encoding the protein of the invention and with DNA encoding other peptides or proteins, so as the frames match, inserting this into an expression vector and expressing it in a host. There is no restriction as to the peptides or proteins fused to the protein of the present invention.
[0046] Commonly known peptides, for example, FLAG (Hopp, T. P. et al., Biotechnology (1988) 6:1204-1210), 6×His constituting six His (histidine) residues, 10×His, Influenza agglutinin (HA), human c-myc fragment, VSP-GP fragment, p18HIV fragment, T7-tag, HSV-tag, E-tag, SV40T antigen fragment, lck tag, α-tubulin fragment, B-tag, Protein C fragment can be used as peptides that are fused to the protein of the present invention. Examples of proteins that are fused to protein of the invention are, GST (glutathione-S-transferase), HA (Influenza agglutinin), Immunoglobulin constant region, β-galactosidase and MBP (maltose-binding protein). Fusion proteins can be prepared by fusing commercially available DNA encoding these peptides or proteins with the DNA encoding the protein of the present invention and expressing the fused DNA prepared.
[0047] The hybridization technique (Sambrook, J. et al., Molecular Cloning 2nd ed. 9.47-9.58, Cold Spring Harbor Lab. press, 1989) is well known to one skilled in the art as an alternative method for isolating a protein functionally equivalent to the “SGRF” protein (SEQ ID NO:1). In other words, for a person skilled in the art, it is a general procedure to prepare a protein functionally equivalent to the “SGRF” protein, by isolating DNA having a high homology with the whole or part of the DNA encoding the “SGRF” protein used as a base for the preparation of the protein. Therefore, the protein of the present invention also includes proteins, which are functionally equivalent to the “SGRF” protein and are encoded by DNA hybridizing with DNA encoding the “SGRF” protein. The term “functionally equivalent” as used herein, means as mentioned above, proteins that show a cytokine activity equivalent to that of the “SGRF” protein. Apart from humans, for example, mice, rats, cows, monkeys and pigs can be used as animals from which functionally equivalent proteins can be isolated. One skilled in the art can suitably select the stringency of hybridization for isolating DNA encoding a functionally equivalent protein, but normally, it is equilibrium hybridization at about 42° C., 2×SSC, 0.1% SDS (low stringency); about 50° C., 2×SSC, 0.1% SDS (medium stringency); or about 65° C., 2×SSC, 0.1/% SDS (high stringency). If washings are required to reach equilibrium, then the washings are performed using the same buffer as the original hybridization solution, a listed above. In general, the higher the temperature, the higher is the homology of the DNA obtainable. “High homology” refers to, in comparison with the amino acid sequences of the “SGRF” protein, normally a homology of 40% or higher, preferably 60% or higher, more preferably 80% or higher, even more preferably 95% or higher. The homology of a protein can be determined by following the algorithm in Wilbur, W. J. and Lipman, D. J. Proc. Natl. Acad. Sci. USA (1983) 80:726-730.
[0048] The “percent identity” of two amino acid sequences or of two nucleic acids is determined using the algorithm of Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87:2264-2268, 1990), modified as in Karlin and Altschul (Proc. Natl. Acad. Sci. USA 90:5873-5877, 1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al. (J. Mol. Biol. 215:403-410, 1990). BLAST nucleotide searches are performed with the NBLAST program, score=100, wordlength=12. BLAST protein searches are performed with the XBLAST program, score=50, wordlength=3. Where gaps exist between two sequences, Gapped BLAST is utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) are used. See http://www.ncbi.nlm.nih.gov.
[0049] This invention also relates to a DNA encoding the above protein. There is no particular restriction as to the DNA of the present invention as long as it encodes the protein of the present invention and includes cDNA, genomic DNA and chemically synthesized DNA. cDNA can be prepared by, making a primer using the nucleotide sequence of the “SGRF” cDNA, disclosed in SEQ ID NO:2, and performing RT-PCR using the mRNA prepared from cells expressing the “SGRF” protein as the template. In the case of genomic DNA, preparation can be done by the plaque hybridization method using a genomic DNA inserted λ phage library and the cDNA probe obtained. The nucleotide sequence of the DNA acquired can be decided by ordinary methods in the art using the commercially available “dye terminator sequencing kit” (Applied Biosystems). The DNA of the present invention, as stated later, can be utilized for the production of a recombinant protein and gene therapy.
[0050] An “isolated nucleic acid” is a nucleic acid the structure of which is not identical to that of any naturally occurring nucleic acid or to that of any fragment of a naturally occurring genomic nucleic acid spanning more than three separate genes. The term therefore covers, for example, (a) a DNA which has the sequence of part of a naturally Occurring genomic DNA molecule but is not flanked by both of the coding sequences that flank that part of the molecule in the genome of the organism in which it naturally occurs; (b) a nucleic acid incorporated into a vector or into the genomic DNA of a prokaryote or eukaryote in a manner such that the resulting molecule is not identical to any naturally occurring vector or genomic DNA; (c) a separate molecule such as a cDNA, a genomic fragment, a fragment produced by polymerase chain reaction (PCR), or a restriction fragment; and (d) a recombinant nucleotide sequence that is part of a hybrid gene, i.e., a gene encoding a fusion protein. Specifically excluded from this definition are nucleic acids present in mixtures of different (i) DNA molecules, (ii) transfected cells, or (iii) cell clones: e.g., as these occur in a DNA library such as a cDNA or genomic DNA library.
[0051] The term “substantially pure” as used herein in reference to a given polypeptide means that the polypeptide is substantially free from other biological macromolecules. The substantially pure polypeptide is at least 75% (e.g., at least 80, 85, 95, or 99%) pure by dry weight. Purity can be measured by any appropriate standard method, for example, by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.
[0052] The present invention also features a vector into which the DNA of the present invention has been inserted. There is no restriction as to the vector to which DNA is inserted, and various vectors such as those for expressing the protein of the present invention in vivo and those for preparing the recombinant protein can be used according to the objective. To express the protein of the present invention in vivo (especially for gene therapy), various viral vectors and non-viral vectors can be used. Examples of viral vectors are, adenovirus vectors (pAdexLcw and such) and retrovirus vectors (pZlPneo and such). Expression vectors are especially useful when using vectors for the objective of producing the protein of the invention. For example, when using Escherichia coli the “pQE vector” (Qiagen, Hilden, Germany), when using yeast “SP-Q01” (Stratagene, La Jolla, Calif.), when using insect cells “Bac-to-Bac baculovirus expression system” (GIBCO-BRL, Gaithersburg, Md.) are highly appropriate, but there is no restriction. Also, when using mammalian cells such as CHO cells, COS cells, NIH3T3 cells, for example, the “LacSwitch II expression system (Stratagene, La Jolla, Calif.) is highly suitable, but there is no restriction. Insertion of the DNA of the present invention into a vector can be done using ordinary methods in the art.
[0053] The present invention also refers to a transformant, carrying, in an expressible manner, the DNA of the present invention. The transformant of the present invention includes, those carrying the above-mentioned vector into which DNA of the present invention has been inserted, and those host genomes into which the DNA of the present invention has been integrated. As long as the DNA of the present invention is maintained in an expressible manner, no distinction is made as to the form of existence of the transformants. There is no particular restriction as to the cells into which the vector is inserted. When using the cells to express the protein of the present invention for the purpose of gene therapy by the ex vivo method, various cells (for example, various cells of the immune system) can be used as target cells according to the type of disease. Also, when the purpose is to produce the protein of the present invention, for example, E. coli , yeast, animal cells and insect cells can be used in combination with the vectors that are utilized. Introduction of a vector into a cell can be done using commonly known methods such as electroporation and calcium phosphate method.
[0054] The separation and purification of the recombinant protein from the transformant made to produce the protein can be done using ordinary methods. The recombinant protein can be purified and prepared by, for example, ion exchange chromatography, reverse phase chromatography, gel filtration, or affinity chromatography where an antibody against the protein of the present invention has been immobilized in the column, or by combining two or more of these columns. Also when expressing the protein of the present invention inside host cells (for example, animal cells and E. coli ) as a fusion protein with glutathione-S-transferase protein or as a recombinant protein supplemented with multiple histidines, the expressed recombinant protein can be purified using a glutathione column or nickel column. After purifying the fusion protein, it is also possible to exclude regions other than the objective protein by cutting with thrombin or factor-Xa as required.
[0055] The present invention also features an antibody binding to the protein of the invention. There is no particular restriction as to the form of the antibody of the present invention and include, apart from polyclonal antibodies, monoclonal antibodies as well. The antiserum obtained by immunizing animals such as rabbits with the protein of the present invention, polyclonal and monoclonal antibodies of all classes, humanized antibodies made by genetic engineering, human antibodies, are also included., The antibodies of the present invention can be prepared by the following methods. Polyclonal antibodies can be made by, obtaining the serum of small animals such as rabbits immunized with the protein of the present invention, attaining a fraction recognizing only the protein of the present invention by an affinity column coupled with the protein of the present invention, and purifying immunoglobulin G or M from this fraction by a protein G or protein A column. Monoclonal antibodies can be made by immunizing small animals such as mice with the protein of the present invention, excising the spleen from the animal, homogenizing the organ into cells, fusing the cells with mouse bone marrow cells using a reagent such as polyethylene glycol, selecting clones that produce antibodies against the protein of the invention from the fused cells (hybridomas), transplanting the obtained hybridomas into the abdominal cavity of a mouse, and extracting ascites. The obtained monoclonal antibodies can be purified by, for example, ammonium sulfate precipitation, protein A or protein G column, DEAE ion exchange chromatography, or an affinity column to which the protein of the present invention is coupled. The antibody of the invention can be used for purifying and detecting the protein of the invention. It can also be used as a pharmaceutical drug to control the function of the present protein. When using the antibody as a drug for humans, in the point of immunogenicity, the human antibodies or the humanized antibodies are effective. The human antibodies or humanized antibodies can be prepared by methods commonly known to one skilled in the art. For example, human antibodies can be prepared by, immunizing a mouse whose immune system has been changed to that of humans, using the protein of the invention. Also, humanized antibodies can be prepared by, for example, cloning the antibody gene from monoclonal antibody producing cells and using the CDR graft method which transplants the antigen-recognition site of the gene into an already known human antibody.
[0056] The present invention also relates to a method for screening a chemical compound that binds to the protein of the invention. The screening method of the invention includes the steps of, (a) exposing a test sample to the protein of the invention, (b) detecting the binding activity between the test sample and the protein of the invention, and (c) selecting a compound having an activity to bind to the protein of the invention. Any test sample call be used without particular restrictions. Examples are, synthetic low molecular weight compound libraries, purified proteins, expression products of gene libraries, synthetic peptide libraries, cell extracts, and culture supernatants. Selection of a compound that has an activity to bind to the protein of the invention can be done using methods commonly known to one skilled in the art.
[0057] The screening of a protein which binds to the protein of the invention can be done by, for example, creating a cDNA library from tissues or cells (for example, testis, lymph nodes and thymus) predicted to express a protein binding to the protein of the invention using a phage vector (λgtl1 and Zap11), expressing this cDNA library on LB-agarose, fixing the expressed proteins on the filter, biotin-labeling the protein or the invention or purifying it as a fusion protein with GST protein, reacting this with the above-described filter, and detecting plaques expressing the binding proteins using streptavidin or anti-GST antibody (West Western Blotting method) (Skolnik E Y, Margolis B, Mohammadi M, Lowenstein E, Fischer R, Drepps A, Ullrich A, and Schlessinger J (1991) Cloning of Pl3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65:83-90).
[0058] The screening of a protein binding to the protein of the invention or the gene of the protein, can also be done by following “the two hybrid system” (“MATCHMAKER Two-hybrid System”, “Mammalian MATCHMAKER Two-hybrid Assay Kit”, “MATCHMAKER One-Hybrid System” (Clontech), “HybriZAP Two-Hybrid Vector System” (Stratagene), Reference, “Dalton, S. and Treisman, R. (1992) Characterization of SAP-l, a protein recruited by serum response factor to the c-fos serum response element. Cell 68:597-612”). Namely, the protein of the invention is fused to the SRF binding region or GAL4 binding region and expressed in yeast cells. A cDNA library, is prepared from cells predicted to express a protein binding to the protein of the invention so as to express the ligand fused to the VP16 or GaL4 transcriptional activation region. The cDNA library is then introduced into the above yeast cells and the cDNA derived from the library is isolated from the positive clones detected (when a protein binding to the protein of the invention is expressed in yeast cells, the binding of the two activates a reporter gene making positive clones detectable). The isolated cDNA is expressed by introducing it into E. coli to obtain a protein encoded by the cDNA. Furthermore, a protein binding to the protein of the invention can be screened by, applying the culture supernatants or cell extracts of cells predicted to express a protein binding to the protein of the invention onto an affinity column in which the protein of the invention is immobilized and purifying the protein that binds specifically to the column.
[0059] Also, the method of screening molecules which bind when the immobilized protein of the invention is exposed to synthetic chemical compounds, or natural substance banks, or a random phase peptide display library, or the method of screening using high-thoughput based on combinatorial chemistry techniques (Wrighton N C; Farrel F X; Chang R; Kashyap A K; Barbone F P; Mulcahy L S; Johnson D L; Barret R W; Jolliffe L K; Dower W J. Small peptides as potent mimetics of the protein hormone erythropoietin, Science (UNITED STATES) Jul. 26 1996, 273 p458-68, Verdine G L., The combinatorial chemistry of nature. Nature (ENGLAND) Nov. 7 1996, 384 p11-13, Hogan J C Jr., Directed combinatorial chemistry Nature (ENGLAND) Nov. 7 1996, 384 p17-9) to isolate low molecular weight compounds, proteins (or the genes) and peptides are methods well known to one skilled in the art.
[0060] The present invention also relates to a method for screening a compound able to promote or inhibit the activity of the protein of the invention. It was found that the protein of the invention has a proliferation-supporting activity for bone marrow cells in the presence of the kit ligand. Therefore, using this activity as an indicator, screening of a compound able to promote or inhibit activity of the protein of the invention can be performed. Namely, this screening can be done using the method comprising the steps of: (a) exposing the protein of the invention and the kit ligand to mammalian bone marrow cells under the presence of a test compound; (b) detecting the proliferation of the bone marrow cells; and (c) selecting a compound which promotes or inhibits the proliferation of bone marrow cells when compared with the assay in the absence of a test sample (control).
[0061] There are no particular restrictions as to the test sample used. Examples are, libraries of synthetic low molecular compounds, purified proteins, expression products of gene libraries, synthetic peptide libraries, cell extracts and culture supernatants. The compound isolated by the above-described screening of a protein binding to the protein of the invention may also be used as a test compound.
[0062] The protein of the present invention and the kit ligand may be recombinant or natural proteins. Also, as long as the activity is maintained, may be a partial peptide. The kit ligand may also be a commercially available one.
[0063] Lin negative, Sca-1 positive and c-kit positive bone marrow cells are preferred for the screening. Bone marrow cells that are additionally CD34 positive are preferred more.
[0064] The culture conditions and detection of proliferation of bone marrow cells can be done, for example, in conformance with Example 11.
[0065] As a result of the detection, compared with the proliferation of bone marrow cells ill the absence of the test compound (control), if the proliferation of bone marrow cells is suppressed with the addition of a test compound, then the test compound is judged to be a compound (or includes the compound), which inhibits the activity of the protein of the invention. On the other hand, if the proliferation is promoted by the addition of the test compound (or includes the compound), it is judged to be a compound that promotes the activity of the protein of the invention.
[0066] The protein of the present invention can be used as a reagent in research to control the proliferation of cells of the lymphoid and hematopoietic systems. The compound isolated by the above-mentioned screening, can be used as an inhibitor or promoter of the protein in the invention. Moreover, the protein of the invention or these compounds can also be utilized as drugs for the prevention and therapy of diseases associated with defects in cell proliferation and lymphoid and hematopoietic systems.
[0067] When using the protein of the invention or a compound that controls the activity of the protein as drugs, they can be formulated into a dosage formulated using commonly known pharmaceutical preparation methods. For example, according to the need, the drugs can be taken orally (as sugar-coated tablets, capsules, elixirs and microcapsules) or non-orally (such as, percutaneously, intranasally, bronchially, intramuscularly and intravenously) in the form of injections of sterile solutions or suspensions with water or any other pharmaceutically acceptable liquid. For example, the protein of the invention or compounds controlling the activity of the protein can be mixed with physiologically acceptable carriers, flavoring agents, excipients, vehicles, preservatives, stabilizers and binders, in a unit dose form required for generally accepted drug implementation. The amount of active ingredients in these preparations makes a suitable dosage within the indicated range acquirable.
[0068] Examples for additives which can be mixed to tablets and capsules are, hinders such as gelatin, corn starch, tragacanth gum and arabic gum; excipients such as crystalline cellulose; swelling agents such as cornstarch, gelatin and alginic acid; lubricators such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin; flavoring agents such as peppermint, Gaultheria adeuothrix oil and cherry. When the unit dosage form is a capsule, a liquid carrier, such as oil, can also be included in the above ingredients. Sterile composites for injections can be formulated following normal drug implementations using vehicles such as distilled water used for injections.
[0069] Physiological saline, glucose, and other isotonic liquids including adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, can be used as aqueous Solutions for injections. These can be used in conjunction with suitable solubilizers, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and poly ethylene glycol, non-ionic surfactants, such as Polysorbate 80 (TM) and HCO-50.
[0070] Sesame oil or soy-bean oil can be used as a oleaginous liquid and may be used in conjunction with benzyl benzoate or benzyl alcohol as a solubilizer; may be formulated with a buffer such as phosphate and sodium acetate; a pain-killer such as procaine hydrochloride; a stabilizer such as benzyl alcohol, phenol, and an anti-oxidant. The prepared injection is filled into a suitable ampule.
[0071] One skilled in the art can suitably select the dosage and method of administration according to the body-weight, age, and symptoms of a patient.
[0072] For example, although there are some differences according to the patient, target organ, symptoms and method of administration, the dose is about 1 μg to about 100 mg per day for a normal adult (weight 60 kg) when the protein is given as an injection.
[0073] For a compound controlling the activity of the protein of the invention, although it can vary according to the symptoms, the dosage is about 0.1 to about 100 mg per day, preferably about 0.1 to about 50 mg per day and more preferably about 0.1 to about 20 mg per day, when administered orally.
[0074] When administering non-orally in the form of an injection to a normal adult (weight 60 kg), although there are some differences according to the patient, target organ, symptoms and method of administration, it is convenient to intravenously inject a dose of about 0.01 mg to about 30 mg per day, preferably about 0.1 to about 20 mg per day and more preferably about 0.1 to about 10 mg per day. Also, in the case of other animals too, it is possible to administer an amount converted to 60 kg of body-weight.
[0075] This invention also features a DNA containing at least 15 nucleotides, which can specifically hybridize with DNA encoding the “SGRF” protein. The term “specifically hybridize” as used herein, indicates that cross-hybridization does not occur significantly with DNA encoding other proteins, in the above-mentioned hybridizing conditions, preferably under stringent hybridizing conditions.
[0076] Such DNA can be utilized to detect DNA encoding the “SGRF” protein, as an isolation probe, and also as a primer for amplification. Specifically, the primers in SEQ ID NOs:3 to 20 can be given as examples. Such DNA can also be used as an oligo nucleotide or a ribozyme.
[0077] An antisense oligonucleotide is preferably an antisense oligonucleotide against at least 15 continuous nucleotides in the nucleotide sequence of SEQ ID NO:2. The above-mentioned antisense oligonucleotide, which contains an initiation codon in the above-mentioned at least 15 continuous nucleotides, is even more preferred.
[0078] Derivatives or modified products of antisense oligonucleotides can be used as antisense oligonucleotides. Examples are, lower class alkyl phosphate modifications such as methyl-phosphonate-type or ethyl-phosphonate-type and phosphothioate or phosphoramidate.
[0079] The term “antisense oligonucleotides” as used herein means, not only those in which the nucleotides corresponding to those constituting a specified region of a DNA or nRNA are complementary, but also those having a mismatch of one or more nucleotides, as long as DNA or mRNA and an oligonucleotide can specifically hybridize with the nucleotide sequence of SEQ ID NO:2.
[0080] Such DNAs are indicated as those having, in the “at least 15 continuous nucleotide sequence region”, a homology of at least 70% or higher, preferably at 80% or higher, more preferably 90% or higher, even more preferably 95% or higher to the nucleotide sequence of SEQ ID NO:2. The algorithm stated herein can be used to determine homology.
[0081] The antisense oligonucleotide derivative of the present invention, acts upon cells producing the protein of the invention by binding to the DNA or mRNA encoding the protein and inhibits its transcription or translation, promotes the degradation of the mRNA, inhibiting the expression of the protein of the invention resulting in the inhibition of the protein's function.
[0082] The antisense oligonucleotide derivative of the present invention can be made into an external preparation such as a liniment and a poultice by mixing with a suitable base material, which is inactive against the derivatives.
[0083] Also, as needed, the derivatives can be formulated into tablets, powders, granules, capsules, liposome capsules, injections, solutions, nose-drops and freeze-drying agents by adding excipients, isotonic agents, dissolving auxiliaries, stabilizers, preservatives and pain-killers. These can be prepared using usual methods.
[0084] The antisense oligonucleotide derivative is given to the patient by, directly applying onto the ailing site or by injecting into a blood vessel so that it will reach the site of ailment. An antisense-mounting medium can also be used to increase durability and membrane-permeability. Examples are, liposome, poly-L lysine, lipid, cholesterol, lipofectin or derivatives of these.
[0085] The dosage of the antisense oligonucleotide derivative of the present invention can be adjusted suitably according to the patient's condition and used in desired amounts. For example, a dose range of 0.1 to 100 mg/kg, preferably 0.1 to 50 mg/kg can be administered.
BRIEF DESCRIPTION OF THE DRAWINGS
[0086] [0086]FIG. 1 shows the “SGRF” cDNA nucleotide sequence together with the deduced amino acid sequence. The mRNA destabilizing sequence is underlined.
[0087] [0087]FIG. 2 shows the alignment of the consensus sequence of “SGRF” and proteins belonging to the IL-6/G-CSF/MGF family. The consensus sequence of this family is thought to be C-x(9)-C-x(6)-G-1-x(2)-[FY]- x(3)-L, is well preserved in “SGRF” as well, excluding the point that the number of the first x is 11 instead of 9. In the figure, Sooty Mangabey is an animal of the Cercocebus species and Rhesus Macaque is of the Rhesus Monkey species.
[0088] [0088]FIG. 3 shows the hydrophobicity of “SGRF”.
[0089] [0089]FIG. 4 shows the electrophoretic pattern of the “SGRF” expression in normal human tissue as detected by Northern blot analysis. Markers are, from the left, 9.5 kb, 7.5 kb, 4.4 kb, 2.4 kb, and 1.35 kb.
[0090] [0090]FIG. 5 shows the electrophoretic pattern of the “SGRF” expression in human fetal tissue and tumor cells as detected by Northern blot analysis. Markers are, from the left, 9.5 kb, 7.5 kb, 4.4 kb, 2.4 kb, and 1.35 kb.
[0091] [0091]FIG. 6 shows the amino acid sequence of a protein presumed to be the genomic DNA nucleotide sequence of SGRF. Introns are shown in simple letters, exons in capitals. Sequences expected to be those of the TATA Box and poly A addition signal are underlined.
[0092] [0092]FIG. 7 shows the result of PCR analysis using NIGMS human/rodent somatic cell hybrid mapping panel #2. The numbers show the human chromosomes contained in the hybridoma DNA. shows human (female) genomic DNA, M shows mouse genomic DNA. 100 bp ladder has been used as a marker. The band seen around 200 bp is thought to be a non-specific background derived from mouse chromosomes.
[0093] [0093]FIG. 8 shows the pCHO-SGRFg map.
[0094] [0094]FIG. 9 shows the pCHO-SGRF map.
[0095] [0095]FIG. 10 shows the pLG-SGRF map.
[0096] [0096]FIG. 11 shows the pLG-SGRFg map.
[0097] [0097]FIG. 12 shows the effect of the SGRF-gene-inserted, CHO cell culture supernatant on the proliferation of bone marrow cells.
DETAILED DESCRIPTION OF THE INVENTION
[0098] The present invention will be explained in detail below with reference to examples, but it is not limited thereto.
EXAMPLE 1
[0099] Isolation of the “SGRF” Gene
[0100] When the GenBank EST database was searched by means of TBLAST using the human G-CSF protein sequence, the EST of Reg. No: AA418955 showed a weak homology to G-CSF. Based on this sequence, when an EST sequence considered to be reading the same gene was searched, four other registered ESTs (AA418747, U38443, AA729815, AA418955) were found. These sequences were aligned using DNASIS, the consensus sequence was extracted, and the following primers were designed:
“ILX-1”(GAGAAGAGGGAGATGAAGAGACTAC;/SEQ.ID.NO:3) “ILX-2”(CTGAGTCCTTGGGGGTCACAGCCAT;/SEQ.ID.NO:4) “ILX-3”(GTGGGACCTGCATATGTTGAAAATT;/SEQ.ID.NO:5 “ILX-4”(CCCCAAATTTCCCTTCCCATCTAATA;/SEQ.ID.NO:6) “ILX-5”(CCCTACTGGGCCTCAGCCAACTCCT;/SEQ.ID.NO:7) and “ILX-6”(GGAGCAGAGAAGGCTCCCCTGTGAA./SEQ.ID.NO:8
[0101] Using the human fetal spleen library (Marathon-Ready cDNA; Clontech), sequential PCR was performed in combinations of primers stated below, divided into 3 fragments, and amplified separately (5′side, central area, and 3′side). The primers used for the 5′side amplification were, “AP1” (Clontech) and “ILX-6” in the primary PCR, “AP2” (Clontech) and “ILX-2” in the nested PCR. As to the central area, “ILX-1” and “ILX-4” were used for the primary and nested PCRs. For the 3′ side, “AP1” (Clontech) and “ILX-5” were used in the primary PCR, “AP2” (Clontech) and “ILX-3” in the nested PCR. Amplifications by both the primary and nested PCRs were done under conditions in which those recommended by the Manufacturer were partially changed (touchdown PCR: 1 min at 96° C., following 30 sec at 96° C., 5 cycles of “4 min at 72° C.”, following 30 sec at 96° C., 5 cycles of “4 min at 70° C.”, following 20 sec at 96° C. and 26 cycles of “4 mil at 68° C.”. However, TaKaRa Ex Taq (Takara Shuzo) and attached buffers were used instead of Advantage Klentaq Polyerase Mix). The obtained DNA were then electrophoresed on agarose gel, the corresponding bands were cut-off, after purifying by QIAEX II Gel Extraction Kit (QIAGEN), were cloned into the plasmid pT7Blue (R) T-vector (Novagen). The obtained plasmids were named pT7Blue-ILX1-4 (the vector which cloned the central area), pT7Blue-ILX5′ (the vector which cloned the 5′end area), and pT7Blue-ILX3′ (the vector which cloned the 3′end area), respectively. Each nucleotide sequence cloned was determined using ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit with Amplitaq DNA Polymerase FS and 377 A DNA Sequencer (Perkin-elmer).
[0102] As a result, the full length of the isolated cDNA was 1 Kb, and encoded a protein comprising 189 amino acids (FIG. 1). This protein, not only had a consensus sequence typical of IL-6/G-CSF/MGF family (FIG. 2), but also a hydrophobic region considered to be a signal peptide in the N terminal (FIG. 3). Also, the binding site of N-type sugar-chain was not seen. In the 3′ non-coding region, four mRNA destabilizing sequences called ARE (AT Rich element), often seen in cytokine mRNAs (FIG. 1), were detected, having characteristics of a typical cytokine. Based on the structural homology, this molecule was named “SGRF” (Interleukin-Six, G-CSF Related Factor).
EXAMPLE 2
[0103] Northern Blot Analysis of “SGRF” Expression
[0104] A 500 bp fragment obtained by treating pT7Blue-ILX1-4 with BamH1 was used as the probe of “SGRF”. The above probe was “□-32P”dCTP labeled by random priming method using Ready-to Go DNA labeling beads (Pharmacia), and hybridization was done according to methods recommended by the Manufacturer within the ExpressHyb Hybridization Solution (Clontech) against the Multiple Tissue Northern Blot (Human, Human III, Human IV, Human Fetal II, Human Cancer Cell Line (Clontech) Filters. As a result, in normal tissues, “SGRF” was mainly expressed in the testis and lymph nodes, and an mRNA of approximately I kb was detected. An extremely low expression was Found in the thymus. However, since a long autoradiography (1 week) was required For the detection of these bands, the expression level in these are considered to be low. “SGRF” mRNA was not in a detectable level in other tissues.
[0105] When cancer cell lines were analyzed, very strong levels of expression were detected in two cell lines; K(562 (Chronic Myelogenous Leukemia) and SW480 (Colorectal Adenocarcinoma) (FIG. 5). In the other cell lines, “SGRF” mRNA was not in a detectable level.
EXAMPLE 3
[0106] Construction of the “SGRF” Expression Vector
[0107] Two primers, “ILXATG” TTGAATTCCACCATGCTGGGGAGCAGAGCTGT/SEQ ID NO:14), “ILXTAA” (AAAGATCTTAGGGACTCAGGGTTGCTGC/SEQ ID NO:15), were constructed, a gene consisting all the coding regions reconstituted by pT7Blue-1 LX 1-4 and pT7Blue-ILX5′, and introduced into an animal cell expression vector. Namely, the band amplified using pT7Blue-ILX5′as the template and “ILX-2” and “ILXATG” as primers, and the band amplified using pT7Blue-ILX1-4 as the template and “ILX-1” and “ILXTAA” as primers, were mixed in equal amounts, and re-amplification was done using this as the new template with the primers “ILXATG” and “ILXTAA”. The resulting band was treated with restriction enzymes EcoRI and BamHI, and cloned into the EcoRT, Bgl II site of all animal cell expression plasmid pCOS1 to create pCOS-SGRF. TaKaRa ExTaq (Takara Shuzo) was used for DNA amplification for 20 cycles of 30 sec at 96° C., following 40 sec at 60° C., and following I min 20 sec at 72° C.
EXAMPLE 4
[0108] The Polyclonal Antibody Corresponding to “SGRF”
[0109] Two kinds of partial peptides of “SGRF” (GGSSPAWTQCQQLSQ/24-38 position of the amino acid sequence of SEQ ID NO:1, GDGCDPQGLRDNSQF, 74-88 position of the amino acid sequence of SEQ ID NO:1) were chemically synthesized. Two rabbits were immunized with these, respectively, to obtain polyclonal antibodies (Sawady). The respective antibodies were affinity-purified using respective peptide columns. The following analyses were done using one of the antibodies against the peptide of SGRF (24-38 position of the amino acid sequence of SEQ ID NO:1).
[0110] Alkyl phosphatase-binding, mouse-anti-rabbit IgG antibody and alkyl phosphatase substrate were used for detection.
EXAMPLE 5
[0111] Genomic DNA of SGRF
[0112] The following sequences were prepared and used for the analysis of the promoter regions-5′non translating region, translating region, 3′ non-translating region from the genomic DNA library.
(SEQ ID NO:3) ILX-1 5′-GAGAAGAGGGAGATGAAGAAGACTAC-3′ (SEQ ID NO:4) ILX-2 5′-CTGAGTCCTTGGGGGTCACAGCCAT-3′ (SEQ ID NO:5) ILX-3 5′-GTGGGACCTGCATATGTTGAAAATT-3′ (SEQ ID NO:6) ILX-4 5′-CCCCAAATTTCCCTTCCCATCTAATA-3′ (SEQ ID NO:7) ILX-5 5′-CCCTACTGGGCCTCAGCCAACTCCT-3′ (SEQ ID NO:8) ILX-6 5′-GGAGCAGAGAAGGCTCCCCTGTGAA-3′ (SEQ ID NO:9) ILX-7 5′-GGGCAGAGATTCCAGGAGGACTGGT-3′ (SEQ ID NO:10) ILX-8 5′-CCAGTCCTGGTGGAATCTCTGCCCA-3′ (SEQ ID NO:11) ILX-9 5′-GAAGCTCTGCACACTGGCCTGGAGT-3′ (SEQ ID NO:12) ILX-10 5′-CACTCCAGGCCAGTGTGTGCAGAGCTT-3′ (SEQ ID NO:13) ILX-11 5′-CTGAAGGGCTATGGTGGAGAA-3′ (SEQ ID NO:14) ILX-ATG 5′-TTGAATTCCACCATGCTGGGGAGCAGAGCTGT-3′ (SEQ ID NO:15) ILX-TAA 5′-AAAGATCTTAGGGACTCAGGGTTGCTGC-3′ (SEQ ID NO:16) ILX-TAAECO 5′-AAGAATTGTAGGGACTCAGGGTTGCTGC-3′ (SEQ ID NO:17) SGRFg5′5′-GGTTTAAATATTTGTTCTCCCTTACCCC-3′ (SEQ ID NO:18) SGRFg37 5′-TTCAGCTGCTTGGGAGGCTGAGGCAGG-3′ (SEQ ID NO:19) SGRFg5′-2 5′-AGGAATTCCACCAGGACTGGTGCAAGGCGCA-3′ (SEQ ID NO:20) SGRFg3′-2 5′GTCTCGAGAAAATATCATTCTCCACCATCGCCCT-3′
[0113] Genomic DNA was amplified by PCR using, for the translation region, the above mentioned ILX-ATG primer and ILX-TAA primer and human genomic DNA (Clontech) as the template, resulting in a band amplified to approximately 1.5 kb. After treating this fragment with restriction enzymes EcoRI and BglII, cloning was done by inserting into the EcoRI-BamHI site of the CHO expression plasmid pCHO1. The nucleotide sequence or the vector obtained (pCHO-SGRFg) (FIG. 8) was analyzed using the primers described above. As a result, it was revealed to be the SGRF gene including 3 introns.
[0114] The amplifications of the 5′ non-translating region containing the promoter, and the 3′ non-translating region, were done using Genome Walker Kit as the template (Clontech), the attached AP1 and AP2 primers and the above-mentioned synthetic primers according to methods recommended by the Manufacturer.
[0115] First, for the 5′ non-translating region, the 1 st PCR was done using Dra1 library as the template with AP1 and ILX-10 primers. Then, the 2 nd PCR was done with the AP2 and ILX-8 primers to obtain a band of approximately 400 bp.
[0116] For the 3′ non-translating region, the 1 st PCR was done using PvuII library as the template with AP1 and ILX-5 primers, the 2 nd PCR with the AP2 and ILX-3 primers to obtain a band of app 800 bp.
[0117] The bands obtained were cut off from the agarose gel, and after purification , sequencing was done using 377 A DNA Sequencer (Perkin-Elmer). The genomic DNA sequence of SGRF (SEQ ID NO:21) is shown in FIG. 6 together with the deduced amino acids.
[0118] Also, NIGMS human/rodent somatic cell hybrid mapping panel #2 and GeneBridge 4 Radiation Hybrid Panel (Research Genetics) were analyzed by PCR using ILX-1 and Ilx-6 primers to examine the chromosome location. As a result, from NIGMS human/rodent somatic cell hybrid mapping panel #2 analysis, it was revealed that the SGRF gene exists on the 12 th chromosome (FIG. 7).
[0119] The analysis from GeneBridge 4 Radiation Hybrid Panel, revealed that SGRF exists in 12q13 and is, Chromosome Chr12, Places 8.77 cR from WJ-7107 (lod>3.0).
EXAMPLE 6
[0120] Establishment of a CHO Cell Line Expressing SGRF
[0121] Similarly to pCOS-SGRF described in Example 3, DNA fragment of SGRF encoding region was prepared, was cloned to the EcoRI, BamHI site of the animal cell expression plasmid pCHO1 to create pCHO-SGRF (FIG. 9). PCHO-SGRF was then transfected into CHO cells by calcium phosphate method and gene-introduced cells were selected in alpha-MEM culture medium, which does not contain nucleotides. The culture supernatant was analyzed by SDS-PAGE and Western blotting using rabbit-polyclonal antibody.
[0122] As a result, a band with a molecular weight of about 20,000 was detected only in the culture supernatant of CHO cells having this vector.
[0123] Thereafter, the MTX concentration was increased sequentially to 20 nM, 100 nM and so on, and the gene was amplified while verifying the expression to establish a CHO cell strain, which constitutively secretes SGRF. This cell strain has been deposited in the depository institution given below.
[0124] (a) Name and address of the Depository Institution
[0125] Name: National Institute of BioScience and Human-Technology Agency of Industrial Science and Technology
[0126] Address: 1-3,Higashi-1-chome, Tsukaba-shi, Ibaraki 305-8566, Japan.
[0127] (b) Date of deposit (date of original deposit): April 9, 1999.
[0128] (c) Accession Number: FERM BP-6699
EXAMPLE 7
[0129] Purification of SGRF
[0130] In order to review purification of SGRF, producing cells (CHO-SGRF 16-5 strain) proliferated to a confluent state, were rinsed with PBS, the medium was changed to a serum-free culture medium ASF104 (AJINOMOTO), cultured for 3 to 4 clays, and the culture supernatant was collected after filtering.
[0131] A 30 ml column was prepared using Phenyl-Sepharose HP (Amersham Pharmacia Biotech), equilibrated by 10 mM Tris pH 7.5, 100 mM NaCl, and the culture supernatant of the above mentioned CHO-SGRF16-5 strain cultured in ASF medium, was 1.5 times diluted using 10 mM Tris pH 7.5 and applied onto the column. After washing well with the equilibrating buffer, extraction was done with the same buffer containing 0.1%/Tween 20. The extracted solution was applied to a DEAE-Sepharose FF column equilibrated with 10 mM Tris pH 7.5, 100 mM NaCl, washed well with the equilibrating buffer, and extracted using 10 mM Tris pH 7.5, 300 mM NaCl, recovering most of the SGRF. The extracted sample was according to normal methods by SDS-PAGE analysis, Western blot analysis as a crudely purified product. As a result, a band binding to the polyclonal antibody was detected at the site of a molecular weight of around 20,000 which was concentrated enough lo be detected by Silver-staining and Coomassie-staining.
[0132] This crudely purified SRF protein was blotted onto a PVDF membrane, stained with Coomassie blue, and a band with a molecular weight of about 20,000 was cut off to determine the N-terminal amino acid sequence using Model 492 protein sequencer (Applied Biosystems). As a result, the sequence was found to be X-Ala-Val-Pro-Gly-Gly-Ser. This matched the SGRF sequence of 20th Arg from the N-terminal to the 29th Ser, and the signal peptide was found to be cleaved between the 19th GLY and the 20th Arg.
[0133] From the above results, the mature protein of SGRF was calculated to be having 170 amino acids with a presumed molecular weight of 18,676 and an expected isoelectric point of 5.84.
EXAMPLE 8
[0134] SGFR Vector for the Creation of a Transgenic Mouse
[0135] SGRF cDNA was amplified from pCHO-SGRF using the primers ILX-ATG and ILX-TAAECO, cleaved with the restriction enzyme EcoRI, then inserted into the EcoRI site of transgenic expression plasmid pLG1 to create pLG-SGRF (FIG. 10).
[0136] Also, the region containing SGRF genomic DNA was amplified from human genomic DNA(clontech) using primers SGRF-5′ — 2 and SGRF-3′ — 2, treated with the restriction enzyme EcoRI, and then inserted into the EcoRI-XhoI site of the plasmid pLG1 to create pLG-SGRFg (FIG. 11).
EXAMPLE 9
[0137] Production of the Monoclonal Antibody
[0138] Five 8-week male Balb/c mice are immunized 2 mg/head with aluminum hydroxide gel as the adjuvant, and 20 μg/head of the above mentioned SGRF protein or the partial peptide as the antigen by injection into the peritoneal cavity. Re-immunization is done six times in every 2 weeks by injecting 20 μg/head of the above mentioned SGRF protein or the partial peptide. After the 3 rd immunization, blood is drawn from the eye-ground venous plexus and anti SGRF antibody titer in the serum is examined.
[0139] Three days after the final immunization, spleen cells are prepared from mice, an(l used for cell fusion. 1×108 splenocytes from the immunized mice washed well with MEM (Nissui Pharmaceuticals), and murine myeloma P3-U 1×108 are mixed and centrifuged for 5 min at 1000 rpm. 2 g Polyethylene glycol-1500 (PEG-1500), and 2 ml MEM are added while mixing well at 37° C. and centrifuged after I mini at 600 rpm for 5 mil. Further, 5 ml HBSS solution and 5 ml 20% FBS/MEM solution are added calmly, cells are suspended well, and centrifuged at 1000 rpm after 1 min, and the culture supernatant is discarded. The cells are re-suspended by adding 5 ml HAT medium (10-4M hypoxanthine, 4×10-7M aminopterin, and 1.5×10-5M thymidine supplemented medium). The cell suspension is seeded in I ml/well into a 24-well culture plate (Nunc), and cultivated for 24 hr in a CO 2 incubator at 37° C., 5% CO 2 , 95% air. 1 mil/well HAT medium is added and cultured further for another 24 hr. Then, 1 ml of culture supernatant is discarded, I ml HAT medium is newly added and cultivated further for another 12 days.
[0140] For those wells in which colonized fusion cells can be detected, I ml culture supernatant is discarded, 1 ml HAT medium (aminopterin-excluded, above-mentioned HAT medium) added and cultured at 37° C. Exchange of the HAT medium is similarly done for the next two days and after culturing for 4 days, a portion of the culture supernatant is collected to measure the anti-SGPF antibody titer by ELISA.
[0141] For wells in which the antibody titer was detected, cloning is performed by limiting dilution twice more, and clones for which a stable antibody titer was detected, are selected as hybridomas producing anti-SGRF monoclonal antibody.
EXAMPLE 10 ELISA Method
[0142] 50 μl/well of SGRF protein solution or the partial peptide solution is seeded into a 96-well culture plate (Immunoplate, Nunc)and is left to stand at room temperature for 2 hours to coat the antigen onto the bottom of the plate-well. Then, 200 μl/well of 10% FCS/PBS is added and left to stand at room temperature for 30 min. The above-mentioned plate is washed 3 times with PBS, serially diluted test sample (mouse serum, hybridomas culture supernatant, monoclonal antibody and such) is seeded in 50 μl/well, and left to stand at room temperature for 2 hours. Then, the plate is washed 3 times with PBS, and 100 times-diluted peroxidase-binding goat-anti-mouse IgG antibody is seeded in 50 μl/well as the secondary antigen and left to stand at room temperature for 2 hours. After washing with PBS, 200 μl/well of peroxidase substrate (1% hydrogen peroxide, 0.1M acetic acicl-0.05M phosphate buffer, 2 mM 2,2′-azino-di-3-ethyl-benzothiazine sulfate) is added and after leaving at room temperature for 10 to 30 min, the antibody titer is calculated using calorimetry at 414 nm.
EXAMPLE 11
[0143] Bone marrow cells were prepared by extracting the thigh-bone and shank-bone of 8 to 15 week C57BL/6 male mice (CLEAR JAPAN). After suspending in Nycodenz (Nycomed Pharm AS), the specific gravity was adjusted to 1.063, stratified to NycoPrep 1.077 Animal (Nycomed Pharm AS) and centrifuged for 30 min at 2300 rpm (Hitachi, 05PR22), 20° C. The intermediate layer was collected, suspended in FACS buffer (2% fetal Bovine Serum (FBS, Moregate) containing Dulbecco's phosphate buffer), was collected by centrifuging for 10 min at 1500 rpm, after which 1 μg of biotin-labeled anti-Mac-1 antibody, biotin-labeled anti-Gr-1 antibody, biotin-labeled anti-TER119 antibody, biotin-labeled anti-CD3ε antibody, and biotin-labeled B220 antibody (all by Pharmingen) were added per 1×106 cells. After leaving aside for 30 min on ice, was washed with FACS buffer, 1 μl avidin-labeled microbeads (10 Beads Avidin, ImmunoTech) were added and left to stand for 15 min oil ice. Beads were then excluded by a magnetic holder-, the floating cells were collected by centrifuging for I min (Tomy MRX-150) at 5000 rpm. After discarding the supernatant, 1 ρg per 1×106 cells of FITC-labeled anti-CD34 antibody, PE-labeled anti Sca-1 antibody, APC-labeled c-kit antibody (all 3 by Pharmingen), RED613-lebeled streptavidin (LifeTech Oriental) were added and reacted for 30 min on ice. After washing with FACS buffer, was suspended in 1 ml FACS buffer for 1×10 6 cells, and fractionated by EPICS ELITE (Beckman Coulter). The definitions of the respective fractions are as follows:
[0144] RED613-negative PE-negative APC-positive=Lin(−) Sca-1(−) c-kit(+) fraction
[0145] RED613-negative PE-positive APC-positive=Lin(−) Sca-1(+) c-kit(+)fraction
[0146] RED613-negative PE-positive APC-positive FITC-positive=Lin(−) Sca-1(−) c-kit(+) CD34(+) fraction
[0147] RED6 13-negative PE-positive APC-positive FITC-negative=Lin(−) Sca-l(+) c-kit(+) CD34(−) fraction
[0148] The obtained cell fractions were diluted by the Iscove's modi fied DDulbecco's medium (10% FBS/IMDM) so that there were 10,000, 2000, and 400 cells per I ml of medium and were seeded in 50 ml into a 96-well culture plate.
[0149] To this, 50 μl of, (1) medium only (10% FBS/IMDM), (2) medium to which mock has been diluted to 20% (mock), (3) SGRF-expressed CHO culture supernatant (SGRF), (4) medium to which mouse kit ligand 10 ng/ml has been added (KL), (5) medium to which 20% mock, 10 ng/ml mouse kit ligand have been added (mock +ILL), (6) SGRF-expressed CHO culture supernatant to which 10 ng/ml mouse kit ligand has been added (SGRF+KL), (7) medium to which 10 ng/ml mouse kit ligand, 5 ug/ml IL-1 I has been added (KL+IL-11, were supplemented and then cultured for 10 days at 37° C., 5% CO 2 .
[0150] Also, as for (1) and (3) mentioned above, 10 ng/ml, 1 ng/ml mouse kit ligand IL-11 were added respectively to prepare a similarly cultured lot as well (medium/expand, mock/expand, SGRF/expand, respectively).
[0151] After completion of culture, cell number was detected using a Cell proliferation Assay Kit (Promega) as measured by Microplate Reader Model 3550 (Bio-Rad) for the absorbance at 490 nm (FIG. 12).
[0152] As a result, although SGRF-alone showed no proliferation supporting activity towards Lin negative, Sca-I positive and c-kit positive cells, such a proliferation supporting activity was shown under the presence of the mouse kit ligand. This activity was stronger in CD34 positive cells. Also, if the mouse kit ligand did not exist at the initial stages of culture, cells did not proliferate even when the ligand was supplemented afterwards. From this fact it can be assumed that SGRF does not have an activity to support stem cells.
INDUSTRIAL APPLICABILITY
[0153] The present invention provided a novel cytokine-like protein and the DNA encoding the protein. Furthermore, a vector into which the DNA is inserted, a transformant possessing said DNA and the methods of production of a recombinant protein are provided. A compound that binds to the protein and a screening method for a compound that regulates its activity are also provided.
[0154] Since the protein of the invention and the gene, alike other cytokines, are believed to be associated with the activity or cell proliferation and differentiation of cells of the immune and hematopoietic systems, the use of a compound that controls said protein is anticipated in diseases relating to the immune or hematopoietic systems and defects in cell proliferation. A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.
0
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Pro
ccaagataaa tctaccaccc caggcacctg tgagccaaca ggttaattag tccattaatt 1627
ttagtgggac ctgcatatgt tgaaaattac caatactgac tgacatgtga tgctgaccta 1687
tgataaggtt gagtatttat tagatgggaa gggaaatttg gggattattt atcctcctgg 1747
ggacagtttg gggaggatta tttattgtat ttatattgaa ttatgtactt ttttcaataa 1807
agtcttattt ttgtggctat atgagtctaa tttctaggct caattgggaa agagaaatcg 1867
atggaaaaat aaggccaaga gactacaata tgcatccctt tcttctattc tgaagggcta 1927
tggtggagaa tgatattttc tcatgacccc ctggtgtata gaataactgg gatctcttta 1987
gtattaattc ctatatggct gagcaagcag aatgggatta ccagattagg aagtgggatc 2047
atacctaagg gtcacttgct ccctgatcca gtgtctcctt ccctgctttc ttggccaaga 2107
gtatatctga tcaaagacgg gagtcctgat cattgcagga tcaaaagtca gagttcagct 2167
ttgagcagga agggcattcc agggaaatga agataaatat cctagaataa tgggactttc 2227
ctctcaaagg acaattggaa tccctttttt tttttttttt tttttttttt tttttgagat 2287
ggagtctcat tctgttgccc aggctggagt gcagtggcgt gatctctgct cactgcaacc 2347
tccgcctccc acgttgaagc gattctcctg cctcagcctc ccaagcagct g 2398
<210> SEQ ID NO 22
<211> LENGTH: 54
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 22
Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr
1 5 10 15
Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln
20 25 30
Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His
35 40 45
Pro Leu Val Gly His Met
50
<210> SEQ ID NO 23
<211> LENGTH: 33
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 23
Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr Thr Asn Asp Val Pro His
1 5 10 15
Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln Gly Leu Arg Asp Asn Ser
20 25 30
Gln
<210> SEQ ID NO 24
<211> LENGTH: 49
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 24
Phe Cys Leu Gln Arg Ile His Gln Gly Leu Ile Phe Tyr Glu Lys Leu
1 5 10 15
Leu Gly Ser Asp Ile Phe Thr Gly Glu Pro Ser Leu Leu Pro Asp Ser
20 25 30
Pro Val Gly Gln Leu His Ala Ser Leu Leu Gly Leu Ser Gln Leu Leu
35 40 45
Gln
<210> SEQ ID NO 25
<211> LENGTH: 53
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 25
Pro Glu Gly His His Trp Glu Thr Gln Gln Ile Pro Ser Leu Ser Pro
1 5 10 15
Ser Gln Pro Trp Gln Arg Leu Leu Leu Arg Phe Lys Ile Leu Arg Ser
20 25 30
Leu Gln Ala Phe Val Ala Val Ala Ala Arg Val Phe Ala His Gly Ala
35 40 45
Ala Thr Leu Ser Pro
50
<210> SEQ ID NO 26
<211> LENGTH: 26
<212> TYPE: PRT
<213> ORGANISM: Artificial Sequence
<220> FEATURE:
<223> OTHER INFORMATION: Consensus sequence
<220> FEATURE:
<221> NAME/KEY: VARIANT
<222> LOCATION: 2-10, 12-17,20-21, 23-25
<223> OTHER INFORMATION: Xaa = any amino acid
<220> FEATURE:
<221> NAME/KEY: VARIANT
<222> LOCATION: 22
<223> OTHER INFORMATION: Xaa = Phe, or Tyr
<400> SEQUENCE: 26
Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Gly Leu Xaa Xaa Xaa Xaa Xaa Xaa Leu
20 25
<210> SEQ ID NO 27
<211> LENGTH: 7
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<220> FEATURE:
<221> NAME/KEY: UNSURE
<222> LOCATION: (1)
<223> OTHER INFORMATION: Xaa = unsure
<400> SEQUENCE: 27
Xaa Ala Val Pro Gly Gly Ser
1 5
<210> SEQ ID NO 28
<211> LENGTH: 55
<212> TYPE: PRT
<213> ORGANISM: Mustela vison
<400> SEQUENCE: 28
Ala Glu Asn Asn Leu Lys Leu Pro Lys Leu Ala Glu Lys Asp Lys Cys
1 5 10 15
Phe Gln Ser Gln Phe Asn Gln Glu Thr Cys Met Thr Arg Ile Thr Thr
20 25 30
Gly Leu Gln Glu Phe Gln Ile His Leu Lys Tyr Leu Glu Ala Asn Tyr
35 40 45
Glu Gly Asn Lys Asn Asn Ala
50 55
<210> SEQ ID NO 29
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Capra hircus
<400> SEQUENCE: 29
Lys Thr Glu Ala Leu Ile Lys His Ile Val Asp Lys Ile Ser Ala Ile
1 5 10 15
Arg Lys Glu Ile Cys Glu Lys Asn Asp Glu Cys Glu Asn Ser Lys Glu
20 25 30
Thr Leu Ala Glu Asn Lys Leu Lys Leu Pro Lys Met Glu Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Ala Ile Cys Leu Ile Lys Thr
50 55 60
Thr Ala Gly Leu Leu Glu Tyr Gln Ile Tyr Leu Asp Phe Leu Gln Asn
65 70 75 80
Glu Phe Glu Gly Asn Gln Glu Thr Val
85
<210> SEQ ID NO 30
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Ovis aries
<400> SEQUENCE: 30
Lys Thr Glu Ala Leu Ile Lys His Ile Val Asp Lys Ile Ser Ala Ile
1 5 10 15
Arg Lys Glu Ile Cys Glu Lys Asn Asp Glu Cys Glu Asn Ser Lys Glu
20 25 30
Thr Leu Ala Glu Asn Lys Leu Lys Leu Pro Lys Met Glu Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Ala Ile Cys Leu Ile Lys Thr
50 55 60
Thr Ala Gly Leu Leu Glu Tyr Gln Ile Tyr Leu Asp Phe Leu Gln Asn
65 70 75 80
Glu Phe Glu Gly Asn Gln Glu Thr Val
85
<210> SEQ ID NO 31
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Bos taurus
<400> SEQUENCE: 31
Lys Thr Glu Ala Leu Ile Lys Arg Met Val Asp Lys Ile Ser Ala Met
1 5 10 15
Arg Lys Glu Ile Cys Glu Lys Asn Asp Glu Cys Glu Ser Ser Lys Glu
20 25 30
Thr Leu Ala Glu Asn Lys Leu Asn Leu Pro Lys Met Glu Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Ala Ile Cys Leu Ile Arg Thr
50 55 60
Thr Ala Gly Leu Leu Glu Tyr Gln Ile Tyr Leu Asp Tyr Leu Gln Asn
65 70 75 80
Glu Tyr Glu Gly Asn Gln Glu Asn Val
85
<210> SEQ ID NO 32
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Equus caballus
<400> SEQUENCE: 32
Lys Thr Lys Gln His Ile Lys Tyr Ile Leu Gly Lys Ile Ser Ala Leu
1 5 10 15
Lys Asn Glu Met Cys Asn Asn Phe Ser Lys Cys Glu Asn Ser Lys Glu
20 25 30
Val Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Glu Thr Cys Leu Met Lys Ile
50 55 60
Thr Thr Gly Leu Ser Glu Phe Gln Ile Tyr Leu Glu Tyr Leu Gln Asn
65 70 75 80
Glu Phe Lys Gly Glu Lys Glu Asn Ile
85
<210> SEQ ID NO 33
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Sus scrofa
<400> SEQUENCE: 33
Lys Thr Glu Glu Leu Ile Lys Tyr Ile Leu Gly Lys Ile Ser Ala Met
1 5 10 15
Arg Lys Glu Met Cys Glu Lys Tyr Glu Lys Cys Glu Asn Ser Lys Glu
20 25 30
Val Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Glu Thr Cys Leu Met Arg Ile
50 55 60
Thr Thr Gly Leu Val Glu Phe Gln Ile Tyr Leu Asp Tyr Leu Gln Lys
65 70 75 80
Glu Tyr Glu Ser Asn Lys Gly Asn Val
85
<210> SEQ ID NO 34
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Canis familiaris
<400> SEQUENCE: 34
Lys Val Glu Glu Leu Ile Lys Tyr Ile Leu Gly Lys Ile Ser Ala Leu
1 5 10 15
Arg Lys Glu Met Cys Asp Lys Phe Asn Lys Cys Glu Asp Ser Lys Glu
20 25 30
Ala Leu Ala Glu Asn Asn Leu His Leu Pro Lys Leu Glu Gly Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Glu Thr Cys Leu Thr Arg Ile
50 55 60
Thr Thr Gly Leu Val Glu Phe Gln Leu His Leu Asn Ile Leu Gln Asn
65 70 75 80
Asn Tyr Glu Gly Asp Lys Glu Asn Val
85
<210> SEQ ID NO 35
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Felis catus
<400> SEQUENCE: 35
Lys Met Glu Glu Leu Ile Lys Tyr Ile Leu Gly Lys Ile Ser Ala Leu
1 5 10 15
Lys Lys Glu Met Cys Asp Asn Tyr Asn Lys Cys Glu Asp Ser Lys Glu
20 25 30
Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Leu Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Glu Thr Cys Leu Thr Arg Ile
50 55 60
Thr Thr Gly Leu Gln Glu Phe Gln Ile Tyr Leu Lys Phe Leu Gln Asp
65 70 75 80
Lys Tyr Glu Gly Asp Glu Glu Asn Ala
85
<210> SEQ ID NO 36
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Cercocebus torquatus atys
<400> SEQUENCE: 36
Arg Ile Asp Lys His Ile Arg Tyr Ile Leu Asp Gly Ile Ser Ala Leu
1 5 10 15
Arg Lys Glu Thr Cys Asn Arg Ser Asn Met Cys Asp Ser Thr Lys Glu
20 25 30
Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Glu Asp Thr Cys Leu Val Lys Ile
50 55 60
Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr Leu Glu Tyr Leu Gln Asn
65 70 75 80
Arg Phe Glu Ser Ser Glu Glu Gln Ala
85
<210> SEQ ID NO 37
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Macaca mulatta
<400> SEQUENCE: 37
Arg Ile Asp Lys His Ile Arg Tyr Ile Leu Asp Gly Ile Ser Ala Leu
1 5 10 15
Arg Lys Glu Thr Cys Asn Arg Ser Asn Met Cys Glu Ser Ser Lys Glu
20 25 30
Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Glu Asp Thr Cys Leu Val Lys Ile
50 55 60
Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr Leu Glu Tyr Leu Gln Asn
65 70 75 80
Arg Phe Glu Ser Ser Glu Glu Gln Ala
85
<210> SEQ ID NO 38
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 38
Arg Ile Asp Lys Gln Ile Arg Tyr Ile Leu Asp Gly Ile Ser Ala Leu
1 5 10 15
Arg Lys Glu Thr Cys Asn Lys Ser Asn Met Cys Glu Ser Ser Lys Glu
20 25 30
Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Glu Glu Thr Cys Leu Val Lys Ile
50 55 60
Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr Leu Glu Tyr Leu Gln Asn
65 70 75 80
Arg Phe Glu Ser Ser Glu Glu Gln Ala
85
<210> SEQ ID NO 39
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Mus musculus
<400> SEQUENCE: 39
Gln Val Gly Gly Leu Ile Thr His Val Leu Trp Glu Ile Val Glu Met
1 5 10 15
Arg Lys Glu Leu Cys Asn Gly Asn Ser Asp Cys Met Asn Asn Asp Asp
20 25 30
Ala Leu Ala Glu Asn Asn Leu Lys Leu Pro Glu Ile Gln Arg Asn Asp
35 40 45
Gly Cys Tyr Gln Thr Gly Tyr Asn Gln Glu Ile Cys Leu Leu Lys Ile
50 55 60
Ser Ser Gly Leu Leu Glu Tyr His Ser Tyr Leu Glu Tyr Met Lys Asn
65 70 75 80
Asn Leu Lys Asp Asn Lys Lys Asp Lys
85
<210> SEQ ID NO 40
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Rattus norvegicus
<400> SEQUENCE: 40
Gln Val Gly Gly Leu Ile Thr Tyr Val Leu Arg Glu Ile Leu Glu Met
1 5 10 15
Arg Lys Glu Leu Cys Asn Gly Asn Ser Asp Cys Met Asn Ser Asp Asp
20 25 30
Ala Leu Ser Glu Asn Asn Leu Lys Leu Pro Glu Ile Gln Arg Asn Asp
35 40 45
Gly Cys Phe Gln Thr Gly Tyr Asn Gln Glu Ile Cys Leu Leu Lys Ile
50 55 60
Cys Ser Gly Leu Leu Glu Phe Arg Phe Tyr Leu Glu Phe Val Lys Asn
65 70 75 80
Asn Leu Gln Asp Asn Lys Lys Asp Lys
85
<210> SEQ ID NO 41
<211> LENGTH: 88
<212> TYPE: PRT
<213> ORGANISM: Bos taurus
<400> SEQUENCE: 41
Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Ala Asp Gly Ala Glu Leu
1 5 10 15
Gln Glu Arg Leu Cys Ala Ala His Lys Leu Cys His Pro Glu Glu Leu
20 25 30
Met Leu Leu Arg His Ser Leu Gly Ile Pro Gln Ala Pro Leu Ser Ser
35 40 45
Cys Ser Ser Gln Ser Leu Gln Leu Arg Gly Cys Leu Asn Gln Leu His
50 55 60
Gly Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile
65 70 75 80
Ser Pro Glu Leu Ala Pro Thr Le
85
<210> SEQ ID NO 42
<211> LENGTH: 88
<212> TYPE: PRT
<213> ORGANISM: Canis familiaris
<400> SEQUENCE: 42
Lys Cys Leu Glu Gln Met Arg Lys Val Gln Ala Asp Gly Thr Ala Leu
1 5 10 15
Gln Glu Thr Leu Cys Ala Thr His Gln Leu Cys His Pro Glu Glu Leu
20 25 30
Val Leu Leu Gly His Ala Leu Gly Ile Pro Gln Pro Pro Leu Ser Ser
35 40 45
Cys Ser Ser Gln Ala Leu Gln Leu Met Gly Cys Leu Arg Gln Leu His
50 55 60
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ala Gly Ile
65 70 75 80
Ser Pro Glu Leu Ala Pro Thr Leu
85
<210> SEQ ID NO 43
<211> LENGTH: 88
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens
<400> SEQUENCE: 43
Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu
1 5 10 15
Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu
20 25 30
Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser
35 40 45
Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His
50 55 60
Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile
65 70 75 80
Ser Pro Glu Leu Gly Pro Thr Leu
85
<210> SEQ ID NO 44
<211> LENGTH: 88
<212> TYPE: PRT
<213> ORGANISM: Mus musculus
<400> SEQUENCE: 44
Lys Ser Leu Glu Gln Val Arg Lys Ile Gln Ala Ser Gly Ser Val Leu
1 5 10 15
Leu Glu Gln Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu
20 25 30
Val Leu Leu Gly His Ser Leu Gly Ile Pro Lys Ala Ser Leu Ser Gly
35 40 45
Cys Ser Ser Gln Ala Leu Gln Gln Thr Gln Cys Leu Ser Gln Leu His
50 55 60
Ser Gly Leu Cys Leu Tyr Gln Gly Leu Leu Gln Ala Leu Ser Gly Ile
65 70 75 80
Ser Pro Ala Leu Ala Pro Thr Leu
85
<210> SEQ ID NO 45
<211> LENGTH: 88
<212> TYPE: PRT
<213> ORGANISM: Gallus gallus
<400> SEQUENCE: 45
Lys Asn Leu Glu Phe Thr Arg Lys Ile Arg Gly Asp Val Ala Ala Leu
1 5 10 15
Gln Arg Ala Val Cys Asp Thr Phe Gln Leu Cys Thr Glu Glu Glu Leu
20 25 30
Gln Leu Val Gln Pro Asp Pro His Leu Val Gln Ala Pro Leu Asp Gln
35 40 45
Cys His Lys Arg Gly Phe Gln Ala Glu Val Cys Phe Thr Gln Ile Arg
50 55 60
Ala Gly Leu His Ala Tyr His Asp Ser Leu Gly Ala Val Leu Arg Leu
65 70 75 80
Leu Pro Asn His Thr Thr Leu Val
85
<210> SEQ ID NO 46
<211> LENGTH: 89
<212> TYPE: PRT
<213> ORGANISM: Artificial Sequence
<220> FEATURE:
<223> OTHER INFORMATION: Consensus sequence
<400> SEQUENCE: 46
Lys Cys Leu Glu Met Ile Arg Tyr Ile Leu Gly Asp Ile Ser Ala Leu
1 5 10 15
Arg Lys Glu Leu Cys Asp Thr Tyr Gln Leu Cys His Asn Glu Glu Glu
20 25 30
Val Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp
35 40 45
Gly Cys Phe Gln Ser Gly Phe Asn Gln Glu Thr Cys Leu Thr Gln Ile
50 55 60
Thr Thr Gly Leu Met Glu Tyr Gln Ile Tyr Leu Glu Tyr Leu Gln Asn
65 70 75 80
Asn Tyr Pro Gly Asn Lys Glu Asn Val
85 | A full-length cDNA corresponding to an EST (AA418955), which does not show any homology to other proteins in the database but has a weak homology to G-CSF, has been successfully isolated by synthesizing printers based on the EST sequence, and effecting PCR-cloning from a human fetal spleen library. Sequencing of the thus-isolated cDNA and analysis of its structure revealed that the cDNA has typical characteristics of a factor belonging to the IL-6/G-CSF/MGF family. It is also found out that the culture supernatant of said sequence-transfected CHO cells shows a proliferation supporting activity towards bone marrow cells in the coexistence of kit ligand. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage of International Application No. PCT/CH2006/000662 filed on Nov. 27, 2006, claiming priority based on Switzerland Patent Application No. 01901/05, filed Nov. 30, 2005, the contents of all of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention relates to a pole grip for, in particular, cross-country ski poles, downhill ski poles and Nordic walking poles, having a hand-retaining device, such as a hand strap or glove, which can be fastened in a releasable manner to the pole grip via a coupling element secured on the hand-retaining device, the pole grip having a top end as well as a bottom end, on or in which a pole shaft can be fastened and/or is fastened.
PRIOR ART
There is an increasing need, as far as cross-country ski poles, downhill ski poles and Nordic walking poles are concerned, for the hand strap, or a correspondingly specially configured glove, to be connected in a releasable manner to the pole grip rather than being fixed thereto. Correspondingly, a wide variety of different designs which allow such hand-retaining devices to be connected in a releasable manner to a pole grip have already been proposed.
In the case of the pole grip which is known from DE-A-196 36 852, the pole-grip recess is accessible, from a peripheral side, for the first connecting element, which is fixed to the hand strap, and is covered, on the end side of the grip head, by a release cover and the actuating member. The actuating member can be moved in the axial direction of the pole grip and is coupled to the second connecting element in order to move the latter axially. In the case of this known pole grip, the access to and exit from, the pole-grip recess are thus arranged essentially perpendicularly to one another, which is expedient for the configuration of, in particular, downhill ski poles since the grips for such poles are usually provided with a slightly curved grip-head end side which runs essentially perpendicularly to the pole axis.
In the case of a pole grip which is known from EP-A-0 370 900, the pole-grip recess contains an actuating lever for clamping the hand-strap connecting element in place, which actuating lever can be moved manually, counter to the action of a spring, out of its release position into its clamping position. The connecting element of the hand strap here is pushed into the pole-grip recess perpendicularly to the longitudinal axis of the pole.
In the case of the pole grip which is known from DE 299 04 591 U1, the pole-grip recess between the access for the first connecting element of a hand strap and the opposite exit opening for the actuating member runs at an acute angle to the longitudinal axis of the pole grip or ski pole. This means that the connecting element which is secured on the hand strap is latched in obliquely from beneath the top pole-grip end and is removed obliquely downward in the opposite direction. Since the actuating member and the second connecting member are in one piece and, since the pivot axis is arranged at the end of the second connecting member, are designed as a single-armed lever, the latching-in action, on account of the latching region being very close to the pivot axis, is problematic and requires a high level of force to be exerted. Moreover, the direction of latching in the first connecting element on the hand strap behind the second connecting element on the single-armed actuating lever does not give rise to an ergonomic movement, and this movement, moreover, is difficult to carry out using just one hand.
WO-A-2004052476 describes a pole grip having a hand-retaining device which is in the form of a hand strap or a glove and can be latched in a releasable manner to the pole grip via a first connecting element secured on the hand-retaining device. A pole-grip recess here contains a second connecting element which interacts with the first connecting element and can be moved, counter to resilient mounting, by means of an actuating member which is accessible in the region of the grip head. In order for it to be possible for the hand-retaining device to be more easily and ergonomically fastened in a releasable manner, it is provided that the access to the pole-grip recess into which the first connecting elements can be inserted, and from which it can be removed, is formed by a longitudinal slot which runs parallel to the longitudinal axis of the pole grip, or in an inclined manner in relation thereto, in a first wall, which is directed toward the location of the hand-retaining device and bounds the pole-grip recess, the longitudinal slot extending in over a region from above to beneath the movement region of the second connecting element. As seen in a section perpendicular to the running direction of the slot, the longitudinal slot here is, to a certain extent, of T-shaped design, i.e. it has an entry channel or longitudinal slot from which extends, in the interior of the pole grip, two channel-widening grooves which are directed toward one another. The connecting element has a stem, which is guided in this longitudinal slot or channel, and a head, which widens this stem to the side and thereby engages in the grooves by way of lateral ribs.
The problem with such a design, under certain circumstances, is the fact that dirt or snow/ice can penetrate into the longitudinal slot, or into the grooves of the same which are concealed in the interior of the pole grip, and, correspondingly, it is then no longer possible for the connecting element to be inserted.
DESCRIPTION OF THE INVENTION
Accordingly, the object of the invention, inter alia, is to propose an alternative pole-grip construction which is of straightforward design and, inter alia, can also be handled easily at all times when in contact with snow. The concern here, in particular, is to improve a pole grip for in particular, cross-country ski poles, downhill ski poles and Nordic walking poles, having a hand-retaining device, such as a hand strap or glove, which can be fastened in a releasable manner to the pole grip via a coupling element secured on the hand-retaining device, the pole grip having a top end as well as a bottom end, on or in which a pole shaft can be fastened and/or is fastened.
This object is achieved, inter alia, in that provided in, but in particular preferably on, the pole grip is a retaining element which has at least two lateral grooves which are open essentially in opposite directions and, at least in certain regions, run essentially from top to bottom in relation to the pole grip, and in that the coupling element, for fastening on the retaining element, has two corresponding protrusions or ribs engaging laterally in these grooves. Lateral grooves on the retaining element which are open in opposite directions is intended to be understood, as can be gathered unequivocally from the language used and, in particular, from the following, as meaning that the grooves on the retaining element are arranged on both sides, i.e. indeed laterally, and are open in the direction of the outside, i.e. indeed are open essentially in opposite directions.
In the case of the prior-art designs, the fastening of the retaining device on the pole grip is always ensured via a coupling element which has to be pushed into a recess in the pole grip. The problem with such solutions, inter alia, is that the corresponding recess can become blocked in particular on contact with dirt, snow or ice and, correspondingly, it is no longer possible, in these conditions, for the retaining device to be fastened. This is the case, for example, in WO 2004/052476, which was discussed in the introduction. In this document, on the one hand, there is no retaining element provided on the pole grip on which a coupling element can be fastened; rather, a pole-grip recess is provided there. Also provided there is a longitudinal slot containing grooves which are directed toward one another rather than grooves which are open laterally in opposite directions. Correspondingly, for example, a solution such as that in WO 2004/052576 is problematic in respect of dirt.
The core of the invention, then, is to provide an, as it were, external but nevertheless functionally optimal design in the case of which in particular preferably the coupling element can be pushed into the grooves in the retaining device, for example, from above by way of the two protrusions, and the above problems can thus be avoided.
In addition, it has been found that such designs in which there is no need, in principle, for a recess in the pole grip can be rendered more stable as a result of the solid construction.
Such designs are basically possible without any need for a mechanism for the latching in of the coupling element if, for example, the grooves are curved or sufficiently long. According to a first preferred embodiment, however, the coupling element can be latched in a releasable manner on the retaining element.
A further preferred embodiment is characterized in that the two grooves of the retaining element, as seen in or along the running direction, are open at their first end, in which case the coupling element can be pushed in at this first end of the grooves, and in that the two grooves of the retaining element, as seen in the running direction, are closed at their second end, in which case, once it has been pushed in, the coupling element stops against this second end, this stop position defining the state in which the coupling element is fastened on the retaining element for use. In view of the hand-retaining device usually being subjected to downward pulling during use, the open ends of the grooves here are preferably open in the upward direction, and the closed ends of the grooves are closed in the downward direction, in which case the coupling element, for fastening on the retaining element, is pushed onto the retaining element from above, preferably with latching-in action.
As an alternative, it is possible for the grooves to be designed to be closed at the top and bottom and for the widened portion in front of the grooves to taper in the top region, at least over a height corresponding to the height of the coupling element, to the width of the retaining web, in which case the coupling element, in this region, can be inserted, as it were, horizontally and then pushed downward.
In general, the grooves mentioned in the introduction may have a depth in the range from 0.5-5 mm, in particular preferably in the range from 1-3 mm. In general, they may have a width in the range from 0.5-5 mm, in particular preferably in the range from 1-3 mm.
The coupling element is preferably designed as a rigid element in the manner of a clip, C-profiled rail portion or the like, preferably in one piece. The coupling element may be produced from metal or from plastic. In the same way, the pole grip may be produced, for example, from a thermoplastic material, or else also from cork, rigid plastic or from a combination of these materials or the like.
The coupling element is preferably designed, in cross section, in the form of a clamp or of a clip which has a recess in the form of a through-opening, the through-opening being opened, as seen in the running direction, toward the side directed toward the retaining element, so as to form two lateral protrusions adapted to the grooves. As seen in a section perpendicular to the running direction of the through-opening, this correspondingly results, as it were, in a C-shaped profile which may be of basically different shapes, for example angular (polygonal), oval or round (circular).
A further preferred embodiment is characterized in that the retaining element is positioned on the hand side of the pole grip, on the outside of the pole grip, in the region of the top end of the pole grip. In the case of such a construction, sensitivity in respect of dirt, snow or ice can be kept to a minimal level. The retaining element here may be designed as a metal rail, for example with a T-like profile, in which case the crossbar of the T-profile serves for fastening the coupling element and the vertical bar has its bottom end fastened on the pole grip. In particular, the retaining element preferably has a length, running in the running direction of the pole grip, which is at least greater, in particular preferably 2-10 times greater, than the width of the retaining element as seen perpendicularly to the running direction of the pole grip, that is to say than the width as seen transversely to the running direction of the pole grip.
The retaining element may have a retaining web, which runs from top to bottom and is fastened on the pole grip, and a widened portion, which runs from top to bottom (and may be round or angular in the manner of a bar), it being the case that the width of the retaining web is smaller than the width of the widened portion, and that the width of the retaining web may be, for example, in the range from 1-10 mm, in particular preferably in the range from 2-5 mm, and the width of the widened portion may be, for example, in the range from 2-15 mm, in particular preferably in the range from 3-10 mm.
The pole grip, preferably in the region of the top end, has a recess in which is arranged a locking mechanism, in particular preferably in the form of a locking lever, which blocks the coupling element with self-latching action, in particular preferably with at least the indirect aid of the restoring force of a spring or of a resilient element or even with the aid of the elastic deformation of the locking lever itself, in the position in which it is fastened on the retaining element, which locking mechanism or locking lever can be actuated by the user from the outside, in particular preferably from the top side, or even from the side, of the pole grip, in order to release the coupling element. The locking lever (for example made of metal or plastic) is preferably a locking lever which is mounted in a rotatable manner via a pin, projects out of the pole grip, essentially at the top end of the same, through a top opening of the recess, and projects through a bottom opening of the recess by way of a locking nose such that the coupling element can be pushed in from above without any additional actuation of the locking lever, the locking nose latching in automatically in the process. This is possible, for example, by the locking lever being arranged obliquely, in which case it has a beveled flank past which the coupling element can be drawn, preferably with self-latching action, as it is pushed in.
The present invention also relates to a glove or a hand strap having a coupling element as has been described above, that is to say in particular in the form of a single-piece clamp which is made of metal or plastic and is capable of engaging in the above-mentioned grooves by way of the protrusions. It is preferably the case with a glove that the coupling element is fastened in the region between the thumb and forefinger, it being possible for fastening to take place via rivets, or else also via appropriate stitched or adhesive-bonding connections. It is also possible for the coupling element to be integrally formed on the strap by injection molding. The hand strap is preferably one which can be fastened on the user's hand for example with the aid of a touch-and-close fastener, for example a hand strap which has three openings, one for the wrist, one for the thumb and one for the back of the hand or the other four fingers.
The present invention additionally relates to a cross-country ski pole, downhill ski pole and/or Nordic walking pole having a pole grip as has been described above.
Further preferred embodiments of the invention are described in the dependant claims.
BRIEF EXPLANATION OF THE FIGURES
The invention will be explained in more detail hereinbelow with reference to exemplary embodiments and in conjunction with the drawings, in which:
FIG. 1 shows a perspective view of the head region of a pole grip, part of the housing having been omitted in order to give a better view of the internal components;
FIG. 2 shows the head region according to FIG. 1 from a different direction;
FIG. 3 shows a contoured illustration of a pole grip in its entirety; and
FIGS. 4 a )- c ) show sections through different retaining elements and coupling elements, the sections being taken along a plane essentially perpendicular to the running direction of a pole grip.
WAYS OF IMPLEMENTING THE INVENTION
The invention will be explained hereinbelow with reference to exemplary embodiments. The exemplary embodiments here serve exclusively for illustrating and explaining the functioning of the invention, but are not to be seen as in any way restricting the scope of protection as defined in the appended patent claims.
FIGS. 1 and 2 illustrate the head region of a pole grip 1 , the housing on the viewer's side having been removed in order to give a better view of the components arranged in a recess 5 . FIG. 3 depicts a transparent contoured illustration of the same pole grip.
The pole grip 1 has a hand side 2 against which usually the palm of the hand, in particular the region between the thumb and forefinger, rests during use. The front side 3 is located opposite. The top end is designated 22 , and the bottom end is designated 23 . At the bottom end, the pole grip 1 has a recess into which the pole shaft 18 has been pushed. The pole shaft, at its bottom end, has a pole tip (not illustrated).
The recess 5 , which, in the direction of the top end 22 , has a top opening 6 and, obliquely downward in the direction of the hand side 2 , has a bottom opening 7 , contains a locking lever 8 . This locking lever 8 is mounted in a rotatable manner about a pin 10 . The locking lever 8 projects out of the pole grip 1 in the direction of the top end of the latter to form an actuating region 9 . There, the locking lever 8 can be actuated, for example, by the hand or a finger if the hand-retaining device 17 is to be released from the pole grip 1 . The locking lever 8 is braced in the recess 5 by means of a spring (not illustrated), in which case, in an illustration according to FIGS. 1-3 , it is subjected to force in the counterclockwise direction. The spring here may be, for example, a leaf spring which is fastened in a slot 13 in the locking lever, but it may also be in the form of correspondingly arranged helical springs, leg springs or elastomeric elements. The locking lever has its bottom end projecting out of the bottom opening 7 , and the bottom tip of the locking lever 8 forms a locking nose 11 .
An elongate retaining element 4 is arranged on the hand side, in the uppermost region of the pole grip 1 . It essentially comprises a T-shaped profile made of metal or plastic, the crossbar of this profile being the widened portion 15 and the other bar being the retaining web 14 , which is fastened on the pole grip 1 . The retaining web here extends over a first part; in the region of the bottom opening 7 , however, there is a region 16 in which the retaining web 14 has been omitted. Correspondingly, there, the locking nose 11 can project right up to the widened portion 15 . The retaining element 4 correspondingly forms two lateral grooves 19 which extend essentially along the running direction of the pole grip 1 and are arranged opposite one another. The grooves 19 are open in the direction of the top end 22 of the pole grip 1 , but are closed in the direction of the bottom end such that the coupling element 12 , which in FIGS. 1-3 is illustrated in the position in which it is fastened on the pole grip, comes to a stop as it reaches the lowermost position. The locking nose 11 here is arranged essentially above the top edge of the coupling element 12 in the lowermost position.
It is also possible, as it were, to dispense with the entire top region of the retaining element 4 , i.e. it is possible to allow the widened portion 15 to project, as seen in FIG. 1 , only to some way beyond the position of the locking nose 11 , as it were in the manner of a hook. All that is then required is for the coupling element 12 to be pushed onto the retaining element 4 over a significantly shorter distance, and the design becomes narrower.
This design makes it possible for the coupling element 12 to be pushed into the upwardly open grooves 19 from above and moved downward. When the locking nose is reached, the latter is deflected into the interior of the pole grip 1 counter to the spring force, which allows the coupling element 12 to slide into the lowermost position, that is to say until its stop. When the lowermost position has been reached, the locking lever moves back again in the counterclockwise direction and thus locks the coupling element 12 . Correspondingly, this mechanism provides a self-latching design.
Should the user wish to release the coupling element again from the pole grip, then he actuates the actuating region 9 (pressing in the clockwise direction) until the locking nose 11 releases the coupling element 12 and the latter can be pushed out of the retaining element 4 once again in the upward direction.
FIG. 4 illustrates different configurations of the retaining element 4 and coupling element 12 . FIGS. 4 a )- c ) each illustrate a section taken along a plane perpendicular to the axis of the pole grip 1 . Each figure shows the longitudinally running grooves 19 arranged on both sides and the T-shaped profile of the retaining element 4 .
FIG. 4 a ) shows the exemplary embodiment as has been illustrated in FIGS. 1-3 . In this case, the coupling element 12 fastened on the hand-retaining device 17 is, as it were, an angular, C-shaped clip which has an undercut recess 20 which is configured as a through-opening and gives rise to two elongate protrusions arranged opposite one another. The coupling element 12 has, for example, a height (as seen perpendicularly to the plane of the paper in FIG. 4 ) in the range from 2-15 mm, preferably in the range from 4-10 mm. It is generally produced, for example, from metal (aluminum) or from plastic (possibly fiber-reinforced plastic) or else from a combination, e.g. from a metal encapsulated, coated or sheathed by plastic.
An alternative embodiment is illustrated in FIG. 4 b ). The widened portion 15 here, rather than being an angular crossbar, is an oval widened portion. Such a design with no edges may be desirable if, for example, the risk of injury is to be kept low. In the case of FIG. 4 b ), as far as the coupling element 12 is concerned, only the shape of the recess 20 ′ is, correspondingly, likewise oval; the external shape, however, remains angular. It is, of course, also possible for the external shape to be rounded as well. FIG. 4 c ) illustrates a fully rounded design. In this case, the widened portion 15 is configured as a round pin which is connected to the pole grip via the retaining web 14 . Correspondingly, the coupling element 12 is designed as a straightforward tube portion which has a slot on one side, in which case the retaining web 14 can be arranged in this region when the coupling element is pushed onto the retaining element 4 .
LIST OF DESIGNATIONS
1 Pole grip
2 Hand side
3 Front side
4 Retaining element
5 Recess in 1
6 Top opening of 5
7 Bottom opening of 5
8 Locking lever
9 Actuating region of 8
10 Pin of 8
11 Locking nose
12 Coupling element, clamp
13 Slot for leaf spring or the like
14 Retaining web of 4
15 Widened portion/transverse element of 4
16 Region of 4 without 14
17 Hand-retaining device, in particular glove or hand strap
18 Pole shaft
19 Notch, groove
20 Undercut recess, angular
20 ′ Undercut recess, oval
20 ″ Undercut recess, round
21 Protrusion, rib
22 Top end of 1
23 Bottom end of 1 | A description is given of a handle ( 1 ) for in particular (cross-country) ski sticks and Nordic walking sticks, having a hand-retaining device ( 17 ), such as a hand loop or glove, which can be fastened in a releasable manner to the stick handle ( 1 ) via a coupling element ( 12 ) secured on the hand-retaining device ( 17 ), the stick handle ( 1 ) having a top end ( 22 ) and a bottom end ( 23 ), on or in which a stick tube can be, and/or is, fastened. A particularly straightforward releasable fastening arrangement which is stable, of reliable design and can also be utilized at low temperatures and in the presence of snow is made available by a retaining element ( 4 ) being provided on and/or in the stick handle ( 1 ), this retaining element having at least two lateral grooves ( 19 ) which are open essentially in opposite directions and, at least in certain regions, run essentially from top to bottom in respect of the stick handle ( 1 ), and by the coupling element ( 12 ) having, for the purpose of fastening on the retaining element ( 4 ), two corresponding protrusions which engage laterally in these grooves ( 19 ). | 0 |
BACKGROUND OF THE INVENTION
[0001] The present invention addresses the shortage of suitable biomaterials and scaffolds for soft tissue engineering. A specific example of the present invention relates to tissue engineering of small diameter blood vessels (SDBV).
[0002] Tissue engineering, or regenerating fully functional and viable tissue grafts, is conventionally limited to tissue thickness less than 1 mm thick. Regenerating vascularized tissue remains elusive as well. Tissue engineering faces many challenges, most of them related to biocompatibility. Biocompatibility comprises factors such as material, chemical, and mechanical compatibility with the host. Limitations in cell sources, cell availability, also compounds the challenges of tissue engineering. Since the National Science Foundation coined the term “tissue engineering” in 1987, creating suitable biomaterials and appropriate scaffold engineering designs have been an ongoing endeavor.
[0003] The common tissue engineering model is to seed cells, autologous adult cells, stem cells, or progenitor cells into biodegradable scaffolds. The biodegradable scaffold acts as a temporary template for diseased tissues. The cell-seeded construct is then implanted to the target site in the body for tissue regeneration. The plan is that cells produce their own matrix, and new tissues form while the scaffold is gradually absorbed.
[0004] Biodegradable polymers with elastomeric properties have recently received attention for their potential use in the engineering of soft tissues such as blood vessel, heart valves, cartilage, tendon, and bladder, which exhibit elastic properties.
[0005] Vascular disease and the need for a suitable replacement of diseased tissue remains a challenge, with atherosclerotic vascular disease being the leading cause of mortality in the United States. (A report from the American Heart Association statistics committee and stroke statistics subcommittee. Heart Disease and Stroke Statistics—2006 update, 2006) . Coronary artery and peripheral vascular, SDBVs, of less than 6 mm diameter, frequently require bypass grafts. Autogenous veins, expanded polytetrafluoro-ethylene (ePTFE), and Dacron bypass grafts have been used for replacing diseased blood vessels. However, a large number of bypass grafts fail postoperatively. Acute thrombosis occurs in the early postoperative period or intimal hyperplasia (IH) occurs within months or years. Hence, multiple surgical or coronary angioplasty procedures are often required.
[0006] Tissue engineering may be able to provide a biocompatible graft with long tern patency. However, tissue engineered SDBV have not attained long term patency to date.
[0007] The challenges to SDBV tissue engineering and corresponding biocompatibility are many. A suitable biomaterial needs to perform mechanical graft functions such as support for the vascular cells, a temporary extra-cellular matrix. The desired biomaterial performs analogous to a native blood vessel, having suitable strength, elasticity, and compliance. The scaffold should permit even cell distribution and nutrient delivery at matrix depths greater than 300 μm.
[0008] Compliance mismatch and or lack of strength can lead to thrombosis and/or significant inflammatory responses. Early efforts on vascular tissue engineering focused on using biodegradable synthetic polymer, such as polylactide (PLA), polyglycolide (PGA), and polycaprolactone (PCL) and their copolymers. These polymers were rolled into tubes and implanted in vivo but did not yield favorable results due to mismatch in mechanical properties and inflammatory responses.
[0009] Natural polymers, such as collagen, hyaluronic acid, chitosan, and fibrin often lack the strength and elasticity needed for vascular graft materials. (Neider et al., Biomaterials, 2002, 23(17): p. 3717-3731; Boccafoschi et al., Biomaterials, 2005, 26(35): p. 7410-7417; Remuzzi et al., Tissue Eng., 2004. 10(5-6): p. 699-710; 37. Zhang et al., J Biomed Mater Res A, 2006, 77A(2): p. 277-284). Studies using natural polymers have been unsuccessful and none of the tubes made from the natural materials above can fully represent the anatomical structure of blood vessels. Some studies have explored the use of two dimensional cell sheets to regenerate tissue, for example, SDBV. However, these tissue constructs require months of in vitro maturation and one study failed to maintain patency in vivo for more than 7 days. (L'Heureux et al., Faseb J, 1998. 12(1): p. 47-56.)
[0010] Polyurethanes are a family of polymers which have the requisite strength, elasticity and other mechanical properties to serve as functional vascular grafts. However, some of the limiting factors for urethanes is their tendency to produce creep under cyclic deformation, their poor cell compatibility and their long degradation times.
[0011] Crosslinked polyesters, like polydiol citrates have been shown to demonstrate good tolerance to creep, excellent cell compatibility and hemocompatibility and controllable degradation times. However, polydiol citrates don't have the necessary elasticity and strength to be suturable, which is one of the primary requirements of a vascular graft material
[0012] Good scaffold candidates for engineering SDBV would have good biocompatibility, which includes hemocompatibility and biodegradability. Potential scaffolds would be cell, tissue, and blood compatible. Vascular cells seeded in the scaffold would yield collagen and elastin in quantities similar to those of the native vessels. Ideal scaffolds should be non-thrombogenic and conducive to continuous endothelium layer formation. The degradation rate of the scaffolds should approach the tissue growth or remodeling rate.
[0013] It is desirable for a scaffold to have architecture which is similar to the native blood vessel. The scaffolds should compartmentalize and support fibroblasts, smooth muscle cells (SMCs), and endothelial cells (ECs). Cells should adhere to the scaffold, grow, and differentiate. The scaffold should afford communication of the cells within and across cell types.
[0014] Scaffolds should provide mechanical biocompatibility, soft and elastic, similar to the native blood vessel. Elasticity is desired to avoid compliance mismatch which was believed to contribute intimal hyperplasia, a major reason for graft failure. (Teebken et al., Eur. J. Vasc. Endovasc., 2002. 23(6): p. 475-48518; 58. He et al., Tissue Eng, 2002. 8(2): p. 213-224; Lemson et al., Eur. J. Vasc. Endovasc., 2000. 19(4): p. 336-350.) They should be able to withstand cyclic deformation without irritation to the surrounding tissues. (Wang et al., Nat. Biotechnol., 2002. 20(6): p. 602-606.)
[0015] Even when scaffolds are used for other soft tissue generation, they should permit rapid angiogenesis provide a blood supply by which nutrients are supplied to the repair site and through which waste is removed, it also provides direct access of the graft to the host's immune system to limit infection. (Hodde J., Tissue Eng, 2002. 8(2): p. 295-308.) Soft scaffolds should promote scaffold-tissue adaptation without significant mechanical irritation to the hosting tissues. Soft scaffolds should also facilitate scaffold-assembling into various shapes through, for example, folding, rolling trimming, and bending. For in vivo tissue engineering, the scaffolds should be functional for immediate implantation.
[0016] More recently, the use of soft and elastic biodegradable crosslinked poly(diol citrates) elastomers with a biphasic scaffold design showed promise for SDBV applications. However, the low molecular weight of these polymers raises processing concerns. And further, the outermost adventia layer is absent these SDBVs and suturability of the scaffold is lacking. (Yang et al., Tissue Engr., 2005, 11(11-12): p 1876-1886). Linear polyurethanes possess strong mechanical properties depending on the composition of their hard and soft segment. However, the degradability, biocompatibility, and susceptibility to permanent creep of polyurethanes still challenge their use for vascular regeneration.
[0017] Promising scaffold candidate material will be somewhat porous. It has been shown that ECs and SMCs can influence each other via heterocellular junctions and the signaling molecules secreted by both cell types. In turn, porosity which allows transfer of bio-macromolecules is desirable.
SUMMARY OF THE INVENTION
[0018] The present invention addresses the shortage of suitable biomaterials and scaffolds for soft tissue engineering. In particular, tissue-engineered SDBVs benefit from the present invention. A novel family of biodegradable elastomers, Crosslinked Urethane-containing Polyester (CUPE) is developed and employed in engineering SDBV via a scaffold-sheet design.
[0019] One aspect of the present invention is to use a porogen to obtain surface roughness and scaffold openings or tunnels. In an exemplary embodiment, poly(ethylene glycol) dimethyl ether (PEGDM) is used as a porogen mixed with pre-poly 1,8-octanediol citrate (POC) polymer solution. After solvent evaporation and post-polymerization, the PEGDM was leached out to obtain a POC′ film featured with a couple of sub-micron (nano) of surface roughness and tortuous tunnels inside which are similar in dimension to the fenestrations of elastic lamina.
[0020] Another aspect of the present invention is to permit bovine serum albumin (BSA) to penetrate into tortuous POC′ film. In contrast to regular POC, in which BSA only adsorbed on the surface.
[0021] Another aspect of the POC′ is that it is cohesive but not sticky. Further this nano-featured membrane can physically bond to itself. That is one POC′ membrane can bond to another POC′ membrane.
[0022] Another aspect of the present invention is to facilitate compartmentalization of cell types. For example in SDBV, the present invention enables compartmentalization of the three types of cells (fibroblasts, SMCs and ECs) without hampering the cell-cell communication between SMCs and ECs.
[0023] Another aspect of the present invention is to promote even cell distribution across a scaffold.
[0024] Another aspect of the present invention is to provide compliance matching with native tissue.
[0025] Another aspect of the present invention is to provide off-the-shelf availability for in vivo tissue-engineering of SDBV.
[0026] Other aspects of the present invention include adequate strength, creep-resistance, and suture-ability.
[0027] Other aspects of the present invention include providing biocompatibility through rate of degradation commensurate with tissue regeneration.
BRIEF DESCRIPTION OF THE FIGURES
[0028] For more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures, wherein:
[0029] FIGS. 1A-1B are photographs of scanning electron microscopy (SEM) images of a POC membrane, according to an exemplary embodiment of the present invention, where A) shows surface morphology and B) shows a cross-section of the membrane;
[0030] FIGS. 2A-2B show the schematic reaction of an exemplary CUPE synthesis and a schematic of an exemplary CUPE network, respectively;
[0031] FIGS. 3A-3C show an SEM picture of a cross section of a tubular scaffold diameter at different magnifications according to an exemplary embodiment of the present invention;
[0032] FIGS. 4A and 4B graphically represent the results of cell attachment and proliferation assays, respectively, in accordance with an exemplary embodiment of the present invention;
[0033] FIGS. 5A and 5B show SEM images of a CUPE polymer, where A) depicts the morphology of fibroblasts seeded and adhered to a CUPE polymer in accordance with an exemplary embodiment of the present invention and B) depicts a CUPE polymer film without any cell seeding;
[0034] FIGS. 6A and 6B show a flowchart and a schematic of vascular graft fabrication, respectively, tissue engineering, by cell sheet design, in accordance with an exemplary embodiment of the present invention;
[0035] FIGS. 7A and 7B show an FT-IR spectrum of CUPE with pre-polymer-isocyanate in a 1:0.6 molar ratio, according to an exemplary embodiment of the present invention, and thermogram results of an exemplary embodiment of the present invention, respectively;
[0036] FIGS. 8A and 8B show photographs of a porous CUPE scaffold before stretching (A) and after stretching with near 220% elongation (B); and
[0037] FIG. 9 shows the results of a tensile strength test on an exemplary embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The invention, as defined by the claims, may be better understood by reference to the following detailed description. The description is meant to be read with reference to the figures contained herein. This detailed description relates to examples of the claimed subject matter for illustrative purposes, and is in no way meant to limit the scope of the invention. The specific aspects and embodiments discussed herein are merely illustrative of ways to make and use the invention, and do not limit the scope of the invention.
[0039] Intermittent fenestrations in the internal elastic lamina, at 0.5-1.5 μm in large vessels and 0.1-0.45 μm in capillaries, allow direct contact between the two cell types, SMCs and ECs. The permeable membrane, according to an exemplary embodiment of the present invention allows bio-macromolecules to pass through, proteins, for example. Exemplary synthesis of the exemplary membrane includes using PEGDM as a porogen mixed with pre-POC polymer solution. After solvent evaporation and post-polymerization, the PEGDM was leached out to obtain a POC′ film featured with a couple of sub-micron (nano) surface roughness and with tortuous tunnels inside which are at the same order of fenestration size of elastic lamina. FIGS. 1A and 1B shows SEM images of a POC′ membrane in accordance with an exemplary embodiment of the present invention. FIG. 1A shows surface morphology of the membrane, where the scale bar equals 300 nm and FIG. 1B shows the membrane cross-section, where the scale bar equals 1 μm.
[0040] Bovine serum albumin (BSA) release experiments indicate that BSA loaded permeable elastic POC′ membrane could maintain significant BSA release even at the fourth day while regular POC membrane stopped release in one day. Results support that BSA could penetrate into the tortuous tunnels of the POC′ film, while the same is only adsorbed on the surface of regular POC.
[0041] This POC′ membrane can physically bond to itself. That is one POC′ membrane can bond to another POC′ membrane, although it is not sticky. The bonding mechanism is attributed to the sub-micron nano-featured surface roughness. Regular POC is not able to bond to itself.
[0042] The synthesis of CUPE comprises at least two distinct steps, as shown in FIG. 2A . In a first step, citric acid and 1,8 octane diol, for example, were added in a molar ratio of 1:1.1 to a 250 ml three necked round bottom flask, fitted with an inlet adapter and an outlet adapter. The mixture was melted within 20 minutes by placing and stirring the contents in the flask in a silicon oil bath maintained at a temperature of 160-165° C. Once the constituents melted, the temperature of the oil bath was reduced to 140° C. and the reaction was allowed to progress for another 75 minutes to create the pre-polymer. This pre-polymer was dissolved in dioxane and then precipitated in water in order to remove any unreacted monomers and oligomers. Following precipitation, the polymer solution was then freeze dried. FIG. 2A shows the schematic reaction of CUPE synthesis.
[0043] In a second step, also shown in FIG. 2A , the freeze dried pure polymer was dissolved in N,N′-dimethylformamide (DMF). The urethane linkage is then introduced in this pre-polymer solution by adding 1,6-hexane diisocyanate (HDI) in a 1:0.9, prepolymer to HDI ratio, under continuous stirring to form pre-CUPE.
[0044] The time of complete reaction was assessed by Fourier Transform Infra Red Spectroscopy (FT-IR). Some amount of the solution was taken out periodically at 1, 2, 3, and 4 day time points and analyzed by Fourier Transform Infra Red Spectroscopy (FT-IR). The absence of any isocyanate group in the analysis signaled the time point at which the reaction was complete. Pre-CUPE solution was then purified by dropping the solution into water while stirring.
[0045] After drying the purified pre-CUPE under vacuum, the CUPE polymers were obtained by heating pre-CUPE at a temperature range from 60-120° C. for times ranging from one day to 2 weeks with or without vacuum in an oven.
[0046] According to one exemplary embodiment, an anti-coagulant is incorporated into the CUPE. The ability to incorporate an anti-coagulant into a scaffold for tissue engineered SDBVs may improve the success of the SDBV in vivo. Sodium citrate, the salt form of citric acid, is an anti-coagulant used clinically. In turn, using citric acid as one of the major building blocks for CUPE, is expected to yield a biomaterial with good hemocompatibility.
[0047] At least the following monomers can be used to react with citric acid for CUPE synthesis: 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol. In additional to 1,6-hexamethyl diisocyanate. Any other diisocyanate, such as 1,4-butyl diisocyanate, can be used to synthesize CUPEs.
[0048] Ester bonds and urethane bonds present in the CUPE polymer network are degradable. In one exemplary embodiment, 1,4-butyl diisocyanate is used because of its potential for exceptional biocompatibility. One of the degradation products of CUPE, during break-down of urethane bonds, will be putrescine which is already present in the body. Putrescine is believed to play a role in cell growth and differentiation.
[0049] In accordance with the present invention, by varying the selection of diols, combination of diols, diisocyanate, and postpolymerization conditions, different CUPE biopolymers may be created.
[0050] The multifunctional monomer citric acid is one of the major monomers which can be used to create pre-polymers for CUPE synthesis. Other multifunctional monomers such as malic acid can also be used to create pre-polymers through polycondensation reaction. Multifunctional monomers can be reacted with di-functional monomers, diols to create the pre-polymers. Exemplary aliphatic diols include any diols of between about 2 carbons and about 20 carbons. The diols may be aliphatic, linear, unsaturated diols, with the hydroxyl moiety being present at the C1 and Cx position (where x is the terminal carbon of the diol). The diols may be an unsaturated diol in which the aliphatic chain contains one or more double bonds. Diols can also be macrodiols such poly(ethylene glycol) (PEG) with various molecular weight. Diols can also be a combination of any type of above diols to synthesize the pre-polymers with multifunctional monomers. Amino acids can also be incorporated into the pre-polymers through condensation reactions, for example L-cysteine. Any diisocyanate can be used as linker to bridge pre-polymer chains. For biomedical applications, the diisocyanate used as linker to bridge pre-polymer chains may be any of diphenylsulfone di-isocyanate (SDI), hexamethylene di-isocyanate (HDI) and lysine di-isocyanate (LDI), for example.
[0051] CUPE films can be prepared by casting pre-CUPE solution into a Teflon mold followed by solvent evaporation and then post-polymerization under the conditions described as above. Fourier Transform Infra Red Spectroscopy (FT-IR): FT-IR spectroscopy measurements were recorded at room temperature for both CUPE and pre-CUPE. Pre-CUPE FTIR samples were created by casting pre-CUPE solution onto a KBr pellet followed by solvent evaporation to form thin films. CUPE FTIR samples were created by post-polymerizing the pre-CUPE thin films on the KBr pellet. FTIR spectroscopy measurements were recorded at room temperature for both CUPE and pre-CUPE. CUPE in the following exemplary embodiments are made with citric acid, 1,8-octanediol, and HDI except where specified otherwise.
[0052] Differential Scanning Calorimetry (DSC) was performed on a DSC550(Instrument Specialists Inc. Spring Grove, Ill.) to study the thermal behavior of the new polymers. Samples are first scanned up to 150° C. with a heating rate of 10° C./min under nitrogen purge (50 ml/min). A hole was drilled in the aluminum crucible.
[0053] Two cycles of cooling were performed. The first round of heating can help to get rid of the trace of water from sample. Thereafter cooled with a cooling rate of −40° C./min to −60° C. and recorded a second time up to 230° C. The glass transition temperature (Tg) is determined as the middle of the recorded step change in heat capacity from the second heating run.
[0054] In accordance with an embodiment of the present invention, tubular scaffolds of a CUPE polymer were fabricated using tubular Teflon moulds using a method previously described by Yang et al. (Yang et al., Biomaterials, 2006, 11(11-12): pp. 1876-1886). The CUPE pre-polymer was dissolved in 1,4-dimethylformamide, to form a 30% solution. Sieved salt (106-150 microns) was added in a 1:6, prepolymer: salt weight ratio to form a slurry, which was cast into the tubular Teflon mould and allowed to dry for 24 hours. After solvent evaporation, the moulds were put into an oven maintained at 80° C. for a period of two days for post polymerization under mild conditions. Subsequently, another day of postpolymerization at high temperature and vacuum (120° C., 0.01 inches of Mercury, respectively) is done. The salt was removed by leaching in de-ionized water (produced by a Millipore water purification system, Millipore, Billerica, Mass.) for a period of 72 hours with water changes every 3 hours. The tubular scaffolds obtained after leaching were lyophilized for 48 hours to remove all traces of water.
[0055] The tubular scaffolds obtained were examined qualitatively for elasticity and strength and by SEM observation. Scaffold were freeze fractured using liquid nitrogen and then cross-sectioned. The cross section of the fractured tubes was examined under SEM. FIGS. 3A-3C show a SEM picture of a cross section of a tubular scaffold diameter at different magnifications according to an exemplary embodiment of the present invention.
[0056] Cell seeding can be done on the CUPE polymer films in accordance with the present invention. For example, polymer films, in accordance with the present invention, were formed by casting pre-CUPE solutions in glass vials which could be placed in a 24 well plate. The 24-well plate was divided into 12 wells for the CUPEs and another 12 wells for regular POC, which acted as the control. Three ml of a 30% polymer solution was cast into each vial and allowed to air dry for 24 hours. After drying, the glass vials were allowed to polymerize under mild conditions, in an oven maintained at 80° C. for two days, following which they were post polymerized to introduce further crosslinking, by heating at 120° C. under high pressure (0.01 inches of mercury). The polymer films were sterilized by addition of 70% ethanol. After 30 minutes, the ethanol was removed by exchanging with an excess amount of phosphate-buffered saline (PBS). Ethanol treatment was followed by exposure to ultra-violet (UV) light for another 30 minutes.
[0057] Two ml of cell suspension containing 3×10 3 cells human aortic endothelial cells (HAECs) were added to each of the 24 wells and the 12 glass vials. An attachment assay was conducted after 6 hours using the Pico-Green DNA Assay. The proliferation of the cells on the polymers and the glass was studied one day and three days after seeding the cells on the vials, using the Pico-Green DNA assay. FIGS. 4A and 4B show exemplary results of cell attachment and proliferation assays, respectively, in accordance with an exemplary embodiment of the present invention. FIGS. 4A and 4B are graphs depicting the results of the cell attachment assay (A) and cell proliferation assay (B). Attachment assay was done 6 hours after cell seeding. Proliferation assays were done on Day 1 and Day 2 after seeding. Control—Glass, P1—POC and P2—CUPE polymer film, respectively.
[0058] CUPE polymer films were cut into small pieces (1×2 cm 2 ) and placed in cell culture-petri-dishes (diameter 6 cm). Sterilization was carried out by the aforementioned process. A 5 ml cell suspension with 6×10 4 cells (NIH 3T3 fibroblasts) was added to the film on the culture dish, which was further supplemented with 10 ml of media. Cells were allowed to grow on the surface of the film for two days, after which the films were transferred to a fresh culture dish with the same volume of media. The culture was allowed to go on for a pre-determined time period. After reaching confluence, the polymer samples seeded with cells were fixed by addition of 2.5% glutaraldehyde solution and incubation for 2 hours. Then the films were sequentially dehydrated in 50%, 75%, 95% and 100% ethanol, each for 10 minutes. The samples were lyophilized, sputter coated with copper and examined under a SEM (JEOL 845, Peabody, Mass., U.S.A) . SEM pictures were taken to study the morphology of the cells growing on the surface of the polymer. FIGS. 5A and 5B show 3T3 fibroblast morphology via SEM on seeded CUPE film and non-seeded blank CUPE film, respectively.
[0059] FIGS. 6A and 6B show a flowchart and a schematic of vascular graft fabrication, respectively, in accordance with an exemplary embodiment of the present invention. Tissue engineering of vascular grafts, using a scaffold-sheet design, in accordance with the present invention, begins with a CUPE tubular scaffold (A) and CUPE sheets (D, F), as shown for example in FIG. 6B . A CUPE tube (B) may be dip coated about a Teflon Rod (A). Exemplary dimensions are a 3 mm diameter Teflon rod and a 100 μm thick CUPE tube. Human aortic fibroblasts (HAFBs), human aortic smooth muscle cells (HASMCs), and HAECs (Clonetics, Walkersville, Md.) may be cultured in a 50 ml flask with FGM-2, SmGM-2, and EBM-2 culture medium, respectively. Cell culture may be maintained in a water-jacketed incubator equilibrated with 5% CO 2 at 37° C. Cells may be limited to fifth passage cells.
[0060] CUPE may be used to fabricate a vascular graft using a cell sheet engineering technique. This may be done in a two step process. In step one, the porous polymer scaffolds and nano-porous polymer tubes are fabricated. Briefly, the purified or non-purified CUPE pre-polymer solution in DMF or Dioxane, for example a 10% pre-CUPE solution, may be cast on a stainless steel plate with dimension 5 cm (l)×5 cm (w)×150 μm (d) to obtain a 150 μm thick liquid membrane on the plate. The solution may be cast on a stainless steel plate with dimensions 5 cm (l)×5 cm (w)×150 μm (d), to obtain a 150 μm thick membrane on the plate.
[0061] The above liquid membrane may be freeze-dried to remove all traces of solvent and then subjected to post-polymerization in an oven at 80° C. for 2 weeks to obtain macroporous CUPE scaffolds. Post-polymerization time can vary. CUPE polymer tubes can be produced by dip-coating a Teflon rod with pre-CUPE/PEGDM. PEGDM (Mw=250, 20 wt % of pre-CUPE) acts as a porogen to create nano-features, such as nano-scale tortuous tunnels, on the CUPE tubes. After solvent evaporation, the pre-CUPE/PEGDM coated Teflon rod can be transferred into an oven for post-polymerization and then followed by PEGDM leaching and freeze-drying to obtain nano-featured, nanoporous, CUPE tubes.
[0062] According to the exemplary embodiment shown in FIG. 6B and described in the fabrication flowchart of FIG. 6A , multiple CUPE scaffold sheets and a CUPE tube will be used for cell seeding and fabricating a vascular graft. Referring to FIGS. 6A and 6B , a nano-featured CUPE tube (B) may be made as described above. A CUPE tube (B) is fabricated by dip coating using a Teflon rod (A), forming (C) 620. Three HASMC seeded CUPE scaffold sheets (D) are wrapped around (C), forming( E) 630. Three HAFB seeded CUPE scaffold sheets (F) are wrapped around (E), forming (G) 640. The Teflon rod (A) is removed, forming (H) 650. HAECs (I) are seeded in the lumen of (H) forming (J) 660, which is a vascular graft complete with an endothelial lined lumen.
[0063] More particularly, scaffold sheets 1, 2 and 3 may be seeded with HAFBs by pipetting 5×10 6 cells/ml of human aortic fibroblasts (HAFBs) evenly into the scaffold; Scaffold sheets 4, 5 and 6 may be seeded with human aortic smooth muscle cells (HASMCs) by pitpetting 5×10 6 cells/ml of HASMCs evenly into the scaffold; After two days of in vitro culture, A CUPE tubular graft will be constructed by rolling HASMCs seeded CUPE sheets and HAFBs seeded CUPE sheets on the CUPE tube sequentially with the aid of a Teflon rod (3 mm in diameter) inserted in the CUPE tube. Then human aortic endothelial cells (HAECs) with a density of 1×10 6 cells/ml will be seeded on the lumen of the tubular graft according a method described previously. (Yang et al., Adv Mater, 2006. 18(12): p. 1493-149851). The resulting cell-seeded CUPE graft (about 1 mm thick wall) will be further cultured in vitro for three days for further bonding between the layers of the graft. (Williams et al., Annals of Biomedical Engineering, 2005. 33(7): p. 920-928). The number of respective CUPE scaffold sheets and thickness of the CUPE tube can vary as needed.
[0064] Crosslinked urethane polyester elastomers (CUPEs) eliminate the disadvantages, and combine the advantages of both polyurethanes and crosslinked polyesters. Hence, CUPEs are candidates for tissue engineering scaffolds to include small diameter vascular grafts. This new family of CUPE elastomers, according to the present invention, are an improvement over the previously reported poly(diol citrate) family. Poly(diol citrates) are utilized as a base material for CUPE synthesis.
[0065] In the case of using citric acid, 1,8-octanediol, and 1,6-hexamethyl diisocyanate (HDI), pre-Poly(1,8-octanediol citrates) (pre-POC) are first synthesized by the polycondensation of citric acid and 1,8-octanediol, to result in a pre-polymer which is used for the synthesis of the CUPE. A 1/1.1 molar ratio of citric acid/1,8-octanediol is used for this synthesis, so as to cap the two ends of the polymer chains with hydroxyl groups. In order to synthesize CUPE, small quantities of HDI are added to the pre-polymer solution and the reaction is continued till all the diisocyanate is used up. The diisocyanate will react with the end hydroxyl groups of the POC polymer chains to form the urethane linkages. The urethane linkages act as bridges between the POC polymer chains which link together to form a polymer (pre-CUPE) which has a higher molecular weight compared to the linear pre-POC as depicted in the FIG. 2 . Pre-CUPE can be further crosslinked by heating firstly under mild conditions of 80° C. for two days, followed by 120° C. under vacuum or one day, to form CUPE polymers.
[0066] The typical FT-IR spectrum of pre-CUPE is shown FIG. 7 . The presence of ester bonds is denoted by the intense C═O stretch at 1,735 cm −1 and the intense peak at 3332 cm −1 indicates the formation of the urethane bonds. Note the absence of a peak at 2,267 cm −1 indicating that all the diisocyanate has reacted completely.
[0067] Thermal properties of the CUPEs were investigated using differential scanning calorimetry (DSC). For the thermograms, shown in FIG. 7B , POC is crosslinked during post-polymerization at 80° C. for one day A. CUPE is also crosslinked during during post-polymerization at 80° C. for one day C. And pre-CUPE, shown as B, has not been subject to any crosslinking. From FIG. 7 , it can be seen that the glass transition temperature of the pre-CUPE (B) which has not been subjected to any crosslinking is higher than that of the crosslinked POC (A) control. The higher molecular weight and hydrogen bonding of urethane bonds of the CUPE could be responsible for this phenomenon. The CUPE's ability to crosslink is also demonstrated in the figure. The higher glass transition temperature of the crosslinked CUPE (C) compared to the un-crosslinked CUPE (B) indicates that the polymer chains have been crosslinked and a greater amount of heat must be supplied to make the polymer chains flow. Another indication of crosslinking is that pre-CUPE can be dissolved in solvent such as 1,4-dioxane, Dimethyl sulfoxide (DMSO), and N,N-Dimethylformamide (DMF) while CUPE is not soluble in any solvent.
[0068] This new family of CUPE polymers was assessed for biocompatibility with respect to cell adhesion and cell growth. NIH 3T3 fibroblasts and human aortic endothelial cells were used as model cells for this study. The 3T3 fibroblasts were seeded and allowed to grow on a small CUPE film for a total of two days and then imaged using high resolution SEM. FIG. 5A shows the morphology of the confluent cells on the surface of the seeded polymer films. From the SEM images, it can be seen that the cells spread out over the surface with extended filopodia, which were in contact with other cells. This indicates that the cells maintained a healthy morphology while they grew on the polymers, which meant that the CUPE polymer films are conducive to cell adhesion and growth.
[0069] The attachment and proliferation assays showed that the human aortic endothelial cells showed a good affinity for the CUPE polymers. The results of the attachment and proliferation assays are depicted in FIG. 4A and 4B , respectively. It was observed that the cells attached to the CUPE in much greater numbers compared to the control glass and POC films. In addition to the initial attachment, the cells showed a greater tendency to grow and proliferate on the CUPE polymer films in comparison to glass and regular POC.
[0070] The graphs of FIGS. 4A and 4B depict the results of the cell attachment assay (A) and cell proliferation assay (B). The attachment assay was done 6 hours after cell seeding. Proliferation assays were done on Day 1 and Day 2 after seeding. Glass was the control (Control) and regular POC is designated (P1), while CUPE polymer film in accordance with an exemplary embodiment of the present invention is (P2).
[0071] The tubular scaffolds fabricated using the CUPE polymer were evaluated for elasticity and compared that of regular POC tubular scaffolds. CUPE tubular scaffolds had greater elasticity and mechanical strength compared to the regular POC tubular scaffolds. The CUPE tubular scaffolds showed an elongation of 220% without break, as shown in FIGS. 8A and 8B . This is a significant achievement over the mechanical and elastic properties of the POC scaffolds which only showed a 70% of elongation before rupturing.
[0072] FIG. 9 is a graph of mechanical tests for CUPE films and POC films synthesized under the same conditions. CUPE films and POC films were synthesized by post-polymerizing pre-CUPE and pre-POC at 80° C. for two days and then at 120° C., 2 Pa, for one day. Tensile mechanical tests for CUPE were conducted on a MTS Insight II mechanical tester. CUPE films were cut into dog-bone-shape samples according to ASTM D412. A 500 N load cell was used at a crosshead speed of 500 mm/min. The mechanical data shown graphically in FIG. 9 supports that introducing urethane bones into the polyester network can greatly increase the tensile mechanical strength and elongation of the polymers. CUPE yielded a 7.84 MPa breaking strength and a 280% elongation, while control POC yielded a 1.2 MPa breaking strength and an elongation of 125%. This result supports that the new CUPE can combine the advantages of strong polyurethane and soft and elastic poly(diol citrates).
[0073] SEM images of the tubular scaffold cross section, FIGS. 3A-3C showed the formation of an interconnected highly porous network, which is expected to be beneficial to the cell growth and interaction. FIG. 3A , shows the thickness of the tube is observed to be uniform (Scale Bar 2 mm). The SEM picture of the cross section showing the pores on the cross section (Scale Bar 2 mm), FIG. 3B . And SEM picture of a single pore on the scaffold cross section shows interconnected pores (Scale Bar 200 microns), FIG. 3C .
[0074] This invention described herein creates a family of crosslinked urethane-containing polyester (CUPE) for biomedical applications, and particularly soft tissue engineering. The synthesis of CUPE is simple, safe, and cost-effective. CUPEs hold great potential for tissue engineering owing to their controlled degradability, mechanical properties, and excellent biocompatibility. In combination with the layer-by-layer scaffold sheet engineering technique, these materials may be fashioned into small diameter vascular grafts or any other tissue implants with the requisite strength and elasticity to be implanted in the body. The introduction of CUPE should expand the repertoire of available biodegradable polymers to meet the requirements of tissue engineering and other biomedical applications.
[0075] The potential applications of this novel family of polymers can be soft tissue engineering, drug delivery and orthopedic devices. Soft tissue engineering applications may include engineering blood vessels, cardiac tissues, heart valves, skin bladder, tendon, ligament, and meniscus.
[0076] The high-molecular-weight pre-CUPEs and CUPEs can all be used as biomaterials for biomedical applications. The layer-by-layer scaffold sheet engineering design can be used to fabricate any tissue grafts, especially for small diameter blood vessel and cardiac tissue grafts. CUPE can potentially be used for any tissue engineering applications, in particularly soft tissue engineering, such as blood vessels, cardiac tissues, ligaments, tendons, cartilage, bladders, skins, trachea, urethral etc. CUPE can also be used to prepare composite materials with other polymers or inorganic materials or combination of them. One example is CUPE can be hybrid with inorganic hydroxyapatite (HA) to prepare bone implants. Degradation rates and mechanical properties of CUPEs can be controlled by varying the types and combinations of the monomers, and the synthesis conditions. Applications for the bio-polymer described herein include, for example, blood vessels.
[0077] CUPE can be used to prepare micro-spheres or nano-spheres for drug delivery applications. CUPE can be fabricated into scaffolds via any method, such as, salt-leaching, freeze-drying, or 3-D printing. CUPE can be spun into micro-or nano-fibers. The fiber scaffolds can act as extracellular matrix (ECM) for biomedical applications. The biodegradable fibers can be used in any woven or nonwoven applications. The available functional groups on CUPE include hydroxyl and carboxyl groups. These groups can be further used for surface modification or functionalization.
[0078] While specific alternatives to steps and elements of composition of the invention have been described herein, additional alternatives not specifically disclosed but known in the art are intended to fall within the scope of the invention. Thus, it is understood that other ions of the present invention will be apparent to those skilled in the art upon reading the described embodiment and after consideration of the appended claims and drawing. | A method of making a new type of biomaterials, biodegrable crosslinked urethane-containing polyester (CUPE) elastomers and a scaffold-sheet engineering method for tissue engineering applications is provided. CUPEs can be synthesized by forming a linear pre-polymer, which is a polyester, introducing the urethane bonds into polyester using a diisocyanate as a linker, and crosslinking the resulting urethane containing linear polymers to form CUPEs via post-polymerization. This family of polymers, CUPEs, exhibit excellent biocompatibility with desired degradation. Tissue engineering scaffolds made of CUPEs are soft and elastic, and have good mechanical strength. Complex tissue grafts can be constructed by a novel layer-by-layer (LBL) scaffold-sheet engineering design using CUPE sheets. CUPE scaffolds can provide openings for cell to cell communication across scaffold layers and angiogenesis into the depth of the construct. Biomolecules, such as anticoagulants, can be incorporated into the CUPE polymers, increasing their viability as vascular graft scaffolds. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to commonly assigned application having U.S. Ser. No. 10/833,484 and a filing date of Apr. 27, 2004, the subject matter of which is incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Hydrogen fueled vehicles, sometimes referred to as the Freedom Car are receiving considerable interest as part of a plan to reduce the reliance on foreign oil and reduce pollution. There are several current designs of hydrogen cars, with one example being a fuel cell powered vehicle commonly called an FCV. In the FCV, hydrogen is supplied to a fuel cell which produces electricity, which is used to power electric motors that propel the vehicle. Another type of hydrogen car is based upon a hydrogen internal combustion engine (HICE). In both designs, hydrogen is the fuel source with water being generated as the combustion byproduct.
[0003] A central issue with respect to both types of hydrogen vehicles, i.e., the FCV and HICE vehicles, is one of fuel supply. Not only is there a large infrastructure required for hydrogen dispensation, if one considers all the service stations, production and distribution equipment that are required, but there are issues with respect to fuel handling and use of the fuel on the vehicle itself. Before there can be a progression to dedicated fuel cell propulsion systems and hydrogen internal combustion engines, one must foresee a fuel infrastructure.
[0004] Two sources of hydrogen for use in hydrogen cars include the reforming of natural gas (fossil fuels) or from water using electrolysis. Once hydrogen gas is generated it must be stored for subsequent filling of cars or converted into a liquid fuel. Storage of hydrogen gas requires compression and transfer to a cylinder storage vessel. And, if the gaseous hydrogen is stored on the vehicle, such storage cylinders are expensive and they can represent a possible safety hazard in the case of an accident. Alternatively, hydrogen can be stored under low pressure in metal hydride canisters, but, at present, hydride canisters are a lot more expensive than cylinders.
[0005] Liquid methanol and other alcohols have been touted as particularly attractive hydrogen sources because they can be catalytically converted over a catalyst allowing pure hydrogen to be released on demand. On site conversion of liquid fuels to gaseous hydrogen overcomes the disadvantages of gaseous storage. Further, fuels such as methanol, and other alcohols are not overly expensive and there is an infrastructure in place today that allows for handling of liquid fuels. Although methanol and alcohols are suitable as a fuel source, they are consumed in the combustion process. In addition, the byproducts of such catalytic conversion, carbon dioxide and water, cannot easily be converted back to a hydrogen source.
[0006] Representative patents illustrating hydrogen storage and use are as follows:
[0007] Hydrogen Generation by Methanol Autothermal Reforming In Microchannel Reactors , Chen, G., et al, American Institute of Chemical Engineers, Spring Meeting, Mar. 30-Apr. 3, 2003 pages 1939-1943 disclose the use of a microchannel reactor as a means for conducting the endothermic steam-reforming reaction and exothermic partial oxidation reaction. Both reactions are carried out in the gas phase.
[0008] Scherer, G. W. et al, Int. J. Hydrogen Energy,1999, 24,1157 disclose the possibility of storing and transporting hydrogen for energy storage via the catalytic gas phase hydrogenation and the gas phase, high temperature, dehydrogenation of common aromatic molecules, e.g., benzene and toluene.
[0009] US 2004/0199039 discloses a method for the gas phase dehydrogenation of hydrocarbons in narrow reaction chambers and integrated reactors. Examples of hydrocarbons for dehydrogenation include propane and isobutane to propylene and isobutene, respectively. Reported in the publication are articles by Jones, et al, and Besser, et al, who describe the gaseous dehydrogenation of cyclohexane in a microreactor. Jones, et al employ a reported feed pressure of 150 kPa and an exit pressure of 1 Pa.
[0010] U.S. Pat. No. 6,802,875 discloses a hydrogen supply system for a fuel cell which includes a fuel chamber for storing a fuel such as isopropyl alcohol, methanol, benzene, methylcyclohexane, and cyclohexane, a catalytic dehydrogenation reactor, a gas-liquid separation device wherein byproduct is liquefied and separated from the gaseous dehydrogenation reaction product, and a recovery chamber for the hydrogen and dehydrogenated byproduct.
BRIEF SUMMARY OF THE INVENTION
[0011] The present invention provides an improved process for the storage and delivery of hydrogen by the reversible hydrogenation/dehydrogenation of an organic compound wherein the organic compound initially is in its fully or partially hydrogenated state. It is subsequently catalytically dehydrogenated and the reaction product comprised of hydrogen and byproduct dehydrogenated or partially dehydrogenated organic compound is recovered. The improvement in a route to generating hydrogen via dehydrogenation of the organic compound and recovery of the dehydrogenated or partially dehydrogenated organic compound resides in the following steps:
[0012] introducing a hydrogenated organic compound, typically a hydrogenated substrate which forms a pi-conjugated substrate on dehydrogenation, to a microchannel reactor incorporating a dehydrogenation catalyst;
[0013] effecting dehydrogenation of said hydrogenated organic compound under conditions whereby said hydrogenated organic compound is present in a liquid phase;
[0014] generating a reaction product comprised of a liquid phase dehydrogenated organic compound and gaseous hydrogen;
[0015] separating the liquid phase dehydrogenated organic compound from gaseous hydrogen; and,
[0016] recovering the hydrogen and liquid phase dehydrogenated organic compound.
[0017] Significant advantages can be achieved by the practice of the invention and these include:
[0018] an ability to carry out the dehydrogenation of a liquid organic compound and generate hydrogen at desired delivery pressures;
[0019] an ability to carry out dehydrogenation under conditions where the liquid organic fuel source and dehydrogenated liquid organic compound remain in the liquid phase, thus eliminating the need to liquefy or quench the reaction byproduct;
[0020] an ability to employ extended pi-conjugated substrates as a liquid organic fuel of reduced volatility in both the hydrogenated and dehydrogenated state, thus easing the separation of the released hydrogen for subsequent usage;
[0021] an ability to carry out dehydrogenation under conditions where there is essentially no entrainment of the hydrogenated organic compound such as the hydrogenated pi-conjugated substrate fuel source and dehydrogenated reaction product in the hydrogen product;
[0022] an ability to carry out dehydrogenation in small-catalytic reactors suited for use in motor vehicles;
[0023] an ability to generate hydrogen without the need for excessively high temperatures and pressures and thereby reduce safety concerns; and
[0024] an ability to use waste heat from the fuel cell or an IC engine for liberating the hydrogen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a flow diagram of a dehydrogenation process for producing hydrogen from a liquid fuel while maintaining the liquid fuel and dehydrogenated byproduct in liquid phase.
DETAILED DESCRIPTION OF THE INVENTION
[0026] In the process described herein, the fuel source is an organic compound which can be catalytically dehydrogenated forming carbon-carbon unsaturated bonds under liquid phase conditions at modest temperatures. The fuel source can further be described as one that has a low vapor pressure in order to avoid entrainment and loss of liquid fuel in the hydrogen product. Preferably, the vapor pressure is less than 10 millimeters mercury at 200 ° C.
[0027] In copending application U.S. Ser. No. 10/833,484 having a filing date of Apr. 27, 2004 which has been incorporated by reference, Pi-conjugated (often written in the literature using the Greek letter π) several molecules are suggested as fuel sources of hydrogen which are in the form of liquid organic compounds. These Pi-conjugated substrates are characteristically drawn with a sequence of alternating single and double bonds. In molecular orbital theory, the classically written single bond between two atoms is referred to as a σ-bond, and arises from a bonding end-on overlap of two dumbbell shaped “p” electron orbitals. It is symmetrical along the molecular axis and contains the two bonding electrons. In a “double” bond, there is, in addition, a side-on overlap of two “p” orbitals that are perpendicular to the molecular axis and is described as a pi-bond (or “π-bond”). It also is populated by two electrons but these electrons are usually less strongly held, and more mobile. The consequence of this is that these pi-conjugated molecules have a lower overall energy, i.e., they are more stable than if their pi-electrons were confined to or localized on the double bonds.
[0028] The practical consequence of this additional stability isthat hydrogen storage and delivery via catalytic hydrogenation/dehydrogenation processes are less energy intensive and can be carried out at mild temperatures and pressures. This is represented by the following. The most common highly conjugated substrates are the aromatic compounds, benzene and naphthalene. While these can be readily hydrogenated at, e.g., 10-50 atm. at H 2 at ca 150° C. in the presence of appropriate catalysts, extensive catalytic dehydrogenation of cyclohexane and decahydronaphthalene (decalin) at atmospheric pressure is only possible at excessively high temperatures leading to gas phase conditions.
[0029] For the purposes of this description regarding suitable organic compounds suitable as hydrogen fuel sources, “extended pi-conjugated substrates” are defined to include extended polycyclic aromatic hydrocarbons, extended pi-conjugated substrates with nitrogen heteroatoms, extended pi-conjugated substrates with heteroatoms other than nitrogen, pi-conjugated organic polymers or oligomers, ionic pi-conjugated substrates, pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms, pi-conjugated substrates with at least one triple bonded group and selected fractions of coal tar or pitch that have as major components the above classes of pi-conjugated substrates, or any combination of two or more of the foregoing.
[0030] In one embodiment, the pi-conjugated substrates have a standard enthalpy change of hydrogenation, |ΔH H2 o |, to their corresponding saturated counterparts (e.g., the at least partially hydrogenated extended pi-conjugated substrates) of less than about 20 kcal/mol H 2 and generally less than 15.0 kcal/mol H 2 . This value can be determined by combustion methods or by the ab initio DFT method. For purposes of the hydrogenation/dehydrogenation cycle to store and release hydrogen and to re-hydrogenate the substrate, the extended pi-conjugated substrate may exist and be cycled between different levels of full or partial hydrogenation and dehydrogenation as to either the individual molecules or as to the bulk of the substrate, depending upon the degree of conversion of the hydrogenation and dehydrogenation reactions.
[0031] The liquid phase pi-conjugated substrates useful according to this invention may also have various ring substituents, such as -n-alkyl, -branched-chain alkyl, -alkoxy, -nitrile, -ether and -polyether, which may improve some properties such as reducing the melting temperature of the substrate while at the same time not adversely interfering with the hydrogenation/dehydrogenation equilibrium. Preferably, any of such substituent groups would have 12 or less carbons. As discussed below in the section on “Pi-conjugated Substrates with Multiple Nitrogen Heteroatoms” alkyl substituents (and it's expected that also alkoxy substituents) will actually favorably slightly lower the modulus of the heat of hydrogenation, ΔH H2 o .
Extended Pi-Conjugated Substrates
[0032] Classes of extended pi-conjugated substrates suitable for the processes of this invention are further and more specifically defined as follows:
[0033] Extended Polycyclic Aromatic Hydrocarbons (EPAH). For the purposes herein, “extended polycyclic aromatic hydrocarbons” are defined to be those molecules having either (1) a polycyclic aromatic hydrocarbon comprising a fused ring system having at least four rings wherein all rings of the fused ring system are represented as 6-membered aromatic sextet structures; or (2) a polycyclic aromatic hydrocarbon of more than two rings comprising a six-membered aromatic sextet ring fused with a 5-membered ring.
[0034] The EPAH molecules represent a particular class of extended pi-conjugated substrates since their pi electrons are largely delocalized over the molecule. While, on a thermodynamic basis, generally preferred are the larger molecules (i.e., those with considerably more than four rings), the value of the standard enthalpy change of hydrogenation, ΔH H2 o , and thus the ease of reversible hydrogenation can be very dependent on the “external” shape or structure of the EPAH molecule. Fundamentally, the EPAH molecules that have the highest aromatic resonance stabilization energy will have the lowest modulus (absolute value) of the standard enthalpy of hydrogenation, ΔH H2 o . As is taught by E. Clar in “Polycyclic Hydrocarbons” Academic Press, 1964, Chapter 6, it is a general principle that the stability of isomers of fused ring substrates increases with the number of aromatic sextets. For instance anthracene
has one aromatic sextet (conventionally represented by three alternating single and double bonds in a single ring or by an internal circle), as for benzene, while phenanthrene,
has two aromatic sextets, with the result that phenanthrene is more stable by 4.4 kcal/mol (based on the molecules' relative heats of formation).
[0035] For an EPAH of a given number of fused-rings the structural isomer that is represented with the largest number of aromatic sextets and yet remain liquid at reaction temperatures will be preferred as a hydrogenation/dehydrogenation extended pi-conjugated substrate. Non-limiting examples of polycyclic aromatic hydrocarbons or derivatives thereof particularly useful as a fuel source include pyrene, perylene, coronene, ovalene, picene and rubicene.
[0036] EPAH's comprising 5-membered rings are defined to be those molecules comprising a six-membered aromatic sextet ring fused with a 5-membered ring. Surprisingly, these pi-conjugated substrates comprising 5-membered rings provide effective reversible hydrogen storage substrates since they have a lower modulus of the ΔH o of hydrogenation than the corresponding conjugated system in a 6-membered ring. The calculated (PM3) ΔH o for hydrogenation of three linear, fused 6-membered rings (anthracene) is −17.1 kcal/mol H 2 . Replacing the center 6-membered ring with a 5-membered ring gives a molecule (fluorene, C 13 H 10 )
[0037] Non-limiting examples of fused ring structures having a five-membered ring include fluorene, indene and acenanaphthylene.
[0038] Extended polycyclic aromatic hydrocarbons can also include structures wherein at least one of such carbon ring structures comprises a ketone group in a ring structure and the ring structure with the ketone group is fused to at least one carbon ring structure which is represented as an aromatic sextet. Introducing a hydrogenable ketone substituent into a polyaromatic substrate with which it is conjugated, acceptable heats and hydrogen storage capacities are achievable. Thus for the pigment pyranthrone,
having a standard calculated enthalpy of hydrogenation is −14.4 kcal/mol H 2 .
[0039] Extended Pi-conjugated Substrates with Nitrogen Heteroatoms can also be used as a fuel source. Extended pi-conjugated substrates with nitrogen heteroatoms are defined as those N-heterocyclic molecules having (1) a five-membered cyclic unsaturated hydrocarbon containing a nitrogen atom in the five membered aromatic ring; or (2) a six-membered cyclic aromatic hydrocarbon containing a nitrogen atom in the six membered aromatic ring; wherein the N-heterocyclic molecule is fused to at least one six-membered aromatic sextet structure which may also contain a nitrogen heteroatom.
[0040] It has been observed that the overall external “shape” of the molecule can greatly affect the standard enthalpy of hydrogenation, ΔH o . The N heteroatom polycyclic hydrocarbons that contain the greatest number of pyridine-like aromatic sextets will be the most preferred structure and have the lowest modulus of the standard enthalpy of hydrogenation ΔH H2 o structures. The incorporation of two N atoms in a six membered ring (i.e., replacing carbons) provides an even further advantage, the effect on ΔH H2 o depending on the nitrogens' relative positional substitution pattern. A particularly germane example is provided by 1,4,5,8,9,12-hexaazatriphenylene, C 18 H 6 N 6 ,
and its perhydrogenated derivative, C 12 H 24 N 6 system
for which the (DFT calculated) ΔH H2 o of hydrogenation is −11.5 kcal/mol H 2 as compared to the (DFT calculated) ΔH H2 o of hydrogenation of −14.2 kcal/mol H 2 for the corresponding all carbon triphenylene, perhydrotriphenylene system. Another representative example is pyrazine[2,3-b]pyrazine:
where the (DFT calculated) of ΔH H2 o of hydrogenation is −12.5 kcal/mol H 2 .
[0041] Pi-conjugated aromatic molecules comprising five membered rings substrate classes identified above and particularly where a nitrogen heteroatom is contained in the five membered ring provide the lowest potential modulus of the ΔH H2 o of hydrogenation of this class of compounds and are therefore effective substrates for dehydrogenation in a microchannel reactor under liquid phase conditions according to this invention. Non-limiting examples of polycyclic aromatic hydrocarbons with a nitrogen heteroatom in the five-membered ring fitting this class include the N-alkylindoles such as N-methylindole, 1-ethyl-2-methylindole; N-alkylcarbazoles such as N-methylcarbazole and N-propylcarbazole; indolocarbazoles such as indolo[2,3-b]carbazole; and indolo[3,2-a]carbazole; and other heterocyclic structure with a nitrogen atom in the 5- and -6-membered rings such as N,N′,N″-trimethyl-6,11-dihydro-5H-diindolo[2,3-a:2′,3′-c]carbazole, 1,7-dihydrobenzo[1,2-b:5,4-b′]dipyrrole, and 4H-benzo[def]carbazole.
[0042] Extended pi-conjugated substrates with nitrogen heteroatoms can also comprise structures having a ketone group in the ring structure, wherein the ring structure with the ketone group is fused to at least one carbon ring structure which is represented as an aromatic sextet. An example of such structure is the molecule flavanthrone, a commercial vat dye,
a polycyclic aromatic that contains both nitrogen heteroatoms and keto groups in the ring structure, and has a favorable (PM3 calculated) ΔH o of hydrogenation of −13.8 kcal/mol H 2 for the addition of one hydrogen atom to every site including the oxygen atoms.
[0043] Extended Pi-conjugated Substrates with Heteroatoms other than Nitrogen can also be used as a fuel source and for purposes of this description “extended pi-conjugated substrates with heteroatoms other than nitrogen” are defined as those molecules having a polycyclic aromatic hydrocarbon comprising a fused ring system having at least two rings wherein at least two of such rings of the fused ring system are represented as six-membered aromatic sextet structures or a five-membered pentet wherein at least one ring contains a heteroatom other than nitrogen. An example of an extended pi-conjugated substrate with an oxygen heteroatom is dibenzofuran, C 12 H 8 O,
for which the (DFT calculated) ΔH H2 o of hydrogenation is −13.5 kcal/mol H 2 . An example of a extended pi-conjugated substrate with a phosphorous heteroatom is phosphindol-1-ol:
[0044] An example of a extended pi-conjugated substrate with a silicon heteroatom is silaindene:
[0045] An example of a extended pi-conjugated substrate with a boron heteroatom is borafluorene:
[0046] Non-limiting examples of extended pi-conjugated substrates with heteroatoms other than nitrogen include dibenzothiophene, 1-methylphosphindole, 1-methoxyphosphindole, dimethylsilaindene, and methylboraindole.
[0047] Pi-conjugated Organic Polymers and Oligomers Containing Heteroatoms can also be used as a fuel source. For the purposes of this description the, “pi-conjugated organic polymers and oligomers containing heteroatoms” are defined as those molecules comprising at least two repeat units and containing at least one ring structure represented as an aromatic sextet of conjugated bonds or a five membered ring structure with two double bonds and a heteroatom selected from the group consisting of boron, nitrogen, oxygen, silicon, phosphorus and sulfur. Oligomers will usually be molecules with 3-12 repeat units. While there are often wide variations in the chemical structure of monomers and, often, the inclusion of heteroatoms (e.g., N, S, O) replacing carbon atoms in the ring structure in the monomer units, all of these pi-conjugated polymers and oligomers have the common structural features of chemical unsaturation and an extended conjugation. Generally, while the molecules with sulfur heteroatoms may possess the relative ease of dehydrogenation, they may be disfavored in fuel cell applications because of the potential affects of the presence of trace sulfur atoms.
[0048] The chemical unsaturation and conjugation inherent in this class of polymers and oligomers represents an extended pi-conjugated system, and thus these pi-conjugated polymers and oligomers, particularly those with nitrogen or oxygen heteroatoms replacing carbon atoms in the ring structure, are a potentially suitable substrate for hydrogenation. These pi-conjugated organic polymers and oligomers may comprise repeat units containing at least one aromatic sextet of conjugated bonds or may comprise repeat units containing five membered ring structures. Aromatic rings and small polyaromatic hydrocarbon (e.g., naphthalene) moieties are common in these conducting polymers and oligomers, often in conjugation with heteroatoms and/or olefins. For example, a heteroaromatic ladder polymer or oligomer containing repeat units such as:
which contains a monomer with a naphthalene moiety in conjugation with unsaturated linkages containing nitrogen atoms.
[0049] A pi-conjugated polymer or oligomer formed from a derivatised carbazole monomer repeat unit,
can also be used as a fuel source. Other oligomers that contain 5-membered ring structures with nitrogen atoms are also subject of the present invention. For example, oligomers of pyrrole such as:
which has four pyrrole monomers terminated by methyl groups has an ab initio DFT calculated ΔH H2 o of hydrogenation of −12.5 kcal/mol H 2 . Other members of this class of pi-conjugated organic polymers and oligomers which are particularly useful according to this invention as extended pi-conjugated substrates are polyindole, polyaniline, poly(methylcarbazole), and poly(9-vinylcarbazole).
[0050] Ionic Pi-conjugated Substrates can also be used as fuel source, i.e., a hydrogen source. These ionic pi-conjugated substrates are defined as those substrates having pi-conjugated cations and/or anions that contain unsaturated ring systems and/or unsaturated linkages between groups. Pi-conjugated systems which contain a secondary amirie function, HNR 2 can be readily deprotonated by reaction with a strong base, such as lithium or potassium hydride, to yield the corresponding lithium amide or potassium amide salt. Examples of such systems include carbazole, imidazole and pyrrole and N-lithium carbazole. Non-limiting examples of ionic pi-conjugated substrates include N-lithiocarbazole, N-lithioindole, and N-lithiodiphenylamine and the corresponding N-sodium, N-potassium and N-tetramethylammonium compounds.
[0051] Pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms are another form of hydrogen fuel source. For the purposes of this description “pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms” are defined as those molecules having a five-membered or six-membered aromatic ring having two or more nitrogen atoms in the aromatic ring structure, wherein the aromatic ring is not fused to another aromatic ring. The pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms may have alkyl, N-monoalkylamino and N, N-dialkylamino substituents on the ring. A non-limiting example of a pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms is pyrazine.
[0052] Pi-conjugated substrates with triply bonded groups can be used as a fuel source. For the purposes of this description, “pi-conjugated substrates with triply bonded groups” are defined as those molecules having carbon-carbon and carbon-nitrogen triple bonds. The pi-corijugated molecules described thus far comprise atom sequences conventionally written as alternating carbon-carbon single, and carbon-carbon double bonds, i.e., C—C═C—C═C— etc., incorporating, at times, carbon-nitrogen double bonds, i.e., imino groups as in the sequence, C—C═N—C═C—.
[0053] An illustration is provided by 1,4-dicyanobenzene:
which can be reversibly hydrogenated to 1,4-aminomethyl cyclohexane:
[0054] The enthalpy for this reaction, ΔH H2 o , is −6.4 kcal/mol H 2 . Table 1a. provides representative extended polycyclic aromatic hydrocarbon substrates, some of which can be used as a liquid hydrogen fuel source or converted to a liquid by incorporating substituents groups such as alkyl groups on the substrate and relevant property data therefor. Comparative data for benzene (1), naphthalene (2, 3), anthracene (46) and phenanthrene (47).
TABLE 1a Substrate ΔH° H2 (300 K) ΔH° H2 (298 K) T 95% ° C. T 95% ° C. Number Substrate Structure (cal.) (exp.) (cal.) (exp.) 1 −15.6 −16.42 319 318 2 a −15.1 −15.29 244 262 3 b −15.8 −15.91 273 280 6 −14.6 226 7 −13.0 169 22 −13.9 206 26 −52.2 27 −17.9 333 28 −14.4 223 31 −14.1 216 34 −14.2 216 46 −15.8 271 47 −14.8 237 a Heat of hydrogenation to form cis/decalin. b Heat of hydrogenation to form the trans-decalin.
[0055] Table 1b shows extended pi-conjugated substrates with nitrogen heteroatoms some of which may be liquids or converted to liquids and thus suited as a hydrogen fuel source. Property data are included.
TABLE 1b Substrate ΔH° H2 (300 K) ΔH° H2 (298 K) T 95% ° C. T 95% ° C. Number Substrate Structure (cal.) (exp.) (cal.) (exp.) 4 −13.2 −13.37 248 274 5 −15.2 −14.96 268 262 8 −12.2 153 9 −11.9 164 10 −12.5 182 11 −11.2 117 12 −10.6 96 13 −10.7 87 14 −11.4 131 15 −14.4 225 16 −11.5 124 17 −9.7 66 18 −11.7 132 19 −8.7 27 20 −12.1* −12.4* 128 128 21 −12.4 164 23 −14.2 220 24 −14.8 239 25 −12.5 168 30 −12.2 139 35 −13.8 201 36 −15.1 245 37 −12.5 163 38 −15.2 413 39 −9.9 82 40 −8.8 70 41 −6.4 42 −9.0 43 −10.5 88. 53 −13.5 54 −7.7 *Calculated and experimental data, both at 150° C.
[0056] Table 1c shows extended pi-conjugated substrates with heteroatoms other than nitrogen some of which may be liquids or converted to liquids and thus suited for use as fuels. Property data are included. Comparative data for diphenylsilanes also are shown.
TABLE 1c Substrate ΔH° H2 (300 K) ΔH° H2 (298 K) T 95% ° C. T 95% ° C. Number Substrate Structure (cal.) (exp.) (cal.) (exp.) 29 −10.2 52 32 −13.5 197 33 −16.4 285 44 −15.6 275 45 273 55 −17.0 56 −16.4
[0057] Table 1d shows pi-conjugated organic polymers and oligomers some of which may be liquids or converted to liquids and thus suited for use as fuels. Property data are included. Comparative data for phenylene oligomers also are shown.
TABLE 1d Substrate ΔH° H2 (300 K) ΔH° H2 (298 K) T 95% ° C. T 95% ° C. Number Substrate Structure (cal.) (exp.) (cal.) (exp.) 52 −12.5 57 −15.1 48 −16.0 298 49 −15.7 50 −15.6 51 −15.8
[0058] Sometimes one can convert hydrogenated extended pi-conjugated substrates which normally would be solid under reaction conditions to a liquid by utilizing a mixture of two more components. In some cases, mixtures may form a eutectic mixture. For instance chrysene (1,2-benzophenanthrene, m.p. 250° C.) and phenanthrene, (m.p. 99° C.) are reported to form a eutectic melting at 95.5° C. and for the 3-component system consisting of chrysene, anthracene and carbazole (m.p. 243° C.), a eutectic is observed at 192° C. (Pascal, Bull. Soc. Chim. Fr. 1921, 648). The introduction of n-alkyl, alkyl, alkoxy, ether or polyether groups as substituents on the ring structures of the polycyclic aromatic molecules, particularly the use such substituents of varying chain lengths up to about 12 carbon atoms, often can lower their melting points. But, this may be at some cost in “dead eight” and reduced hydrogen capacity. As discussed above, certain substituents, e.g., nitriles and alkynes, can provide additional hydrogen capacity since each nitrile group can accommodate two molar equivalents of hydrogen.
[0059] The dehydrogenation catalysts suited for use in microchannel reactors generally are comprised of finely divided or nanoparticles of metals, and their oxides and hydrides, of Groups 4, 5, 6 and 8, 9, 10 of the Periodic Table according to the International Union of Pure and Applied Chemistry. Preferred are titanium, zirconium of Group 4; tantalum and niobium of Group 5; molybdenum and tungsten of Group 6; iron, ruthenium of Group 8; cobalt, rhodium and iridium of Group 9; and nickel, palladium and platinum of Group 10 of the Periodic Table according to the International Union of Pure and Applied Chemistry. Of these the most preferred being zirconium, tantalum, rhodium, palladium and platinum, or their oxide precursors such as PtO 2 and their mixtures, as appropriate.
[0060] These metals may be used as catalysts and catalyst precursors as metals, oxides and hydrides in their finely divided form, as very fine powders, nanoparticles or as skeletal structures such as platinum black or Raney nickel, or well-dispersed on carbon, alumina, silica, zirconia or other medium or high surface area supports, preferably on carbon or alumina.
[0061] Having described candidates for use a source of hydrogen and their use as fuels for vehicles, their conversion for on site use is described. To facilitate an understanding of the improved step of dehydrogenation of the liquid hydrogen fuel sources described herein, reference is made to FIG. 1 . FIG. 1 illustrates the use of three microchannel reactors with serial flow of a liquid fuel through the reactors. This reactor scheme illustrated in the flow diagram has been designed for to provide a constant volume of hydrogen to be generated within each channel of the microchannel reactors.
[0062] Microchannel reactors, which term is intended by definition to include monolith reactors, are well suited for the liquid phase dehydrogenation process. They offer ability to effect the dehydrogenation of hydrogen fuel sources while obtaining excellent heat transfer and mass transfer. In gas phase dehydrogenation, their main deficiency has been one of excessive pressure drop across the microchannel reactor. Compression of the gaseous reactants comes at a high cost. However, because, in accordance with this invention, the feed to the microchannel reactors is a liquid, the ability to pressurize the reactor becomes easy. One can pump the liquid fuel to a desired reaction pressure. Thus, pressure drop does not become an insurmountable problem as it is in gas phase production of hydrogen. And, as a benefit of the ability to pressurize, it is easy to generate high-pressure hydrogen as a product of the reaction.
[0063] Microchannel reactors and monolith reactors are known in the art. The microchannel reactors are characterized as having at least one reaction channel having a dimension (wall-to-wall, not counting catalyst) of 2.0 mm (preferably 1.0 mm) or less, and in some embodiments 50 to 500 μm. The height and/or width of a reaction microchannel is preferably 2 mm or less, and more preferably 1 mm or less. The channel cross section may be square, rectangular, circular, elliptical, etc. The length of a reaction channel is parallel to flow through the channel. These walls are preferably made of a nonreactive material which is durable and has good thermal conductivity. Most microchannel reactors incorporate adjacent heat transfer microchannels, and in the practice of this invention, such reactor scheme generally is necessary to provide the heat required for the endothermic dehydrogenation. Illustrative microchannel reactors are shown in US 2004/0199039 and U.S. Pat. No. 6,488,838 and are incorporated by reference.
[0064] Monolith supports which may be catalytically modified and used for catalytic dehydrogenation are honeycomb structures of long narrow capillary channels, circular, square or rectangular, whereby the generated gas and liquid can co-currently pass through the channels. Typical dimensions for a honeycomb monolith catalytic reactor cell wall spacing range from 1 to 10 mm between the plates. Alternatively, the monolith support may have from 100 to 800, preferably 200 to 600 cells per squared inch (cpi). Channels or cells may be square, hexagonal, circular, elliptical, etc. in shape.
[0065] In a representative dehydrogenation process, a liquid fuel 2 , such as N-ethyl carbazole, is pressurized by means of a pump (not shown) to an initial, preselected reaction pressure, e.g., 1000 psia and delivered via manifold 4 to a plurality of reaction chambers 6 within a first microchannel reactor 8 . (Overall dehydrogenation pressures may range from 0.2 to 100 atmospheres.) As shown, dehydrogenation catalyst particles are packed within the reactor chambers 6 , although, as an alternative, the catalyst may be embedded, impregnated or coated onto the wall surface of reaction chambers 6 . The reaction channel 6 may be a straight channel or with internal features such that it offers a large surface area to volume of the channel.
[0066] Heat is supplied to the microchannel reactor by circulating a heat exchange fluid via line 10 through a series of heat exchange channels 12 adjacent to reaction chambers 6 . The heat exchange fluid may be in the form of a gaseous byproduct of combustion which may be generated in a hybrid vehicle or hydrogen internal combustion engine or it may be a heat exchange fluid employed for removing heat from fuel cell operation. In some cases, where a liquid heat exchange fluid is employed, as for example heat exchange fluid from a fuel cell, supplemental heat may be added, by means not shown, through the use of a combustion gas or thermoelectric unit. The heat exchange fluid from a PEM (proton exchange membrane) fuel cell typically is recovered at a temperature of about 80° C., which may be at the low end of the temperature for dehydrogenation. By the use of combustion gases it is possible to raise the temperature of the heat exchange fluid to provide the necessary heat input to support dehydrogenation of many of the fuel sources. A heat exchange fluid from fuel cells that operate at higher temperatures, e.g., 200° C. from a phosphoric acid fuel cell, may also be employed.
[0067] In the embodiment shown, dehydrogenation is carried out in microchannel reactor 8 at a temperature of generally from about 60 to 300° C., at some pressure of hydrogen. Dehydrogenation is favored by higher temperatures, elevated temperatures; e.g., 200° C. and above may be required to obtain a desired dehydrogenation reaction rate. Because initial, and partial, dehydrogenation of the liquid fuel source occurs quickly, high pressures are desired in the initial phase of the reaction in order to facilitate control of the liquid to gas ratio that may occur near the exit of the reactor chambers. High gas to liquid ratios in reaction chambers 6 midway to the exit of the reactor chambers can cause the catalyst to dry and, therefore reduce reaction rate. In a favored operation, the residence time is controlled such that Taylor flow is implemented, in those cases where the catalyst is coated onto the wall surface of the reactor, or trickling or pulsating flow is maintained in those cases where the catalyst is packed within the reaction chamber. (The pulsing flow regime is described by many references (e.g. Carpentier, J. C. and Favier, M. AlChE J 1975 21 (6) 1213-1218) for convention reactors and for microchannel reactors by Losey, M. W. et al, Ind. Eng. Chem. Res., 2001, 40, p2555-2562 and is incorporated by reference.) By appropriate control of the gas/liquid ratio, a thin film of liquid organic compound remains in contact with the catalyst surface and facilitates reaction rate and mass transfer of hydrogen from the liquid phase to the gas phase.
[0068] After a preselected initial conversion of liquid fuel in microchannel reactor 8 is achieved, e.g. one-third the volume of the hydrogen to be generated, the reaction product comprised of hydrogen and partially dehydrogenated liquid fuel is sent by line 14 to gas/liquid or phase separator 16 . Hydrogen is removed at high pressure as an overhead via line 18 and a high pressure partially dehydrogenated liquid fuel source is removed as a bottoms fraction via line 20 . High pressure separation is favored to minimize carry over of unconverted liquid hydrocarbon fuel, which typically has a slightly higher vapor pressure than the dehydrogenated byproduct, and contamination of the hydrogen overhead. Advantageously, then the reaction product need not be quenched and thus rendered liquid in order to effect efficient separation of the partially dehydrogenated organic compound from the hydrogen and minimize carryover into the hydrogenated product. This is a favored feature in contrast to those dehydrogenation processes which use reactants such as isopropanol, cyclohexane and decalin where the dehydrogenation reaction products are in the gas phase.
[0069] The bottoms from gas/liquid separator 16 in line 20 is combined and charged to reaction chambers 22 in second microchannel reactor 24 at the same or higher temperature in order to maintain reaction rate. The cooled heat exchange fluid is removed from heat exchange channels 6 via line 26 and returned to the fuel cell, if liquid or, if the hydrogen exchange fluid is combustion gas, then it is often vented to the atmosphere via line 28 .
[0070] On recovery of the bottoms from gas/liquid separator 16 , the resulting and partially dehydrogenated liquid fuel may be further reduced in pressure than normally occurs because of the ordinary pressure drop which occurs in microchannel reactor. The pressure in second microchannel reactor 24 is preselected based upon design conditions but in general a pressure of from 30 to 200 psia can be employed for N-ethyl carbazole. The temperature of the previously but partially dehydrogenated liquid fuel in reaction chambers 22 is maintained in second microchannel reactor. Heat to second microchannel reactor 24 is supplied from heat exchange fluid line 10 via manifold 30 to heat exchange channels 31 . The use of a lower operating pressure in second microchannel reactor 24 than employed in the first microchannel reactor 8 allows for significant dehydrogenation at the design reaction temperature. Again conversion is controlled in second microchannel reactor in order to provide for a desirable liquid to gas ratio particularly as the reaction product approaches the end of the reaction chamber. The reaction product comprised of hydrogen and further partially dehydrogenation is removed via manifold 32 and separated in gas/liquid separator 34 . Hydrogen is removed as an overhead from gas/liquid separator 34 via line 36 and a further dehydrogenated liquid fuel is removed from the bottom of gas/liquid separator 34 via line 38 . Heat exchange fluid is withdrawn via line 39 from microchannel reactor 24 and returned to heat exchange fluid return in line 28 .
[0071] The final stage of dehydrogenation is carried out in third microchannel reactor 40 . The partially dehydrogenated liquid fuel in line 38 is introduced as liquid to reaction chambers 42 at the same or higher temperature, based on design. Heat is supplied for the endothermic reaction by heat exchange fluid in line 10 via manifold 44 to heat exchange channels 45 . As the dehydrogenation approaches equilibrium in final microchannel reactor 40 , i.e., where the final dehydrogenation reaction is carried out at a pressure at the end of the reactor, at or near atmospheric and at even less than atmospheric conditions if this is required to effect the desired degree of dehydrogenation, it is particularly important to maintain Taylor flow or pulsating flow as the case may be. Mass transfer of the hydrogen from the liquid phase to the gas phase at or near atmospheric pressure is quite limited. However, low hydrogen pressures favor completion of the dehydrogenation reaction.
[0072] The reaction product from third microchannel reactor 40 is passed to gas/liquid separator 46 via manifold 48 where hydrogen is recovered as an overhead via line 50 . The dehydrogenated liquid fuel is recovered as a bottoms fraction from gas/liquid separator 46 via line 52 and ultimately is sent to a hydrogenation facility. Then the dehydrogenated liquid fuel is catalytically hydrogenated and returned for service as a liquid fuel source.
[0073] In the event that the hydrogenation product in line 50 contains traces of organic compounds, these may be removed if desired by passing the gas stream through an adsorbent bed (not shown) or an appropriate separator for the trace organic impurity.
[0074] Although, the dehydrogenation process has been described employing 3 microchannel reactors, other apparatus designs and operating conditions may be used and are within the context of the invention. The operation parameters are one of process design. The use of multiple reactors, as described, allows for better control of gas/liquid ratios as dehydrogenation of the liquid fuel occurs in the reaction chambers as well as providing for optimized pressures in dehydrogenation of the various organic fuel sources. | The present invention is an improved process for the storage and delivery of hydrogen by the reversible hydrogenation/dehydrogenation of an organic compound wherein the organic compound is initially in its hydrogenated state. The improvement in the route to generating hydrogen is in the dehydrogenation step and recovery of the dehydrogenated organic compound resides in the following steps: introducing a hydrogenated organic compound to a microchannel reactor incorporating a dehydrogenation catalyst; effecting dehydrogenation of said hydrogenated organic compound under conditions whereby said hydrogenated organic compound is present as a liquid phase; generating a reaction product comprised of a liquid phase dehydrogenated organic compound and gaseous hydrogen; separating the liquid phase dehydrogenated organic compound from gaseous hydrogen; and, recovering the hydrogen and liquid phase dehydrogenated organic compound. | 2 |
BACKGROUND
[0001] 1. Field of the Invention
[0002] The present invention relates generally to an apparatus for particle synthesis and more particularly to an apparatus capable of clean high temperature synthesis of small particles and nanoparticles.
[0003] 2. Technical Background
[0004] Over the years, there has been rapid progress in the areas of electronics, materials science, and nanoscale technologies resulting in, for example, smaller devices in electronics, advances in fiber manufacturing and new applications in the biotechnology field. The ability to generate increasingly smaller, cleaner and more uniform particles is necessary in order to foster technological advances in areas which utilize small particulate matter. The development of new, efficient and adaptable ways of producing small particulate matter becomes more and more advantageous.
[0005] The size of a particle often affects the physical and chemical properties of the particle or compound comprising the particle. For example, optical, mechanical, biochemical and catalytic properties often change when a particle has cross-sectional dimensions smaller than 200 nanometers (nm). When particle sizes are reduced to smaller than 200 nm, these smaller particles of an element or a compound often display properties that are quite different from those of larger particles of the same element or compound. For example, a material that is catalytically inactive in the macroscale can behave as a very efficient catalyst when in the form of nanoparticles.
[0006] The aforementioned particle properties are important in many technology areas. For example, in optical fiber manufacturing, the generation of substantially pure silica and germanium soot particles from impure precursors in a particular size range (about 5-300 nm) has been key in providing optical preforms capable of producing high purity optical fiber. Also, in the field of pharmaceuticals, the generation of particles having certain predetermined properties is advantageous in order to optimize, for example, in vivo delivery, bioavailability, stability of the pharmaceutical and physiological compatibility. The optical, mechanical, biochemical and catalytic properties of particles are closely related to the size of the particles and the size of the compounds comprising the particles. Gas-phase methods of particle generation are attractive, since gas-phase methods typically yield large quantities of high purity particles which are within a desirable size range.
[0007] Particle generators such as aerosol reactors have been developed for gas-phase nanoparticle synthesis. Examples of these aerosol reactors include flame reactors, tubular furnace reactors, plasma reactors, and reactors using gas-condensation methods, laser ablation methods, and spray pyrolysis methods. In particular, hot wall tubular furnace reactors have proven adept for soot particle generation for silica preform production in optical fiber manufacturing. Hot wall tubular furnace reactors normally use resistive heating elements or use burners to supply energy to reactor walls near the reaction zone.
[0008] Induction Soot Generators (ISGs) are examples of hot wall tubular furnace reactors using inductive heating elements to heat the reactor walls. Examples of such ISGs developed for synthesis of silica soot particles for use in optical fiber manufacturing are described in commonly owned US Patent Application Publication 2004/0206127 the disclosure of which is incorporated herein by reference in its entirety. The ISGs described in that reference have inductively heated reactor walls typically made of platinum, rhodium, or a platinumrhodium compound. A description of one embodiment of an ISG in that reference also shows the use of Radio Frequency (RF) electromagnetic energy to heat certain portions of the reaction zone, and mentions the possible use of graphite as a suitable RF susceptor. ISGs have a number of advantages over other tubular soot generators. For example, combustion is not needed for supplying the energy to heat the reactor walls of the reaction zone in order to support the chemical reaction. Also, there is an increased ability to control the process temperature including the reaction temperature due to the increased control of the energy source as compared to generators using burner heating of the walls of the reaction zone.
[0009] However, ISGs do have some disadvantages. For example, the reactor walls of the reaction zone may become damaged due to exposure of the reactor walls to aggressive chemicals, such as chlorine (Cl) and oxygen (O) ions at high temperatures (above 1500° C.). These aggressive environmental conditions are damaging even for reactor walls made from platinum, rhodium, or a platinumrhodium compound. As a result, the mechanical and induction properties of the reactor walls deteriorate over time. Also, this degradation of the reactor wall materials allows platinum and rhodium compounds to contaminate the synthesized particles. When degradation occurs, the reactor wall material must be replaced, which is both costly and time consuming. It would be advantageous to develop an apparatus capable of high temperature particle synthesis where degradation of the reactor walls is minimized and if any degradation occurs, contamination would be isolated from the reaction area.
SUMMARY OF THE INVENTION
[0010] Apparatuses for generating particles are disclosed herein.
[0011] In one embodiment of the present invention, the apparatus comprises at least one vessel having an interior space where material is heated and at least one susceptor which is capable of generating heat from energy supplied by an energy source. The susceptor is disposed such that the interior space of the vessel is heated. The susceptor is separated from the interior space via a barrier layer.
[0012] In another embodiment of the present invention, the apparatus comprises at least one susceptor which is capable of generating heat from electromagnetic energy in the form of microwave heating or laser heating which provides energy to the susceptor thus heating the precursor materials within the interior space. In this embodiment, the barrier layer may be absent.
[0013] In another embodiment of the present invention, the apparatus comprises a plurality of vessels that are connected in sequence. The interior space of each of the plurality of vessels is in fluid communication with the interior space of the next vessel in sequence.
[0014] In another embodiment of the present invention, the apparatus comprises at least one inlet for receiving material and at least one cylindrical vessel in fluid communication with the inlet having an interior space for accommodating reactants. The cylindrical vessel has at least one cylindrical susceptor, wherein the susceptor material is selected from the group consisting of platinum, rhodium, graphite, and a platinumrhodium compound and is capable of being acted upon by electromagnetic energy, generating heat and being disposed such that heat is applied to the interior space. The cylindrical vessel also comprises a barrier layer, wherein the barrier layer material is selected from the group consisting of silica glass and quartz, encasing the cylindrical susceptor wherein a space is present between the cylindrical susceptor and the barrier layer. An energy source is in communication with the cylindrical vessel for providing electromagnetic energy to the cylindrical susceptor.
[0015] It would be advantageous to develop an apparatus capable of high temperature particle synthesis where the susceptors are not exposed to aggressive environmental conditions and where the susceptors could be made from inexpensive materials.
[0016] Additional features and advantages of the invention will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from the description or recognized by practicing the invention as described in the written description and claims hereof, as well as the appended drawings.
[0017] It is to be understood that both the foregoing general description and the following detailed description are merely exemplary of the invention, and are intended to provide an overview or framework to understanding the nature and character of the invention as it is claimed.
[0018] The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiment(s) of the invention and together with the description serve to explain the principles and operation of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The invention is best understood from the following detailed description when read with the accompanying drawing figures.
[0020] FIG. 1 is a schematic view of an apparatus for generating particles according to one embodiment of the invention.
[0021] FIG. 2 is a schematic cross-sectional view of an alternative apparatus for generating particles according to another embodiment of the invention.
[0022] FIG. 3 is a schematic view of an apparatus for generating particles according to another embodiment of the invention having vessels in series.
[0023] FIG. 4 is an exploded schematic view of an apparatus for generating particles according to another embodiment of the invention having vessels in series.
[0024] FIG. 5 is a schematic cross-sectional view of an apparatus for generating particles according to another embodiment of the invention.
[0025] FIG. 6 is a schematic cross-sectional view of an apparatus for generating particles according to another embodiment of the present invention.
DETAILED DESCRIPTION
[0026] As used herein:
[0027] the term “susceptor” refers to any material capable of generating heat when acted upon by energy from an energy source; and
[0028] the term “barrier layer” refers to a layer of material disposed in proximity to a susceptor such that the material helps to protect the susceptor against degradation due to environmental conditions within the interior space.
[0029] Reference will now be made in detail to the present embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.
[0030] In the embodiment illustrated in FIG. 1 , a particle generator 10 is shown having a susceptor 12 formed into a cylindrically shaped vessel comprising an internal surface which defines an interior space 20 extending generally throughout its axial length for accommodating precursor materials. A continuous flow path 16 goes through the interior space within the vessel, whereby the precursor materials can enter the interior space, e.g., at the bottom of the susceptor, and, after undergoing a chemical reaction resulting from the heat generated by the present invention, emerges from the top of the susceptor in the form of the desired particles. Although the particles emerge from the top of the apparatus in this embodiment, the particles could emerge from the apparatus in other orientations, for example the apparatus could also be positioned horizontally or in other orientation optimizing particle generation and/or flow. The susceptor 12 is capable of absorbing incident energy and thus generating heat, and is disposed such that the heat is transferred to the interior space 20 . In this embodiment, the susceptor preferably comprises graphite. A barrier layer 14 , preferably comprising quartz, is located between the susceptor and the interior space. An energy source 18 , shown here as an induction coil, is located in proximity to the vessel for providing energy to the susceptor. Other conventional induction heating systems can be adapted to meet the needs of this embodiment of the invention.
[0031] Although the susceptor 12 is shown in FIG. 1 as being generally cylindrical, the susceptor may be of any shape or size that permits the interior space to accommodate the required amount of precursor material, and permits the arrangement of the energy source, the susceptor of choice and the barrier layer to establish the desired environmental conditions for example, a predetermined temperature range or residence time within the interior space and thus, generate particles from the precursor material having the desired properties.
[0032] Although the susceptor 12 shown in FIG. 1 preferably comprises graphite, susceptor materials may alternatively comprise any substantially electrically conductive material such as, platinum, rhodium or a platinum/rhodium compound such as 80/20 platinum/rhodium. The susceptor material should be chosen as to be capable of generating and withstanding the appropriate amount of heat for the intended particle-generating reaction from energy provided by the corresponding energy source as described below.
[0033] Although the energy source 18 shown in FIG. 1 provides energy to the susceptor 12 via induction heating, the energy source alternatively may be a source of electromagnetic radiation that impinges directly on the susceptor 12 , such radiation being for example, in the Infrared Frequency range, Optical Frequency range or Radio Frequency range.
[0034] An alternative energy source is shown in FIG. 5 . In this embodiment the energy source 18 is a dielectric heating system comprising water-cooled copper electrodes connected to water-cooled copper lines 30 circulating back to a tank circuit. The tank circuit is a combination of inductive and capacitive components that function together as an electronic resonator and hold the particle generator at a particular frequency. As electrical current alternates between these components (at an angular frequency or wavelength determined by the combined value of the components), proportional “heating” is provided in the electrically conductive or semiconductive material placed in the center of the inductor and/or proportional “heating” is provided in any “lossy” dielectric material placed between the conductive plates of the capacitor.
[0035] An alternative energy source is shown in FIG. 6 . In this embodiment a microwave heating system comprises a magnetron as the energy source 18 for distributing microwave energy within a resonant chamber 32 .
[0036] A laser heating system may be used as another alternative heating method. The laser source is a high power laser working in either a pulsed or continuous mode, while the susceptor comprises a heat resistant and chemically nonreactive material with respect to the reaction occurring within the interior space. The laser heating system can be effectively used in small particle generators, such as when the flow rates and particle volume outputs are small for example, in electronic applications and nanotechnology.
[0037] Generally, electromagnetic energy sources allow rapid and precise tuning of the temperature of the reaction within the interior space.
[0038] Although the barrier layer 14 shown in FIG. 1 is preferably quartz, the barrier layer may alternatively comprise silica glass, alumina, ceramic or other materials suitable for protecting the susceptor from degradation due to exposure to heat, chemical reactants or chemical byproducts or mechanical abrasion.
[0039] In the embodiment shown in FIG. 2 , the barrier layer 14 encases the graphite susceptor 12 so as to form an envelope surrounding the susceptor. A space 24 is present between the barrier layer and the susceptor to permit expansion of the susceptor within the envelope allowing for some coefficient of thermal expansion (CTE) mismatches between the susceptor material and the barrier layer material. The barrier layer is hermetically sealed and its interior is evacuated. By having the barrier layer completely envelop the susceptor and having the interior volume evacuated, the susceptor is isolated not only from the chemical reactants (i.e., the precursor materials) that produce the desired particles but also from an oxidizing atmosphere that might lead to the oxidation and/or premature degradation of the susceptor. Even if degradation of the susceptor occurs, the susceptor material will remain trapped within the barrier layer envelope. For example, even if a susceptor comprising graphite is reduced to powder form due to degradation from high temperatures, the susceptor material in powder form can still provide heat to the reactant materials within the interior space, since the susceptor material is contained within the barrier layer envelope.
[0040] In FIG. 5 and FIG. 6 , the barrier layer 14 encases the susceptor 12 . Encasing of the susceptor prevents the oxidation of the susceptor and reaction of the susceptor with precursor materials at high temperatures. Without the barrier layer encasing the susceptors, the susceptor may cause arcing to the plates in the dielectric heating system or inside the resonant chamber of the microwave heating system. Although the susceptor 12 in FIG. 5 and FIG. 6 preferably comprises graphite, susceptor materials may alternatively comprise platinum, rhodium, a platinum/rhodium compound such as 80/20 platinum/rhodium, ceramic materials, quartz and silica glass. In some embodiments such as shown in FIG. 5 and FIG. 6 , when the susceptor comprises ceramic materials, quartz or silica glass, the particle generator may provide high temperature particle synthesis without the need for a barrier layer.
[0041] Generally the barrier layer prevents direct contact of the susceptor with environmental conditions in the interior space which may degrade the susceptor material, such as hot and aggressive chemical conditions. For example, platinum, rhodium, or a platinumrhodium compounds used as susceptor materials in vessels not having the barrier layer have the disadvantage of pitting as Cl and O ions at high temperatures (above 1500° C.) degrade the materials and deteriorate the susceptor material's heat generating capabilities.
[0042] In the embodiments shown in FIG. 3 and FIG. 4 , the particle generator is shown having a plurality of vessels 10 . The plurality of vessels is connected in sequence such that the interior space 20 of each of the plurality of vessels is in fluid communication with the interior space of the next vessel in sequence. As a result, the continuous flow path 16 will be connected and flow through each of the plurality of vessels. The energy source 18 of each of the vessels is independent from each other for individual heating of each of the vessels.
[0043] The configuration shown in FIG. 3 and FIG. 4 allows for at least one of the plurality of vessels to act as a preheater for heating precursor material to a temperature below the temperature required for generating the desired particles. A temperature gradient may be imposed by a particle generator having individual heating capabilities for each of the plurality of vessels. This temperature gradient could permit gradual heating of particularly sensitive and volatile materials in a very controlled fashion.
[0044] Further, in FIG. 4 , the continuous flow path 16 in this embodiment is made deliberately tortuous to increase the residence time of the materials and enhance mixing, thereby yielding material with more uniform temperature, composition, and particle size.
[0045] Openings 26 are provided into the interior space for introducing material into the apparatus at locations needed to achieve the desired particle generation. Turbulent flow is induced by a spacer 28 which has an interior space with a smaller volume capacity than the attached vessels and/or by strategic placing of the openings into the interior space. In this embodiment, the vessels 10 are cylindrical in shape and comprise susceptors 12 which are cylindrical in shape. The barrier layer 14 encases the susceptors. Energy is supplied by an energy source 18 to the susceptors. The energy source is a source of electromagnetic radiation via induction heating of the susceptor, and the heat is transferred to the interior space 20 through the susceptor by thermal conductivity and radiation. The energy is supplied to the susceptors via an induction coil located in proximity to the susceptor. The induction coil may be water-cooled via a cooling system.
[0046] Where the generation of particles occurs is dependent upon factors such as the amount of contact of the precursor materials have with each other, the reaction temperature needed for the reaction to occur and the residence time during which the materials have an opportunity to react. In the case when all precursor materials are mixed together prior to the reaction generating particles, the reaction can begin at the location where the necessary reaction temperature is reached, yielding vapors of desired particles.
[0047] In some situations, one or several of the precursor materials are added right after the heated zone, the reaction can start there, at a temperature lower than the maximum temperature achievable in the interior space of the vessel. The subsequent cooling of this gas causes the vapor of the resulting material to nucleate and condense, forming aerosol particles. This nucleation is a result of molecules colliding, escaping (evaporating) and agglomerating until a critical nucleus size is reached and a particle is formed. The particle sizes are typically in the range between several nanometers and hundreds of nanometers, provided the conditions for particle agglomeration exist, for example, high enough concentration of aerosol monomers.
[0048] This plurality of vessels approach can be used for the generation of multilayered particles. For example, if a first aerosol material has high enough vapor pressure and is chemically inert with respect to the environmental conditions needed to form a second aerosol material, the first aerosol material can be injected into the interior space at any location along the continuous flow path of the particle generator simultaneously with other precursor materials so as to form a multilayered particle.
[0049] The particle generator of the present invention has the advantage of operating temperature capabilities at least up to about 1650° C. in aggressive chemical reactions involving halides without the problems associated with susceptor degradation effects associated with other particle generators, since there is a barrier layer between the at least on susceptor and the interior space. Reaction conditions similar to those described for soot particle generation in US Patent Application Publication 2004/0206127 could be withstood without problems associated with susceptor degradation.
[0050] In the present invention, the temperature capability of the vessel is limited only by the heat resistance of the barrier layer of choice. For example, a barrier layer comprising quartz or comprising silica glass could provide heat resistance for temperatures up to 2000° C. in the interior space. This temperature may be even greater if an inert carrier gas such as helium is used. Using an inert carrier gas enables operation even at the softening temperature of the barrier material. In some applications, other carrier gases such as argon and nitrogen may be used. The ability to use inexpensive susceptor materials is provided by the susceptor material being separated by the barrier layer from conditions in the interior space which may be harsh depending on temperature and chemical interactions. For example, a particle generator of the present invention having susceptors separated from the interior space by a quartz barrier layer may have susceptors made from inexpensive materials for example, graphite.
[0051] As a result, particle synthesis processes can be run very cleanly, without contamination by susceptor decomposition products, hydrocarbon combustion products and/or the presence of oxidizing species and impurities in the interior space. For example, a particle generator of the present invention comprising at least one vessel comprising susceptors separated from the interior space by being encased by an evacuated quartz barrier layer may utilize susceptors made from an inexpensive material, even if that material is susceptible to degradation or susceptible to outgassing. Even in the case where there is a space between the susceptor and the barrier layer which is not evacuated, susceptor degradation byproducts will be trapped in the encasing barrier layer. An evacuated space between the barrier layer and the susceptor helps to maintain the integrity of the susceptor material, even if mechanical degradation of the susceptor occurs. In the embodiments shown in FIG. 3 and FIG. 4 , susceptors comprising tungsten, iron, or other substantially conductive materials, even in liquid form upon heating, can function to provide heat to the interior space. It is preferable to have the susceptor material be stable at high temperatures and able to generate heat upon being acted upon by energy from the energy source.
[0052] As a result, a wide spectrum of gas-phase chemical reactions can be used for high purity particle forming, including oxidation (e.g., forming particles of oxides), reduction (e.g., forming pure metal particles, as well as those consisting of nitrides and carbides), combination and decomposition, and physical reactions such as vaporization and condensation, as well as their combinations.
[0053] For the reasons mentioned above, the particle generator of the present invention has advantages over other particle generators, including ISGs and other tubular generators. Because of the barrier layer and/or alternative electromagnetic energy sources, the present invention permits the use of inexpensive susceptor materials, such as graphite and/or fused silica. Because hot reactants contact only the barrier layer, contamination of the produced particles by products of susceptor decomposition is minimized. As a result, it is possible to run cleaner particle synthesis processes at high temperatures with a harsh chemical environment and/or abrasive environment. Also, corrosion of the susceptor is minimized, thus deterioration of the susceptor's mechanical and heat generating properties are minimized.
[0054] It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. | The present invention relates generally to an apparatus for small particle and nanoparticle synthesis. A durable particle generator capable of high temperature particle synthesis is disclosed. The particle generator is configured as to minimize susceptor degradation associated with harsh reaction conditions. | 2 |
CROSS REFERENCE TO RELATED APPLICATIONS
This is the 35 USC 371 national stage of international application PCT/EP02/02237 filed on Mar. 1, 2002, which designated the United States of America.
FIELD OF THE INVENTION
The present invention relates to a procedure for automatically locating the wheels of a motor vehicle. More particularly, but not exclusively, such a procedure is associated with a tire pressure monitoring system.
BACKGROUND OF THE INVENTION
In point of fact it is already known to permanently monitor tire pressures of a vehicle. These pressure measurements (possibly corrected for the temperature and the aging of the tire or for any other parameter) are processed by a computer. A warning signal is emitted when a tire pressure is abnormal. The computer that processes the pressure measurements may be fitted onto the wheel itself or at any appropriate point in the vehicle.
The pressure measurements are carried out by a specific sensor associated with each wheel. This sensor sends, to a remote computer, the pressure measurement associated with a code that identifies the sensor. Of course, it is necessary for the computer to know how to assign a position on the vehicle to this identifying code. Thus, after processing, the computer must be capable of stating that the pressure measurement associated with the identifying code X comes from the right front wheel (for example). To do this, it is necessary for the computer to learn the position of the sensor and its identifying code.
This learning may be carried out manually. For example, the computer is placed in learning mode and requests the codes of each pressure sensor in a pre-established order. However, this learning procedure is relatively slow and must also be repeated each time a tire is changed. It has the drawback of requiring the driver to input data into the vehicle's computer. If the driver forgets to store the new code after a tire change, there is a risk of an error regarding the position of a wheel with abnormal pressure. This may have serious consequences.
It would seem opportune to automatically carry out this learning procedure during running of the vehicle. In particular, it is already known to correlate a radiofrequency signal from the sensors with a wheel position, or else to position, close to each wheel, low-frequency/radiofrequency antennas that, by two-way communication, make it possible to identify the position of the wheels, etc.
However, these various automatic wheel-position learning methods have the drawback that they require a complex and expensive architecture to be installed (antennas close to the wheels, two-way communication) or mathematical processing that is very complicated and difficult to make reliable (correlation between power of the radiofrequency signal and the wheel position.
SUMMARY OF THE INVENTION
The object of the present invention is to make a correlation between the sensor identifier and its position on the vehicle in an automatic, simple and reliable manner.
For this purpose, the present invention relates to a procedure for automatically locating the wheels of a motor vehicle, characterized in that it consists in:
measuring the temperature of each wheel of the vehicle; and determining the position of the wheels on the vehicle according to the temperature measured.
Thus, the position of a sensor on a vehicle is simply detected according to the temperature (and/or the change in temperature) that it measures. This is because, for example in the case of a front wheel drive vehicle, it has been noticed that the front wheels either heat up more rapidly than the rear wheels or they exhibit greater temperature variations.
Advantageously, the most rapid temperature variations are attributed to the wheels located on the front axle.
However, the procedure according to the invention is not limited to determining the front and rear wheel positions. This is because it is also possible to determine the position of the left and right wheels in the same way.
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects, features and advantages will emerge from the following description, given by way of non-limiting example and with reference to the appended drawings in which:
FIG. 1 is a schematic view showing the positioning of the elements of the device according to the invention on a motor vehicle;
FIG. 2 is a schematic diagram showing the temperature changes in the tires according to their position on the vehicle; and
FIG. 3 is a logic diagram representing the procedure according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
According to the embodiment shown in FIG. 1 , a motor vehicle 10 , moving in the direction of the arrow F (FIG. 1 ), is provided with a system for monitoring the pressure of the tires 12 . For this purpose, each tire 12 is provided with a pressure sensor 11 , designed to send a message to a processing unit 13 . This message comprises, firstly, a code that identifies the sensor 11 and, secondly, a series of data, for example pressure and temperature measurements.
The front axle of the vehicle bears the reference A 1 ( FIG. 1 ) and the rear axle A 2 .
The processing unit 13 analyses the data received and determines whether or not the pressure is normal. If the pressure is abnormal, a warning signal is sent to the driver 14 . The processing unit also determines the position of the wheel on the vehicle according to the identifying code of the sensor that has sent the message.
Of course, in order for the processing unit to be able to associate a position on the vehicle with a sensor-identifying code, this association must be taught to the computer.
Within the context of the present invention, this identifying code/position of the sensor on the vehicle association is performed automatically, for example each time the car is started.
In this regard, it has been noted ( FIG. 2 ) that the temperature of each tire differs according to its position on the vehicle. In particular, for example, during braking BR, for a front wheel drive vehicle moving at a constant speed, the front wheels A 1 exhibit a higher temperature rise (average of the temperatures of the front wheels) than the rear wheels A 2 (average of the temperatures of the rear wheels). One of the heat sources for the tire is, in fact, the rim. The temperature of the tire therefore depends on the variation in the temperature on the rim. Now, during braking, the heat-up of the rims due to the friction of the brakes will be greater at the front than at the rear. Consequently, in the case of braking, the front wheels will be subjected to a greater temperature rise than the rear wheels. The use of this information allows us to differentiate the tires of the front axle from those of the rear axle.
In the absence of braking, the main heat source for the tires is the transmission of the drive torque to the road. Consequently, the set of wheels that heats up the most is that on the drive axle.
The same applies in the case of the right and left tires, which, when turning, undergo different temperature rises.
The procedure according to the invention ( FIG. 3 ) consists in:
a) detecting the occurrence of braking 20 . This braking (indicated schematically by the driver's foot 14 pressing on a brake pedal) is one of the data usually delivered to the processing unit 13 ; b) measuring, 21 , the temperature within each tire, the speed S of movement of the vehicle and the steering wheel angle α, and taking into account the type of drive axle da (front or rear); c) determining, 22 , the temperature variation ΔT between two times t 1 and t 2 (FIG. 2 ); and d) if the temperature variation ΔT exceeds, 23 , a certain threshold Thr, then the temperature measured corresponds to a front tire 24 , otherwise it corresponds to a rear tire 25 .
The temperature variation ΔT between two times t 1 and t 2 may be determined in several ways. For example, it is possible to make:
a comparison of the derivatives of the type:
ⅆ T ⅆ t > 0 and ⅆ T 1 ⅆ t > ⅆ T 2 ⅆ t ;
T 1 being the temperature at time t 1 and T 2 the temperature at time t 2 in the same tire;
or a comparison of the difference of the type:
ⅆ ( T 1 - T 2 ) ⅆ t > 0 ;
or else a comparison of the integrals of the type:
∫ t 1 t 2 T 1 × ⅆ t > ∫ t 1 t 2 T 2 × ⅆ t ;
or else a comparison of the values of the type T 1 >T 2 .
Whatever determination procedure is used, if the temperature variation determined is greater than a threshold Thr, the corresponding wheels are the front wheels (in the case of front wheel drive) and vice versa in the case of rear wheel drive. This threshold Thr is determined on a test bed for each type of vehicle.
When the speed of the vehicle is constant, the highest temperature values are in fact considered as belonging to the same axle. If the vehicle has front wheel drive, this axle is the front axle A 1 .
Likewise, the sensors measuring the most rapid temperature variations are considered as belonging to the same axle (front axle).
In the example described, the procedure according to the invention also makes it possible to determine the position of the right and left wheels. This is because the right and left wheels have different temperatures, for example when turning. Knowing the direction of rotation of turning (for example, the steering wheel angle), it is then possible to determine the position of the right and left wheels. By analysing the steering wheel angles α, in the case of a larger angle on one side (for example on the left because of traffic circles), an unsymmetrical temperature rise between the right side and the left side is detected.
The procedure according to the invention therefore consists in making a front/rear identification and a right/left identification of the wheels on one and the same axle, in combination with an analysis of the steering wheel angles α and the temperature changes. Thus, each wheel of the vehicle is identified.
The procedure according to the invention is carried out automatically at each startup. Once the position of the sensors is acquired with certainty, the identification procedure according to the invention is interrupted.
It is also possible to arrange for the procedure according to the invention to be interrupted after a predetermined delay (for example 15 min) and for a position to be assigned to each sensor on the vehicle.
The present invention also relates to a system for automatically locating the wheels of a motor vehicle 10 , of the type comprising a number of pressure sensors 11 each placed on a wheel 12 of the vehicle and transmitting, to a central processing unit 13 , the pressure values measured in each wheel, and an identifier specific to each sensor. These pressure sensors also measure the temperature T within each wheels and transmit the measured values to the central processing unit 13 . The central processing unit being designed to determine the location of each wheel according to the temperatures measured.
Of course, the present invention is not limited to the embodiment described above. Thus, the procedure according to the invention may be carried out when the vehicle has already traveled a certain distance (or after a time delay) so as to wait until the temperature differences between front and rear (or right and left) wheels have been properly established. | The invention relates to a method for automatically determining the position of the wheels of a motor vehicle ( 10 ), characterised in that it consists in:—measuring ( 21 ) the temperature of each wheel ( 12 ) of the vehicle; and determining ( 23 ) the position of the wheels on the vehicle according to the temperature measured. The invention also relates to a corresponding position-finding device. The device is particularly suitable for monitoring the pressure inside tires. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. §119 from U.S. Provisional Application Serial No. 60/386,377 (filed Jun. 6, 2002), which is incorporated by reference herein as if fully set forth.
BACKGROUND OF THE INVENTION
[0002] This invention pertains to inkjet inks, in particular to inkjet inks comprising self-dispersing pigment formulated for improved optical density.
[0003] Inkjet recording is a printing method wherein droplets of ink are ejected through fine nozzles to form letters or figures on the surface of recording media. Inks used in such recording are subject to rigorous demands including, for example, good dispersion stability, ejection stability, and good fixation to media.
[0004] Both dyes and pigments have been used as colorants for inkjet inks. While dyes typically offer superior color properties compared to pigments, they tend to fade quickly and are more prone to rub off. Inks comprising pigments dispersed in aqueous media are advantageously superior to inks using water-soluble dyes in water-fastness and light-fastness of printed images.
[0005] Pigments suitable for aqueous inkjet inks are in general well-known in the art. Typically, pigments are stabilized by dispersing agents, such as polymeric dispersants or surfactants, to produce a stable dispersion of the pigment in the vehicle. More recently, so-called “self-dispersible” or “self-dispersing” pigments (hereafter “SDP(s)”) have been developed. As the name would imply, SDPs are dispersible in water without dispersants.
[0006] SDPs are often advantageous over traditional dispersant-stabilized pigments from the standpoint of greater stability and lower viscosity at the same pigment loading. This can provide greater formulation latitude in final ink. SDPs, and particularly self-dispersing carbon black pigments, are disclosed in, for example, U.S. Pat. No. 2,439,442, U.S. Pat. No. 3,023,118, U.S. Pat. No. 3,279,935 and U.S. Pat. No.3,347,632. Additional disclosures of SDPs, methods of making SDPs and/or aqueous ink jet inks formulated with SDP's can be found in, for example, U.S. Pat. No. 5,554,739, U.S. Pat. No. 5,571,311, U.S. Pat. No. 5,609,671, U.S. Pat. No. 5,672,198, U.S. Pat. No. 5,698,016, U.S. Pat. No. 5,707,432, U.S. Pat. No. 5,718,746, U.S. Pat. No. 5,747,562, U.S. Pat. No. 5,749,950,U.S. Pat. No. 5,803,959, U.S. Pat. No. 5,837,045, U.S. Pat. No. 5,846,307, U.S. Pat. No. 5,851,280, U.S. Pat. No. 5,861,447, U.S. Pat. No. 5,885,335,U.S. Pat. No. 5,895,522, U.S. Pat. No. 5,922,118, U.S. Pat. No. 5,928,419, U.S. Pat. No. 5,976,233, U.S. Pat. No. 6,057,384, U.S. Pat. No. 6,099,632,U.S. Pat. No. 6,123,759, U.S. Pat. No. 6,153,001, U.S. Pat. No. 6,221,141, U.S. Pat. No. 6,221,142, U.S. Pat. No. 6,221,143, U.S. Pat. No. 6,277,183, U.S. Pat. No. 6,281,267, U.S. Pat. No. 6,329,446, U.S. Pat. No. 6,332,919, U.S. Pat. No. 6,375,317, US2001/0035110, EP-A-1086997, EP-A-1114851, EP-A-1158030, EP-A-1167471, EP-A-1122286, WO01/10963, WO01/25340 and WO01/94476.
[0007] All of the preceding disclosures are incorporated by reference herein for all purposes as if fully set forth.
[0008] In general, the STPs are obtained by reaction of pigments. These reactions often lead to anionic or cationic species on the surface of the pigment. In the case of anionic species such as carboxyl groups, the charge of the anionic group is balanced by a cation. Normally, this cation charge comes from monovalent cations such as sodium, potassium or lithium.
[0009] One way to take advantage of the latitude afforded by SDPs is to load more pigment into the ink formulation to increase optical density (OD). However, it would be even more advantageous to achieve high optical density without increasing the level of colorant.
[0010] Previously incorporated U.S. Pat. No. 6,332,919 and EP-A-1086997 disclose a black inkjet ink comprising an SDP and salts of monovalent cations. It is suggested that the presence of these monovalent salts improves optical density at a given pigment loading.
[0011] Previously incorporated U.S. Pat. No. 6,277,183 discloses a black inkjet ink comprising an SDP ink and a metal oxide, where optical density of the ink is higher when metal oxide is present than when it is absent.
[0012] Previously incorporated U.S. Pat. No. 6,153,001 discloses an example of a black inkjet ink containing an SDP (Microjet® CW1) and 9 ppm calcium. No information is provided on the source or physical state of the calcium or on the nature of the SDP. No suggestion is made of any optical density relationship.
[0013] Previously incorporated U.S. Pat. No. 6,375,317 discloses an inkjet ink comprising an SDP and calcium in an aqueous medium. In the only example in such disclosure, the SDP is functionalized with -phenyl-COONa groups, but no indication of degree of treatment (functionality) is provided. These types of SDPs, however, are typically of higher functionality. In addition, in this example, only about 2 ppm of Ca(OH) 2 is used (about 1.2 ppm Ca). The calcium is said to be added to improve the ejection stability of the inks, and no suggestion is made of any optical density relationship connected to the addition of calcium.
[0014] It is an object of this invention to provided inkjet inks, in particular SDP-containing inkjet inks, with increased optical density, and to provide methods for increasing the optical density and/or stability of such inks.
SUMMARY OF THE INVENTION
[0015] We have found that the addition of small amounts of multivalent cations to an inkjet ink comprising certain SDP colorants can significantly increase the optical density of the printed ink on plain paper. It has also been found that adjustment of the multivalent cation level can enhance the optical density of the printed ink and/or enhance the stability of the ink prior to printing.
[0016] In accord with these findings, the present invention pertains in one aspect to an aqueous inkjet ink comprising:
[0017] an aqueous vehicle;
[0018] a self-dispersing pigment having at least one type of hydrophilic functional group bonded onto a surface of the self-dispersing pigment, the at least one type of hydrophilic functional group comprising a carboxyl group, and having a degree of functionalization of less than about 3 μmol/m 2 ; and
[0019] an effective amount of a multivalent cation.
[0020] The present invention also relates to an improved aqueous inkjet ink comprising:
[0021] an aqueous vehicle; and
[0022] a self-dispersing pigment having at least one type of hydrophilic functional group bonded onto a surface of the self-dispersing pigment, the at least one type of hydrophilic functional group comprising a carboxyl group, and having a degree of functionalization of less than about 3 μmol/m 2 ;
[0023] wherein the improvement comprises that said aqueous ink jet ink further comprises an effective amount of a multivalent cation.
[0024] In another aspect, the present invention pertains to a first method of enhancing the optical density of an aqueous inkjet ink, the aqueous ink jet ink comprising:
[0025] an aqueous vehicle; and
[0026] a self-dispersing pigment having at least one type of hydrophilic functional group bonded onto a surface of the self-dispersing pigment, the at least one type of hydrophilic functional group comprising a carboxyl group, and having a degree of functionalization of less than about 3 μmol/m 2 ;
[0027] wherein said method comprises the step of providing in said aqueous inkjet ink an effective amount of a multivalent cation such that the optical density of the printed ink is greater with said effective amount of multivalent cation(s), as compared to without said multivalent cation.
[0028] In another aspect, the present invention pertains to a second method of enhancing the optical density and/or stability of an aqueous inkjet ink, the aqueous ink jet ink comprising:
[0029] an aqueous vehicle;
[0030] a self-dispersing pigment having at least one type of hydrophilic functional group bonded onto a surface of the self-dispersing pigment, the at least one type of hydrophilic functional group comprising a carboxyl group, and having a degree of functionalization of less than about 3 μmol/m 2 ; and
[0031] an amount of a multivalent cation;
[0032] wherein said method comprises the step of adjusting the total amount of multivalent cation(s) in said aqueous inkjet ink such that the optical density of the printed ink is greater with said adjusted level of multivalent cation(s), and/or the stability of said aqueous inkjet ink is enhanced, as compared to without said adjusted level.
[0033] As used above and otherwise herein, “degree of functionalization” refers to the amount of hydrophilic groups present on the surface of the SDP per unit surface area, measured in accordance with the method described further herein.
[0034] As also used above and otherwise herein, an “effective amount” of a multivalent cation is an amount required to achieve an improvement of the optical density of the printed ink. In the context of the aqueous inkjet ink, improved aqueous inkjet ink and first method described above, the improvement is compared to an aqueous inkjet ink without the presence of the multivalent cation. In the context of the second method described above, the improvement is compared to the unadjusted level of the multivalent cation.
[0035] The choice of multivalent cation and the effective amount needed to improve optical density and/or stability is readily determined for each ink as provided for herein.
[0036] These and other features and advantages of the present invention will be more readily understood by those of ordinary skill in the art from a reading of the following detailed description. It is to be appreciated that certain features of the invention which are, for clarity, described above and below in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. In addition, references to in the singular may also include the plural (for example, “a” and “an” may refer to one, or one or more) unless the context specifically states otherwise.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0037] Self-Dispersible Pigments (SDPs)
[0038] As indicated previously, SDPs are in a general sense well known to those of ordinary skill in the art, as exemplified by the numerous incorporated references listed above.
[0039] Typically, SDPs are pigments whose surface has been treated or modified to render them self-dispersible in water such that no separate dispersant is needed. The pigments may be black, such as carbon black, or may be colored pigments such as PB 15:3 and 15:4 cyan, PR 122 and 123 magenta, and PY 128 and 74 yellow.
[0040] Suitable SDPs in the context of the present invention are those in which are treated so as to bond at least one type of hydrophilic functional to the pigment surface. The hydrophilic functionality comprises a hydrophilic carboxyl group (—COOM), or a combination of —COOM and —OM groups, wherein M is a monovalent cation such as hydrogen, alkali metal, ammonium or organic ammonium. The hydrophilic group can be attached by direct bonding to the surface or attached through other atomic group(s). Examples of attachment of hydrophilic groups through other atomic group(s) include —R—COOM, where the group R represents aryl or alkyl. Examples of the alkali metal include lithium, sodium and potassium, rubidium and cesium. Examples of the organic ammonium include mono-, di- or trimethylammonium, mono-, di- or triethylammonium, and mono-, di- or trimethanolammonium.
[0041] More specifically, this surface-treated pigment may be prepared by grafting a functional group or a molecule containing a functional group onto the surface of the pigment, or by physical treatment (such as vacuum plasma), or by chemical treatment (for example, oxidation with ozone, hypochlorous acid or the like). A single type or a plurality of types of hydrophilic functional groups may be bonded to one pigment particle. The type and the degree functionalization may be properly determined by taking into consideration, for example, dispersion stability in ink, color density, and drying properties at the front end of an ink jet head.
[0042] Preferably, the SDP of the present invention is functionalized with hydrophilic groups at a level of less than about 3 μmol/m 2 , more preferably less than about 1.8 μmol/m 2 , even more preferably less than about 1.5 μmol/m 2 .
[0043] Preferably, the hydrophilic functional group(s) on the SDP are primarily is carboxyl groups, or a combination of carboxyl and hydroxyl groups; even more preferably the hydrophilic functional groups on the SDP are directly attached and are primarily carboxyl groups, or a combination of carboxyl and hydroxyl.
[0044] Preferred pigments usable in the present invention may be produced, for example, by a method described in previously incorporated WO01/94476. Carbon black treated by the method described in this publication has a high surface-active hydrogen content that is neutralized with base to provide very stable dispersions in water. Application of this method to colored pigments is also possible.
[0045] A wide variety of organic and inorganic pigments, alone or in combination, are known in the art as suitable for inkjet. As with any pigmented inkjet ink, care must be taken to ensure that the pigment particles are small enough to avoid clogging or plugging the orifice of the nozzles that will be used to fire the ink. Small pigment particles also have an influence on the stability of the pigment dispersion, which is critical throughout the life of the ink.
[0046] Useful particle size is typically in the range of from about 0.005 micron to about 15 micron. Preferably, the pigment particle size should range from about 0.005 to about 5 micron, more preferably from about 0.005 to about 1 micron, and most preferably from about 0.005 to about 0.3 micron.
[0047] The levels of SDPs employed in the instant inks are those levels that are typically needed to impart the desired OD to the printed image. Typically, SDP levels are in the range of about 0.01 to about 10% by weight of the ink.
[0048] Multivalent Cation
[0049] The inks of this invention comprise one or more multivalent cations. The effective amounts needed in a particular situation can vary, and some adjustment, as provided for herein, will generally be necessary.
[0050] “Multivalent” indicates an oxidation state of two or more and, for an element “Z”, are typically described as Z 2+ , Z 3+ , Z 4+ and so forth. For brevity, multivalent cations may be referred to herein as Z x . The multivalent cations are preferably soluble in the aqueous ink vehicle and preferably exist in a substantially ionized state. The multivalent cations should be in a form where they are free and available to interact with ink components, in particular the SDP. A multivalent cation in unavailable form, for example Z x tightly bound as a refractory oxide, is not considered a multivalent cation for the purposes of this invention.
[0051] Z x includes, but is not limited to multivalent cations of the following elements: Mg, Ca, Sr, Ba, Sc, Y, La, Ti, Zr, V, Cr, Mn, Fe, Ru, Co, Rh, Ni, Pd, Pt, Cu, Au, Zn, Al, Ga, In, Sb, Bi, Ge, Sn, Pb. In one embodiment, the multivalent cation is not Ca. In another embodiment, the multivalent cation comprises at least one of Ca, Ba, Ru, Co, Zn and Ga. In yet another embodiment, the multivalent cation comprises at least one of Ba, Ru, Co, Zn and Ga. In a preferred embodiment, Z x comprises a trivalent cation.
[0052] Z x can be incorporated into ink by addition in a salt form or by addition in an alkaline form and used as a base in the adjustment of the ink pH. As with any dispersion, especially one that is ionically stabilized, the presence of large amounts of Z x can be destabilizing. The effective levels of Z x needed for the instant inks are below that which cause instability or other problems.
[0053] There is no particular lower limit of Z x , although minimum levels contemplated by the instant invention are levels greater than trace or incidental amounts. Generally, there is at least about 2 ppm, commonly at least about 4 ppm, and even 10 ppm or more of multivalent in the ink. Likewise, there is no particular upper limit except as dictated by stability or other ink properties. At some level, though, there is no additional OD gain with increasing Z x . In some cases, too much Z x may cause the OD to decrease again. In general, beneficial effects are achieved with less than about 200 ppm of Z x , and typically even less than about 1 00 ppm.
[0054] Although the preceding discussion of Z x in terms of weight percent is provided for the sake of simple, concrete guidance, it will be appreciated from the examples herein after that the appropriate levels of multivalent cations are related in a more complex way to factors such as molar equivalents, atomic weight, valence state; and also, to the amount SDP in the ink and its level of treatment.
[0055] Thus a preferred method for considering multivalent cation content is by adjusted equivalents of Z x per 100 equivalents of surface function. The amount of Z present is adjusted (multiplied by) the valence state (x). An equation can be written as follows:
Adjusted Z per 100 surface function = 100 ( equivalents Z ) ( x ) equiv . of surface funct .
[0056] When Z x comprises more than one species of multivalent cation, the adjusted Z per 100 surface function is the sum of adjusted Z for all Z x species present. Preferred levels of adjusted Z per 100 surface function range between about 0.5 to 20, and more preferably between about 0.8 to 12.
[0057] In the preferred embodiment, the carboxyl functional group will, in general, be associated predominately with monovalent (M) counterions, with only a minor amount of cationic species present in the ink being Z x . In an especially preferred embodiment, M is predominately potassium, rubidium or cesium or any combination thereof.
[0058] Aqueous Medium
[0059] The aqueous vehicle is water or a mixture of water and at least one water-soluble organic solvent. Selection of a suitable mixture depends on requirements of the specific application, such as desired surface tension and viscosity, the selected colorant, drying time of the ink, and the type of substrate onto which the ink will be printed. Representative examples of water-soluble organic solvents that may be selected are disclosed in U.S. Pat. No. 5,085,698 (incorporated by reference herein for all purposes as if fully set forth).
[0060] If a mixture of water and a water-soluble solvent is used, the aqueous vehicle typically will contain about 30% to about 95% water with the balance (i.e., about 70% to about 5%) being the water-soluble solvent. Preferred compositions contain about 60% to about 95% water, based on the total weight of the aqueous vehicle.
[0061] The amount of aqueous vehicle in the ink is in the range of about 70% to about 99.8%, preferably about 80% to about 99.8%, based on total weight of the ink.
[0062] Other Ingredients
[0063] The inkjet ink may contain other ingredients as are well known in the art. For example, anionic, nonionic, cationic or amphoteric surfactants may be used. In aqueous inks, the surfactants are typically present in the amount of about 0.01 to about 5%, and preferably about 0.2 to about 2%, based on the total weight of the ink.
[0064] Co-solvents, such as those exemplified in U.S. Pat. No. 5,272,201 (incorporated by reference herein for all purposes as if fully set forth) may be included to improve pluggage inhibition properties of the ink composition.
[0065] Biocides may be used to inhibit growth of microorganisms.
[0066] Other known additives may also be added to improve various properties of the ink compositions as desired. For example, penetrating agents such as glycol ethers and 1,2-alkanediols may be added to the formulation.
[0067] Glycol ethers include ethylene glycol monobutyl ether, diethylene glycol mono-n-propyl ether, ethylene glycol mono-iso-propyl ether, diethylene glycol mono-iso-propyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol mono-t-butyl ether, diethylene glycol mono-n-butyl ether, triethylene glycol mono-n-butyl ether, diethylene glycol mono-t-butyl ether, 1-methyl-1-methoxybutanol, propylene glycol mono-t-butyl ether, propylene glycol mono-n-propyl ether, propylene glycol mono-iso-propyl ether, propylene glycol mono-n-butyl ether, dipropylene glycol mono-n-butyl ether, dipropylene glycol mono-n-propyl ether, and dipropylene glycol mono-iso-propyl ether.
[0068] 1,2-Alkanediols are preferably 1,2-C1-6 alkanediols, most preferably 1,2-hexanediol.
[0069] The amount of glycol ether(s) and 1,2-alkanediol(s) added must be properly determined, but is typically in the range of from about 1 to about 15% by weight and more typically about 2 to about 10% by weight, based on the total weight of the ink.
[0070] Inclusion of sequestering (or chelating) agents such as ethylenediamine-tetraacetic acid (EDTA), iminodiacetic acid (IDA), ethylenediamine-di(o-hydroxyphenylacetic acid) (EDDHA), nitrilotriacetic acid (NTA), dihydroxyethylglycine (DHEG), trans-1,2-cyclohexanediaminetetraacetic acid (CyDTA), dethylenetriamine-N,N,N′,N″, N″-pentaacetic acid (DTPA), and glycoletherdiamine-N,N,N′,N′-tetraacetic acid (GEDTA), and salts thereof, may be advantageous.
[0071] In addition, binders such as polyurethanes may also be added.
[0072] Ink Properties
[0073] Jet velocity, separation length of the droplets, drop size and stream stability are greatly affected by the surface tension and the viscosity of the ink. Pigmented inkjet inks suitable for use with ink jet printing systems should have a surface tension in the range of about 20 dyne/cm to about 70 dyne/cm, more preferably about 25 to about 40 dyne/cm at 25° C. Viscosity is preferably in the range of about 1 cP to about 30 cP, more preferably about 2 to about 20 cP at 25° C. The ink has physical properties compatible with a wide range of ejecting conditions, i.e., driving frequency of the pen and the shape and size of the nozzle. The inks should have excellent storage stability for long periods. Further, the ink should not corrode parts of the inkjet printing device it comes in contact with, and it should be essentially odorless and non-toxic. Preferred inkjet printheads include those with piezo and thermal droplet generators.
EXAMPLES
[0074] Evaluation
[0075] OD measurements were taken from images made by an inkjet printer such as an Epson Stylus Color 980 printer (quality mode, 720 dpi). The images consisted of a sequence of 1 cm squares printed on plain paper, such as Hammermill Copy Plus. The percent ink coverage was chosen to maximize OD, but was no greater than 100% coverage. Nine squares were printed with each ink. Five different points within each square were measured for OD (with, for example, a Greytag spectro-densiometer); the OD recorded for each square was the highest OD value of these five measurements. The overall OD reported is the average of these nine individual OD values.
[0076] Inks of the instant invention are preferably storage stable for long periods without substantial increase in viscosity or particle size. Long-term storage is sometimes predicted from short-term exposure to elevated temperature in a closed container for a period or days or weeks (e.g. 60° C. for 7 days).
[0077] Determination of Degree of Functionalization (Acid Value)
[0078] The acid value of the SDP in these examples was determined by the equivalent moles of base (in this case KOH) required to neutralize the treated pigment to a pH of 7. As the surface hydrophilic groups are substantially all acidic, the acid value also equals the degree of functionalization.
[0079] The neutralized mixture was purified by ultra-filtration to remove free acids, salts, and contaminants. The purification process was performed to repeatedly wash pigment with de-ionized water until the conductivity of the mixture leveled off and remained relatively constant. Normally a large quantity of de-ionized water ranging from three- to ten-fold of the mixture volume was needed to achieve pigment purification.
[0080] After pigment was purified, the equivalent moles of potassium ions remaining on pigment was determined by atomic absorption (M) analysis using a Perkin Elmer model AA Analyst 300 Atomic Absorption Spectrometer configured with the AS-90 autosampler, AS-90/AS-91 controller, and Lumina lamps for potassium. The content was typically indicated as milligrams of metal counterion per kilogram of SDP, or ppm based on weight. Inductive Coupled Plasma (ICP) analysis was used to independently verify the counterion content; the values for ICP and AA were comparable. The following equations convert ppm into mmoles/g of pigment and μmoles/M 2 of pigment surface: mmoles/g=(ppm/AW)/(1000 g/Kg×pigment %/100), wherein AW is atomic weight of the metal; and μmoles/m2=mmoles/g×(1g/SA)×1000 (μmole/mmole), wherein SA is the pigment surface area in m 2 per gram.
[0081] Pigment Dispersion 1
[0082] Carbon black (Nipex 1801Q, Degussa, surface area=260 m 2 /g) was treated with ozone according to the procedure described in WO0194476 until the desired level of surface functionalization was achieved. During the procedure, the dispersion was neutralized with KOH. The final concentration of pigment was 16.2%. The measured potassium counter ion in the dispersion after ultrafiltration was 2,614 ppm, which indicated a degree of surface functionalization of 0.41 mmole/g of pigment or 1.6 μmol/m 2 of pigment surface.
[0083] Pigment Dispersion 2
[0084] The procedure of pigment dispersion 1 was repeated, except with a lesser degree of treatment. The final concentration of pigment was 14.7%. The measured potassium in the dispersion after ultrafiltration was 1306 ppm, which indicates a degree of surface functionalization of 0.23 mmole/g or 0.90 μmol/m 2 .
[0085] Pigment Dispersion 3
[0086] The procedure of pigment dispersion 1 was repeated. The final concentration of pigment was 13.2 wt % after ultrafiltration. The measured potassium in the dispersion at a pigment concentration of 9.4 wt % was 1090 ppm, which indicates a degree of surface functionalization of 0.29 mmole/g or 1.1 μmol/m 2 .
[0087] Ink Formulation
[0088] Inks were made according to the general formulation below, with the appropriate multivalent cation added as indicated for each example. In each case, the weight percent pigment was 6.5. The multivalent cation was first dissolved in water and added to the formulation as the solution. Ingredients were added together, with stirring, in the sequence shown. After all ingredients were added, the ink was stirred for at least another 40 minutes, then filtered through a 2.5 micron filter. The final pH of the ink was adjusted to 8.0 with triethanolamine, as needed. Final counter ion concentrations in the ink varied from 0.035 to 0.02 adjusted equivalents per Kg of pigment (1 mole of divalent ions is counted as 2 adjusted equivalents).
TABLE 1 Ink Formulation-1 Ingredients Weight % SDP dispersion 6.5 (Pigment Dispersion 1 or 2) Glycerol 9.5 Ethylene glycol 6.0 1-2 hexanediol 4.0 Surfynol ® TG (surfactant) 0.5 Sodium EDTA 0.1 (as 5% solution) Proxel ® (biocide) 0.2 Multivalent cation solution As indicated for each example Water Balance to 100%
[0089] [0089] TABLE 2 Ink Formulation-2 Ingredients Weight % SDP dispersion 3.5 (Pigment Dispersion 3) Glycerol 12.0 Ethylene glycol 6.0 1-2 hexanediol 5.0 Surfynol ® TG (surfactant) 0.1 Sodium EDTA 0.1 (as 5% solution) Multivalent cation solution As indicated for each example Water Balance to 100%
[0090] Results
[0091] Examples 1-9 and Control 1 (C1) in the following table were made with pigment dispersion 1.
TABLE 3 Tests of Ink from Polymer Dispersion 1 Amt Adj. Z per solution (1) in gm ppm Adj. Equiv 100 Pigment EX Z x added per 100 gm ink Z x in ink Per Kg Pigment OD OD Std. Dev. Surface Function C1 none — 0 1.490 0.0146 0 1 Ca 1.14 4.6 0.0035 1.513 0.0112 0.85 2 Ca 3.42 14 0.0100 1.524 0.0120 2.4 3 Ca 5.20 23 0.0175 1.494 0.0071 4.2 4 Zn 1 8.5 0.004 1.534 0.0160 0.97 5 Zn 3 25.2 0.012 1.533 0.0125 2.9 6 Zn 5 42.4 0.020 1.522 0.0078 4.8 7 Ba 0.07 15.1 0.0029 1.500 0.018 0.7 8 Ba 0.21 45.3 0.0088 1.521 0.020 2.13 9 Ba 0.36 75.5 0.015 1.521 0.0093 3.63
[0092] The “Adj. X” column is calculated as the value of the “Adj. Equiv.” column divided by th edegree of surface functionalization (in mmoles/g pigment) for dispersion 1 times 100. Specifically for Examples 1-9, the “Adj. Z” column is thus equal to the (“Adj. Equiv” column×100)/0.41.
[0093] Example 10-24 and Control 2 (C2) in the following table were made with Pigment Dispersion 2.
TABLE 4 Tests of Ink from Polymer Dispersion 2 Amt Adj. Z per solution (2) in gm Ppm Adj. Equiv 100 Pigment EX Zx added per 100 gm ink Z x in ink Per Kg Pigment OD OD Std Dev. C2 none 0 1.625 0.0084 0 10 Ca 1.14 4.6 0.0035 1.663 0.0176 1.4 11 Ca 3.42 14 0.0100 1.650 0.0110 4.2 12 Ca 5.20 23 0.0175 1.642 0.0110 7.4 13 Zn 1 8.5 0.004 1.658 0.0110 1.7 14 Zn 3 25.2 0.012 1.633 0.008 5.1 15 Zn 5 42.4 0.020 1.655 0.011 8.4 16 Ru 1.3 8.75 0.004 1.640 0.011 1.7 17 Ru 3.9 26.25 0.012 1.663 0.016 5.1 18 Ru 6.5 43.75 0.02 1.668 0.01 8.4 19 Co 1.3 5.1 0.004 1.678 0.016 1.7 20 Co 3.9 15.3 0.012 1.683 0.018 5.1 21 Co 6.5 25.1 0.02 1.678 0.013 8.4 22 Ga 1.3 6.0 0.004 1.690 0.011 1.7 23 Ga 3.9 18.0 0.012 1.683 0.02 5.1 24 Ga 6.5 30.0 0.02 1.678 0.0117 8.4
[0094] The “Adj. Z” column is calculated as the value of the “Adj. Equiv.” column divided by the degree of surface functionalization (in mmoles/g pigment) for dispersion 2 times 100. Specifically for Examples 10-24, the “Adj. Z” column is thus equal to the (“Adj. Equiv” column×100)/0.23.
[0095] Examples 25-30 and Control 3 (C3) in the following table were made with Pigment Dispersion 3.
TABLE 5 Tests of Ink from Polymer Dispersion 3 Amt Adj. Z per solution (3) in gm ppm Adj. Equiv 100 Pigment EX Z x added per 100 gm ink Z x in ink Per Kg Pigment OD OD Std. Dev. Surface Function C3 none — 0 0 1.510 0.001 0 25 Cu 0.70 0.2 0.002 1.515 0.002 0.7 26 Cu 4.20 1.4 0.012 1.518 0.002 4.1 27 Cu 25.20 8.2 0.072 1.520 0.001 24.8 28 Sn 0.70 0.4 0.004 1.515 0.002 1.3 29 Sn 4.20 2.4 0.024 1.521 0.001 8.2 30 Sn 25.20 14.4 0.144 1.525 0.001 49.2
[0096] The “Adj. Z” column is calculated as the value of the “Adj. Equiv.” column divided by the degree of surface functionalization (in mmoles/g pigment) for dispersion 3 times 100. Specifically for Examples 25-30, the “Adj. Z” column is thus equal to the (“Adj. Equiv” column×100)/0.29.
[0097] There was a significant increase in OD with the addition of appropriate amounts of multivalent cations, as demonstrated by the examples relative to the controls. The effect was more pronounced in SDP with lower treatment level. The effect was also somewhat more pronounced with trivalent cations than with divalent cations. The effect levels off once a certain amount of Z x was reached; additional Z x did not seem to help and in some cases OD was even reduced. | This invention pertains to aqueous inkjet inks containing self-dispersing pigments and effective amounts of one or more multivalent cations, said inks having increased optical density when printed. | 2 |
BACKGROUND OF THE INVENTION
[0001] The present invention is directed to air moving or air handling units, and especially to air handling devices in which blower housing apparatuses are contained, such as in an HVAC (Heating Ventilating Air Conditioning) system.
[0002] Air handling units for HVAC systems are typically constrained in their physical dimensions to conform with predetermined industry standards. The relevant industry standards are predicated, at least in part, upon a requirement that some components of HVAC systems must be amenable to installation in a residential attic, closet or other restricted space. Such space-restricted components must, therefore, be restricted to a particular “footprint” and be passable through an access opening to the attic, closet or other restricted space. Space utilization within such components is therefore a constraint in their design. Air handling units for use in a residential HVAC system are, by way of example and not by way of limitation, among such components.
[0003] Typical air handling units include an evaporator unit and a blower unit. In some air handling units if a blower unit is placed too close to an associated evaporator unit a problem is created because condensate can be entrained in high velocity air flow from the evaporator unit through the blower unit and cause water damage in the space served by the HVAC system, such as a home or an office. A contributing factor to this problem is the typical bluff shape presented by the housing containing the blower unit to approaching air from the evaporator unit. The bluff shape restricts the air flow channel as the air flows from the evaporator, between the blower housing and a surrounding cabinet, through the blower unit and to the exhaust area of the air handling unit. Such a restricting of air flow area increases speed of the air flow and thereby permits entrained moisture to be carried through the air handling unit to the area being serviced by the HVAC system. As a result of these factors, blower housings are typically placed a separation distance from evaporator units to permit entrained moisture to fall out of air before the air enters the blower unit. Such a design occupies space unnecessarily. Further, the restricted air flow required by such designs contributes to lower static pressure performance and lower efficiency.
[0004] There is a need for a design for an air handling unit that occupies no greater “footprint” than presently dictated by industry standards, that still passes through predetermined openings such as openings accessing attics, closets or other restricted spaces, and that permits freer air flow to enhance static pressure performance and efficiency without entraining moisture in flowing air provided to a serviced area.
SUMMARY OF THE INVENTION
[0005] A housing cooperates with an air mover rotating about a rotation axis to move air received from an approach to an exhaust. The approach is generally oriented about an axis intersecting the housing at upstream and downstream limits. The housing presents an interior surface establishing radii between the axis and the surface. The radii have a generally constant radial value across a width in planes containing the axis in a first zone between the downstream limit and a first surface locus, and in a second zone between a second surface locus and the exhaust. The radii vary between a smallest and a largest radius across the width in planes containing the axis in a variance zone upstream of the axis. The smallest radius is less than the radial value at the first and second surface loci. The largest radius is larger than the radial value at at least one of the first and second surface loci.
[0006] It is, therefore, an object of the present invention to provide an air handling unit that occupies no greater “footprint” than presently dictated by industry standards, that still passes through predetermined openings such as openings accessing attics, closets or other restricted spaces, and that permits freer air flow to enhance static pressure performance and efficiency without entraining moisture in flowing air to a serviced area Further objects and features of the present invention will be apparent from the following specification and claims when considered in connection with the accompanying drawings, in which like elements are labeled using like reference numerals in the various figures, illustrating the preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a schematic diagram of representative air handling equipment in which the present invention may be advantageously employed.
[0008] FIG. 2 is a side view of an air handling unit employing the teachings of the present invention.
[0009] FIG. 3 is a bottom view of the air handling unit illustrated in FIG. 2 taken in direction 3 - 3 in FIG. 2 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0010] The term “locus” is intended herein to indicate a place, location, locality, locale, point, position, site, spot, volume, juncture, junction or other identifiable location-related zone in one or more dimensions. A locus in a physical apparatus may include, by way of example and not by way of limitation, a corner, intersection, curve, line, area, plane, volume or a portion of any of those features. A locus in an electrical apparatus may include, by way of example and not by way of limitation, a terminal, wire, circuit, circuit trace, circuit board, wiring board, pin, connector, component, collection of components, sub-component or other identifiable location-related area in one or more dimensions.
[0011] FIG. 1 is a schematic diagram of representative air handling equipment in which the present invention may be advantageously employed. In FIG. 1 , a representative residential air handling unit 10 is of the sort of air handling unit appropriate, by way of example and not by way of limitation, for use with a heat pump HVAC system. Air handling unit 10 is enclosed in a cabinet 12 and includes an evaporator device 14 and an air handling device or blower device 16 . Evaporator device 14 and blower device 16 are situated generally symmetrically with respect to a flow axis 30 . An air filter 18 closes a first end 19 of cabinet 12 .
[0012] Drain pans 20 , 22 permit operation of air handling unit 10 with flow axis 30 oriented vertically with blower device 16 above evaporator device 14 or operation of air handling unit 10 in a horizontal orientation with flow axis 30 oriented horizontally.
[0013] Evaporator device 14 includes a first evaporating panel 24 and a second evaporating panel 26 . Evaporating panels 24 , 26 generally span drain pan 22 and are arranged generally in a “V” structure having an open end 27 generally spanning drain pan 20 and an apex 29 generally situated at flow axis 30 .
[0014] Blower device 16 includes a housing 40 containing a fan 42 . Fan 42 rotates about an axis 32 and is substantially centered on flow axis 30 . Flow axis 30 intersects housing 40 at an upstream limit 44 and at a downstream limit 46 . Housing 40 has an exhaust locus 48 substantially spanning second end 21 of cabinet 12 . Housing 40 also has a first input locus 50 and a second input locus 52 . Input loci 50 , 52 provide air passages generally centered on axis 32 . Fan 42 operates to draw air through air filter 18 in a flow or approach direction generally symmetrical with respect to flow axis 30 . As air encounters housing 40 generally at upstream limit 44 and across portions of housing 40 facing upstream toward first end 19 , air is routed between housing 40 and cabinet 12 to enter housing 40 through input loci 50 , 52 in a flow direction generally parallel with axis 32 . Air flow may not reach exact parallelism with respect to axis 32 , but general parallelism with axis 32 is achieved until fan 42 redirects air outward from axis 32 in a radial flow direction generally perpendicular with axis 32 against the inner wall 41 of housing 40 .
[0015] In order to facilitate understanding the present invention, air handling unit 10 is illustrated in FIG. 1 representing housing 40 using prior art construction and using construction according to the teachings of the present invention. Prior art construction of housing 40 provided a bluff face 60 (indicated in dotted line format in FIG. 1 ) so that a clearance gap Δ was established between housing 40 and cabinet 12 . Bluff face 60 typically was formed using a substantially rectangular cross-section, as indicated in FIG. 1 , so that corners such as corner 62 generated turmoil in air flow past housing 40 , restricted air flow from evaporator device 14 to fan 42 . Such restriction of air flow increased air flow velocity in regions between housing 40 and cabinet 12 and adversely affected static pressure performance and efficiency of air handling unit 10 . Prior art construction required a minimum spacing between bluff face 60 and apex 29 to ensure moisture would not be entrained in air traversing blower device 16 to enter a space being serviced by an HVAC system employing air handling unit 10 . By way of example and not by way of limitation, a distance on the order of four inches was required between bluff face 60 and apex 29 to achieve the desired operating characteristics without undesired levels of entrained moisture in air traversing blower device 16 .
[0016] It is preferred that housing 40 present an inner surface 41 with respect to axis 32 in a generally Archimedian or logarithmic scroll structure. It is known that larger volute expansion angles in such structures allow a blower wheel such as fan 42 to achieve higher static pressure for a given flow rate and that blower efficiency improves with increased expansion angle in the range of expansion angles employed in air moving units used with HVAC systems (generally, by way of example and not by way of limitation, expansion angles in the range of seven to fifteen degrees). Space constraints imposed by industry standards (discussed generally above) preclude simply providing larger expansion angles as a solution.
[0017] The inventors have discovered that by providing a smoother face to approaching air by housing 40 , less turmoil is imparted to air flowing past housing 40 en route to input loci 50 , 52 and less restriction of air flow between housing 40 and cabinet 12 is presented. A contoured face 61 is provided to establish a gradual transition of air flow from evaporator device 14 around housing 40 and into input loci 50 , 52 . Also provided is a change to inner wall structure of housing 40 to present a revised inner surface 43 . Revised inner surface 43 establishes a variance zone 70 between a first zone-edge 72 and a second zone-edge 74 . It is preferred that variance zone 70 be substantially centered on flow axis 30 . It is further preferred that variance zone 70 include a smaller blunting zone 80 between a first blunting-zone-edge 82 and a second blunting-zone-edge 84 . It is preferred that blunting zone 80 be substantially centered on flow axis 30 .
[0018] Variance zone 70 and blunting zone 80 cooperate to provide a clearance with cabinet 12 that is greater than clearance gap Δ provided by prior art bluff face 60 . Providing the outer profile necessary to accommodate variance zone 70 and blunting zone 80 also accommodates providing revised inner surface 43 . Revised inner surface 43 permits providing a larger volute expansion angle than may be provided by bluff face 60 and inner surface 41 in the same “footprint” area occupied by air handling unit 10 . Providing such a larger expansion angle at least between zone-edges 72 , 74 allows fan 42 to achieve higher static pressure for a given flow rate and improved blower efficiency as compared with prior art bluff face 60 and inner surface 41 . Further details describing the improved structure of the present invention are provided below in connection with FIG. 2 .
[0019] FIG. 2 is a side view of an air handling unit employing the teachings of the present invention. FIG. 3 is a bottom view of the air handling unit illustrated in FIG. 2 taken in direction 3 - 3 in FIG. 2 . Regarding FIG. 2 and FIG. 3 together, blower device 16 includes housing 40 containing fan 42 . Fan 42 rotates about axis 32 and is substantially centered on flow axis 30 . Flow axis 30 intersects housing 40 at an upstream limit 44 and at a downstream limit 46 . A plane 36 containing axis 32 and substantially perpendicular with axis 30 establishes housing intersection loci 100 , 102 ( FIG. 2 ) and 100 a ( FIG. 3 ). Another housing intersection locus is also established behind locus 102 ( FIG. 2 ) and behind locus 100 a ( FIG. 3 ) but is not visible in FIGS. 2 and 3 . Housing 40 includes exhaust locus 48 and input loci 50 , 52 . Input loci 50 , 52 provide air passages generally centered on axis 32 . Fan 42 operates to draw air in a flow or approach direction generally symmetrical with respect to flow axis 30 . As air encounters housing 40 generally at upstream limit 44 and across portions of housing 40 facing upstream, air is routed between housing 40 and cabinet 12 (not shown in FIGS. 2 and 3 ; see FIG. 1 ) to enter housing 40 through input loci 50 , 52 in a flow direction generally parallel with axis 32 . Air flow may not reach exact parallelism with respect to axis 32 , but general parallelism with axis 32 is achieved until fan 42 redirects air outward from axis 32 in a radial flow direction generally perpendicular with axis 32 against inner wall 43 of housing 40 . In the exemplary blower unit 16 of FIGS. 2 and 3 , fan 42 rotates about axis 32 in a rotation direction indicated by an arrow 33 .
[0020] In order to facilitate understanding the present invention, blower device 16 is illustrated in FIGS. 2 and 3 representing housing 40 using prior art construction and using construction according to the teachings of the present invention. Prior art construction of housing 40 provided a bluff face 60 (indicated in dotted line format) typically formed a substantially rectangular cross-section so that distance from axis 32 to interior surface 41 of prior art blower housing 40 (using bluff face 60 ) is a constant value r across the width W (see FIG. 3 ) of blower housing 40 in planes containing axis 32 .
[0021] The present invention provides interior surface 43 so that a plurality of radii R 1 , R 2 , R 3 , R 4 , R n generally perpendicular with rotational axis 32 between axis 32 and interior surface 43 define inner surface 43 in planes containing axis 32 in variance zone 70 between zone-edges 72 , 74 . An example of such a plane containing axis 32 is plane 71 ( FIG. 2 ). Still referring to FIG. 2 , radii generally perpendicular with rotational axis 32 in planes containing axis 32 are substantially constant across width W between downstream limit 46 and a first housing locus or zone-edge 74 , and from a second housing locus or zone-edge 74 a toward exhaust locus 48 in so far as the desired Archimedian or logarithmic scroll structure is maintained. Radial lengths will likely vary among various planes containing axis 32 that are outside variance zone 70 to establish the desired expansion angle for housing 40 with respect to fan 42 , as will be understood by those skilled in the art. It is preferred that zone edges 74 , 74 a be established generally in the vicinity of plane 36 that establishes housing intersection loci 100 , 102 and other housing intersection loci not visible in FIG. 2 , as described above. In the exemplary structure illustrated in FIG. 2 , zone edges 74 , 74 a are established upstream of plane 36 .
[0022] Thus, in FIG. 3 , radii R n have a relationship: R 1 <R 2 <R 3 <R 4 <R n . The portion of variance zone 70 between upstream limit 44 and second zone-edge 74 is preferably configured substantially as a mirror-image of the portion of variance zone 70 between first zone-edge 72 and upstream limit 44 . Some radii R n are smaller than radius r, such as, by way of example and not by way of limitation, radii R 1 , R 2 . Other radii R n are larger than radius r, such as, by way of example and not by way of limitation, radii R 3 , R 4 , R n . By this variable radii construction, a larger expansion angle may be provided for a portion of the flow zone within housing 40 from downstream limit 46 , through upstream limit 44 and toward exhaust locus 48 . Larger volute expansion angles in such structures allow a blower wheel such as fan 42 to achieve higher static pressure for a given flow rate and improve blower efficiency.
[0023] It is preferred that variance zone 70 be substantially centered on flow axis 30 . It is further preferred that variance zone 70 include a smaller blunting zone 80 between a first blunting-zone-edge 82 and a second blunting-zone-edge 84 . It is preferred that blunting zone 80 be substantially centered on flow axis 30 .
[0024] Variance zone 70 and blunting zone 80 cooperate to provide a clearance with cabinet 12 ( FIG. 1 ) that is greater than clearance gap Δ provided by prior art bluff face 60 . Providing the output profile necessary to accommodate variance zone 70 and blunting zone 80 also accommodates providing a larger volute expansion angle than may be provided by bluff face 60 and inner surface 41 and still fit in the available blower compartment space occupied by blower device 16 . Providing such a larger expansion angle at least between zone-edges 72 , 74 ( FIG. 3 ) allows fan 42 to achieve higher static pressure for a given flow rate and improved blower efficiency as compared with prior art housing structures using bluff face 60 and inner surface 41 .
[0025] It is to be understood that, while the detailed drawings and specific examples given describe preferred embodiments of the invention, they are for the purpose of illustration only, that the apparatus and method of the invention are not limited to the precise details and conditions disclosed and that various changes may be made therein without departing from the spirit of the invention which is defined by the following claims: | A housing cooperates with an air mover rotating about a rotation axis to move air received from an approach to an exhaust. The approach is generally oriented about a direction intersecting the housing at upstream and downstream limits. The housing presents an interior surface establishing radii between the axis and the surface. The radii have a generally constant radial value across a width in planes containing the axis in a first zone between the downstream limit and a first locus, and in a second zone between a second locus and the exhaust. The radii vary between a smallest and a largest radius across the width in planes containing the axis in a variance zone upstream of the axis. The smallest radius is less than the radial value at the first and second loci. The largest radius is larger than the radial value at one of the first and second loci. | 1 |
This is a continuation of application Ser. No. 089,113, filed Aug. 25, 1987, now abandoned.
BACKGROUND OF THE INVENTION
This invention relates to an implantable device and in particular, to a vascular access device that is implanted subcutaneously.
Within the prior art, a variety of implantable access devices are known. Typical is the commercially available INFUSAID Infuse-A-Port™. These techniques of providing access via a various implantable device include percutaneous catheters, implantable ports having access to a port at a perpendicular angle to the skin and direct access with a needle. Thus, in the case of the commercially available Infuse-A-Port™, a base having an inlet located under the skin having an access outlet perpendicular to the skin line. The catheter thus extends at a right angle to the direction of needle access to the port's inlet.
Materials which are used in these devices generally include various plastics such as PVC, teflon, polyethylene, polypropylene, polyurethane, polycarbonate, polyethersulfone, polysulfone, polyolefin, nylon and the like. Additionally, silicone rubber, stainless steel and titanium are used.
A hallmark characteristic of all previous techniques of access utilizing implantable ports is a requirement that a needle be placed into the port septum at a 90° angle to the outlet catheter. This is acceptable for bolus injections or infusions over brief periods of time. However, for longer infusions or for continuous infusions with these ports, a right angle needle is required to allow for the hub of the needle to be parallel with the skin. This is required to permit anchoring of the needle to the body during infusions.
Another disadvantage with such prior art devices is that they require minor but, a distinct surgical procedure for implantation. That is, the size of the base is such that a significant incision is required for implantation. Moreover, given the size of the base, implantation is required in specific portions of the body, for example, the chest and stomach area that can physically support and house the port without protuberances or discomfort to the patient.
Given these deficiencies of prior art devices, it is an object of this invention to define an implantable access device for humans having a low profile capable of implantation in a variety of bodily locations, which provides access to multiple body sites.
Yet another object of this invention is to define a low, acute angle implantable port which provides access to multiple body sites for research purposes in animals.
Yet another object of this invention is to provide an acute angle implantable device providing access to multiple body sites in small patients, such as infants, neonates and children.
A further object of this device is to provide for an implantable port which has a reduced size such that implantation can be carried out minimizing both the surgical procedure time and size of the incision.
These and other objects of this invention are achieved by means of an acute angle port having a port body holding a self-sealing septum. The port body has grooves, wings, or flaps which allow for suturing the port to subcutaneous tissue. The self-sealing septum in accordance with this invention has the ability to be connected to various catheters such that when coupled, the port provides direct facile access to the catheter. This direct access to the catheter allows for catheter tip placement or for the management of blockages in the catheter. Such is extremely difficult in the context of ports which are disposed at right angles to the catheter output.
These and other objects of this invention are set forth herein by reference to the attached drawings and the descriptions of the preferred embodiments which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic perspective view of a first embodiment of an implantable port in accordance with this invention;
FIG. 2 is a schematic illustration showing the placement of the implantable port of this invention subcutaneously with the catheter extended into a blood vessel;
FIG. 3 is a schematic cut-away view of a second embodiment of this invention;
FIG. 4 is a perspective view of the embodiment of FIG. 3 utilizing a separately molded tie-down element;
FIG. 5 is an end view of the tie-down element of FIG. 4;
FIG. 6 is a schematic cut-away side view of a third embodiment of this invention; and
FIG. 7 is a schematic cut-away side view of a fourth embodiment of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to FIG. 1, a first embodiment of the implantable port of this invention is illustrated. The port comprises a body member 10 having a self-sealing septum 12 and an outlet connector 14 to which a suitable catheter is mounted. As illustrated in FIG. 1, the port has a generally flat base area 16 with an inclined face 18 into which the septum is placed. The septum provides a small diameter target, typically 0.15-0.20 inches. The overall length of the device from the front face to the tip of the connector is in the range of one inch. The overall height of the device from the flat base 16 to the tapered top portion is at a maximum approximately 0.38 inches. The port and the connector is manufactured from a bicompatible material. Materials of choice for the port are silicone rubber and various plastics such as PVC, teflon, polyethylene, polypropylene, polyurethane, polycarbonate, polyethersulfone, polysulfone, polyolefin, nylon, and the like. The connecter is preferably a metallic member made of stainless steel or titanium. The entire device can be made of one piece, for example a suitable metal.
As illustrated in FIG. 1, the front face 18 is inclined so that access to the self-sealing septum 12 is axially aligned with the connecter 14. This is in contrast to prior art systems wherein normal access to the septum would be disposed at a right angle, that is perpendicular to the outlet connector to the catheter.
Given the low profile of the device, implantation in areas with limited subcutaneous tissue such as forearms, scalp and neck area, infants and children and their appendages is possible.
Referring now to FIG. 2, the device of FIG. 1 including the catheter is shown implanted. Specifically, the port 10 has coupled to it a catheter 20 of suitable length. The catheter is force-fitted onto the connecter 14 having its free end lanced into a suitable blood vessel 22. The catheter made from a biocompatible material such as silicone rubber or polyurethane and depending on the application may have a radiopaque material added. The device is implanted under the skin 24 by making a small localized incision 26. The incision is shallow and does not involve incursion into underlying muscle tissue 28. Given the low profile of the device, a small protrusion 30 in the skin is present but such is not obtrusive or acts in any way as an impediment to normal functioning at the implantation site.
Access to the device 10 is by means of a needle 32. As can be seen from FIG. 2. The needle penetrates the skin at the protrusion 30 directly into the target or port zone 12 and is in line with the outlet 14. A major advantage of this system is that given the in-line nature of the septum, outlet and catheter access to the catheter tip for management of blockages is possible. This also allows the use of straight needles as illustrated in FIG. 2 for access to the port since entry is generally parallel to the skin line. Moreover, if it is necessary to pass a guide wire through the port and into the catheter, such can be done without making any significant bends. The ability to pass a guide wire or other appropriate device into the catheter after implantation provides a significant advantage in terms of clearing the catheter or importantly, initially placing the catheter tip at an appropriate location within the body. Such is extremely difficult in prior art right angle systems.
As can be appreciated from FIG. 2, the use of a straight needle provides a material advantage over prior techniques. Additionally, if the needle is required to be taped down then, it is a simple matter of affixing the needle when in contact with the septum to the skin yet not substantially immobilize the patient. Thus, for example, if the port 10 is implanted in an arm the needle can simply be taped or strapped in place thereby anchoring the needle to the body during infusion or injections requiring a period of time.
FIG. 3 illustrates a second embodiment of an in-line port in accordance with this invention. As illustrated in FIG. 3, the port is generally circular and comprises the body member 30 having an opening 32. A self-sealing septum 34 is placed into the body 30 to close off the opening 32 and provide a suitable target. The port has a hollow portion 36 generally axially in line with the self-sealing septum 34. The hollow portion serving as a reservoir terminates into a zone which is tapped, that is area 38 to allow for the catheter connection. The overall length of the device is in the range of 0.75-1.0 inches. The maximum diameter is in the range of 0.4 inches. The exposed area, that is opening 32 is in the range of 0.25 inches. As in the case of the first embodiment a variety of materials may be used, such as polysulfone.
The device of FIG. 3 has two annular shoulders 40 and 42. These shoulders provide zones for holding a tie-down element (not illustrated) around the device.
Referring now to FIGS. 4 and 5, a perspective vein of the port illustrated in FIG. 3 is depicted. The numeral is used to identify the same aspects of the embodiment of FIG. 3 are used in FIGS. 4 and 5. Additionally, FIG. 4 illustrates the connecter 44 for the catheter coupled to the outlet portion of the port, that is, screwed into the zone 38 and having a series of annular barbs or serrations upon which the catheter is fixed.
As illustrated in FIG. 5 the tie-down comprises a separate element which is a separately molded material. Specifically, the tie-down 50 comprises a body portion 52 inclined to the horizontal relative to a base portion 54. Through an opening 56, the device 30 is inserted such that as illustrated in FIG. 4 the rear portion of the device at shoulder 30 butts against the rear portion of the tie-down while the front shoulder 40 butts against the inclined front wall. Consequently, when snapped into position the tie-down inclines the port and provides a pair of extending "wings" for purposes of suturing the device into place. Various techniques of suturing the wings 56, 58 may be used. As illustrated in FIG. 4, a series of holes 60 can allow for sutures to be stitched through and around each of the wings. Alternatively, a zone of exposed dacron fabirc 62 may be used to provide a confined anchoring area on each of the wing surfaces.
Referring now to FIG. 6, a third preferred embodiment of this invention is illustrated. The embodiment of FIG. 6 departs from that illustrated in FIG. 3 in that the device while retaining its generally truncated conical form eliminates the shoulder zones 40 and 42. In its place, two annular rings 60 and 62 are employed. These provide two suture hold down locations. Another variation is that the hollow area 64 in the embodiment of FIG. 6 is generally rectangular and has a truncated zone 66 coupling a straight in-line portion 68 to the hollow area 64. This serves as a guide for the needle, it being understood that the needle would generally terminate in the zone 64 providing direct fluid access to the catheter. The barbed connector which would be screwed into the device and the threaded portion 38.
Referring now to FIG. 7, a fourth embodiment of this invention is depicted. In FIG. 7, the device comprises a generally squat body portion 70 having a self-sealing septum 72 embedded therein. The septum 72 is inclined relative to the horizontal flat bottom portion of the device and has a cavity portion 74 defined within the body 70. An outlet hollow port 76 is in fluid communication with an external connector piece 78. The connector piece is force-fitted or the like into the body portion 70 and serves as the connector between the port and the catheter. The body portion may be made of polysulfone or the like and, as illustrated in FIG. 7 has a very low profile. Needle access is provided at a shallow, acute angle to the self-sealing septum 72. The device is anchored in place by through-holes, wings or the like which are not illustrated.
It is apparent that while multiple embodiments of this invention have been illustrated, various other modifications can be made without departing from the essential scope of the invention. A key aspect is the geometry of the device so that straight needles can be used with the device implanted at a very shallow implantation site within an arm, the neck area or the like. Such is considered a material advantage over prior art systems which must be implanted in the torso given their overall size and geometry. | A device that is implantable to provide access to multiple body sites for the administration or withdrawal of fluids. A hollow port has a self sealing septum on one end and an outlet at an opposite end. A catheter is connected to the outlet. The septum and outlet are positioned to be substantially in-line. | 0 |
FIELD OF THE INVENTION
The present invention relates to a system for changing and/or evaluating a signal representing the rotation speed of at least one with the features set forth in the preambles of the independent claims.
BACKGROUND INFORMATION
Measuring the speeds of rotation of the vehicle wheels for control of the braking force, drive force and/or driving dynamics of a motor vehicle in open or closed loop is known. To do this in conventional manner, various methods (e.g. Hall or magneto-resistive sensors) are used. In addition, measuring the wear of the brake pad of a vehicle is known in that, for example, contact pins are embedded at a specific depth of the brake pads, which trigger a contact upon actuation of the brake when the brake pad is worn to this depth.
For example, the article “Integrierte Hall-Effekt-Sensoren zur Positions-und Drehzahlerkennung” (Integrated Hall Effect Sensors for Position and Speed Recognition) of the journal “elektronik industries,” 7-1995, pp. 29-31, describes active sensors for use in the motor vehicle for anti-lock braking, traction control, engine and transmission open-loop and closed-loop control systems. Such sensors supply two current levels in a two-wire circuit which are converted into two voltage levels by a measuring resistor in an appropriate controller.
In addition to the Hall effect sensors, the use of magneto-resistive sensors is also known for speed recording, e.g., from the article “Neue, alternative Lösungen für Drehzahlsensoren im Kraftfahrzeug auf magnetoresisitiver Basis,” (New Alternative Solutions for Speed Sensors based on Magnetoresistance of the Motor Vehicle), VDI Reports No. 509, 1984.
German Patent No. 26 06 012 (U.S. Pat. No. 4,076,330) describes a special common arrangement for detecting the wear on a brake pad and for detecting the wheel speed. To do this, the brake pad wear detected and the wheel speed detected by an inductively operating sensor are supplied via a common signal line to an analyzer. This is achieved in that the wheel speed sensor is completely or partially short-circuited in response to a detected brake pad wear.
Other systems as described, for example, in German Patent No. 43 22 440, require at least two signal lines between one wheel unit and the analyzer for detecting the speed and the brake pad wear on a wheel and a wheel brake, respectively.
In the speed detection method mentioned above, it is known that the air gap between the rotating ring gear and the actual sensor element has a considerable influence on the quality of the speed signal. Reference is made in this respect to e.g., German Patent Application No. 32 01 811.
The above-mentioned information (for example, brake pad wear and air gap/signal quality) is generally detected near the wheel and evaluated in a control unit mounted at a distance from the wheel. To do this, the information must be transmitted to the controller.
German Patent Application No. 196 18867.9 describes how to modify a rotational-speed signal in various specifiable ways for transmitting additional information (excessive brake pad wear, air gap that is too large/defective signal quality). The modification is carried out in different ways depending on the additional information to be transmitted. Making the different modifications of the speed signal requires a certain amount of effort.
The object of the present invention is to implement a very simple and reliable transmission of the speed signal and other information.
SUMMARY OF THE INVENTION
The present invention relates to a transmission of several pieces of additional information by a single modification of a rotation speed signal. In addition to the modification of the speed signal according to the present invention in the area near the wheel (modified speed sensor), the system according to the present invention provides the special evaluation of the speed signal modified according to the present invention in the area at a distance from the wheel (controller). In addition, the present system according to the present invention also includes the combination of the special speed sensor and the controller.
During the modification of a signal representing a rotary movement of a vehicle wheel, the system according to the present invention includes first means for generating a first signal representing the rotary movement and second means for generating at least two further signals, in each case one of the additional signals representing various operating conditions of at least two different devices as additional information. Such devices can be, for example, the first means (e.g., speed sensor) itself or the brake pad of a wheel brake present at the vehicle wheel. In addition, third means are provided with which the first signal can be modified in a specifiable manner as a function of the further signals.
According to the present invention, the third means are structured in such a way that the modification is specified in a single way, and this modification is carried out as a function of at least one of the further signals.
The modification according to the present invention of the speed signal has the advantage that the additional information (for example, about the air gap/signal quality and/or the brake-pad wear mentioned at the outset) can be transmitted in a simple and reliable manner via the speed-sensor output line. This eliminates, for example, the second signal line mentioned at the outset provided exclusively for the transmission of the additional information. In particular, the present invention exhibits, in comparison to German Patent Application No. 196 18867.9, the advantage that at least two different pieces of additional information (e.g., excessive brake pad wear, defective signal quality/excessively large air gap) can be transmitted by only a single possible change of the speed signal. In the subject matter of 196 18867.9, either only one single additional piece of information is superimposed on the speed signal or, in the case of several pieces of additional information, this additional information is superimposed on the speed signal in a coded manner which requires a certain amount of effort in circuit and/or programming technology. According to the present invention, at least two additional pieces of information are transmitted simultaneously by a single modification of the speed signal. If it is assumed that only one single speed modification is possible, according to the present invention all the additional pieces of information lead to the possible modification of the speed signal and are thus output, instead of an alternative decision being made for one of several additional pieces of information. In this context, the speed sensor and the detection of the above-mentioned additional information form one compact unit.
In evaluating a signal representing a rotary movement of a vehicle wheel, the invention assumes that the vehicle wheel has a wheel brake and the signal for transmitting additional pieces of information, e.g., wear of the brake pad of the wheel brake or quality of the signal, is changed in a manner that can be specified.
According to another embodiment of the present invention, mean are provided for generating at least one signal representing an actuation of the wheel brake. In addition, the system according to the present invention has evaluation means, by which the signal or the modified signal is (gated) combined at least with the generated signal representing a brake actuation. At least two signals representing the additional pieces of information are then formed as a function of this combination.
The evaluation of the speed signal or of the modified speed signal according to the invention has the advantage that additional pieces of information, e.g., regarding the air gap/signal quality and/or the brake-pad wear mentioned at the outset, can be transmitted via the sensor output line in a simple and reliable manner. The evaluation of the speed signal according to the present invention falls back upon signals that are generally present in the controller anyway. In so doing, use can be made of a brake-lights-switch signal and/or a signal representing the brake pressure as information regarding brake actuation.
The present invention also relates to the overall system that is based on a system for changing and evaluating a signal representing a rotary movement, which has first means for generating a signal representing the rotary movement and second means for generating at least two additional signals. In this context, in each case, one of the additional signals represents different operating conditions of at least two other devices as additional information. Such devices may be the speed sensor itself or the brake pad. In addition, third means are present by which the first signal can be modified as a function of the further signals in a manner that can be specified. By using fourth means, the first or the modified first signal is evaluated, at least one signal being generated as a function of this evaluation, the signal representing the various operating conditions of at least two different devices.
According to another embodiment of the present invention, fifth means for generating at least one signal representing a brake actuation are provided, and the third means are structured in such a way that the change can be specified in a single manner. This change is made as a function of at least one of the further signals. The fourth means are structured in such a way that the first or the modified first signal is combined (gated) with at least the generated signal representing one brake actuation. As a function of this combination, at least two signals are then formed representing the additional pieces of information.
The entire system naturally combines the above-mentioned advantages of the individual systems.
Another embodiment of the present invention provides that at the end of the vehicle production (end of the assembly line) a relatively simple test for correct installation of the speed sensors can be carried out. Since at this point at the end of the line, the brake pad is new, a modification according to the present invention of the speed signal can only result from an incorrectly installed speed sensor.
In another embodiment of the present invention, it is provided that the first means are structured such that the first signal assumes at least two initial current values and/or at least two initial voltage values. The third means are then structured in such a way that to change the first signal in a single manner that can be specified, at least one of the initial current values and/or at least one of the initial voltage values can be changed to a second current value and/or a second voltage value for at least a specific time as a function of the second signal. This embodiment assumes in particular that the first means are designed as an active speed sensor known in and of itself.
The generating means, or the fifth means, can additionally be designed to generate at least one of the signals representing the vehicle velocity.
In addition, the gating in the evaluating means, or in the fourth means, can be advantageously designed so that the signals representing the additional information are formed from the time correlation of the signal representing the wheel brake actuation to the specifiable change of the signal representing the rotary movement of a vehicle wheel.
The second means are advantageously designed to generate a signal representing brake-pad wear on at least one vehicle wheel brake and/or to generate a signal representing the amplitude of a signal joined to the first signal (speed signal).
In particular, the first, second and third means are near the wheel and/or the fourth and fifth means, or the evaluation means, are mounted at a distance from the wheel.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a schematic block diagram of a conventional system.
FIG. 2 shows a diagram of a combination of an active rotation speed sensor with a brake pad wear detector.
FIG. 3 a shows a first embodiment of a circuit arrangement of a speed signal modification system according to the present invention.
FIG. 3 b shows a second embodiment of the circuit arrangement of the speed signal modification system according to the present invention.
FIG. 3 c shows a block diagram of an evaluation arrangement according to the present invention.
FIG. 4 shows a first graphical representation of output signal curves for the system illustrated in FIGS. 3 a and 3 b.
FIG. 5 a shows a second graphical representation of the output signal curves for the system illustrated in FIGS. 3 a and 3 b.
FIG. 5 b shows a third graphical representation of the output signal curves for the system illustrated in FIGS. 3 a and 3 b.
FIG. 6 shows an exemplary arrangement for detecting an excessive air gap.
FIG. 7 shows a graphic representation of output signal generated using the arrangement illustrated in FIG. 6 .
FIG. 8 shows a flow chart diagram of a block illustrated in FIG. 3 c.
DETAILED DESCRIPTION
FIG. 1 shows, as a schematic block diagram, a system for determining brake pad wear and wheel speeds in a motor vehicle.
The wheel units of a motor vehicle are designated with reference numbers 11 a-d . These wheel units include, in particular, the wheels, the rotation speeds of which (wheel speeds) will be measured and the brake system (friction brake) allocated to each wheel unit. The speed sensors and brake-pad-wear sensors allocated to each wheel are indicated with reference symbols 102 a-d , and will be described in more detail using FIGS. 2 , 3 a , 3 b and /or 3 c in so far as they concern the invention. Reference is made explicitly to the related art mentioned above with regard to the structure of these sensors, which is beyond the scope of the present invention.
The output signals of speed sensors and brake-pad-wear sensors 102 a-d are put through to controller 103 , the transmission lines being represented by 105 a-d . The information transmitted by transmission lines 105 a-d is then evaluated centrally for all wheel units in controller 103 . The condition of the brake pads is supplied as evaluation result by controller 103 to display instrument 110 by way of lines 18 a-d . Generally the driver is given appropriate information in the event of a certain degree of wear of one or more brake pads.
For the sake of completeness, the brake systems of individual wheel units 11 a-d which can be controlled from controller 103 are sketched with reference characters 14 a-d.
FIGS. 2 , 3 a and 3 b show various embodiments using a single wheel unit as an example.
FIG. 2 shows a combination of an active speed sensor with a brake pad wear detector. As described above, a known Hall speed sensor or a known magneto-resistive speed sensor can be provided as “active” speed sensor 102 . FIG. 2 shows schematically that a sensor element 1021 scans a passive-magnetic type incremental rotor 101 . As a function of the scanned increments of rotor 101 , sensor element 1021 sets two current levels i 1 and i 2 . This is shown in FIG. 2 with two power sources 1022 and 1023 being switched on and off.
Speed sensor 102 is connected to controller 103 via lines 105 using plug connectors 1021 a and b and 1031 a and b . Input amplifier 1036 detects, with the help of input resistor R, the voltage values corresponding to the current levels of speed sensor 102
U Low =R*i 1
U High =R *( i 1 +i 2 )
FIG. 4 shows a typical curve with wheel speed that is basically constant in lower signal line 301 . The desired wheel speed is obtained by evaluation of the frequency of this signal.
The bottom part of FIG. 2 shows schematically a conventional brake-pad-wear detector 104 on a wheel brake. As described above, the brake-pad-wear sensor, known as such from the related art, determines the wear on the brake pad of a vehicle brake in that e.g., contact pins are embedded at a specific depth of the brake pads and trigger a contact upon actuation of the brakes (the brake pad is pressed onto the brake disc) when the brake pad is worn to this depth. This contact is indicated in FIG. 2 with switch 1041 . In normal cases, (no brake pad wear requiring display) switch 1041 is open, voltage U+ not being grounded. If the brake pad reaches a certain degree of wear, switch 1041 is closed, which is detected because of grounding through connection 106 or plug connectors 1012 and 1031 in evaluation circuit 1037 .
As can be seen in the embodiment shown in FIG. 2 , separate signal lines 105 and 106 are necessary in each case for transmission of wheel speed information and information about brake pad condition.
The system according to the present invention will now be explained using FIGS. 3 a and b . In this embodiment, speed sensor 102 described in FIG. 2 was supplemented with additional current source i 3 , which is arranged in parallel to the speed sensor shown in FIG. 2 .
In FIG. 3 a , additional power source i 3 can be connected via transistor 1029 into the power circuit between the speed sensor and the evaluation unit if transistor 5032 is switched to transmission (forward).
Transistor 1029 is controlled by logical OR gate 1028 . Signal S or BBV coming from switch 1041 already described using FIG. 2 , and signal LS coming from block 5102 are applied to OR gate 1028 . As described above, switch 1041 changes its switching status if during an actuation of the brakes a specific brake pad wear is recognized. Generation of signal LS and the function of sensor element 5030 and comparator 5031 will be described below using FIGS. 6 and 7 .
FIG. 6 shows, as an example, sensor element 5030 and the detection of excess distance of a Hall or magneto-resistive sensor from the ring gear of the vehicle wheel that has already been described, whose speed of rotation will be detected. Sensor element 5030 is the sensor element indicated with the same reference numbers in FIGS. 3 a and 3 b . Sensor element 5030 is a known Wheatstone bridge with a typical ring-shaped arrangement of resistors. As the individual segments of the ring gear that is not shown ( 101 / FIG. 3 a ) pass by, bridge voltage U B is generated in this Wheatstone bridge and is supplied to comparators 5031 and 5101 . Comparator 5031 corresponds to the comparator in FIGS. 3 a and 3 b with the same reference symbols and is used to evaluate the wheel speed. Another evaluation of the bridge voltage takes place in comparator 5101 in such a way that this bridge voltage is compared to a relatively high threshold value U H . More details will be given on the background of the two threshold comparisons in the following using FIG. 7 .
FIG. 7 shows a typical signal curve of the bridge voltage over time. The bridge voltage periodically increases and periodically decreases depending on the speed of passage of the individual ring gear segments ( 101 / FIG. 3 a ). If the distance, the air gap, between the ring gear and Wheatstone bridge 5030 remains constant, the bridge voltage has a constant amplitude. However, if this distance becomes too great, the bridge voltage amplitude decreases. This case is shown in FIG. 7 .
A first threshold comparison in comparator 5031 compares the bridge voltage signal to a relatively low threshold value, e.g., 40 mV. On the output side, comparator 5031 then supplies the triggering signal, shown in bottom signal curve K 1 in FIG. 7 , for current sources i 1 and i 2 (see FIGS. 5 a and 5 b ). Therefore, signal K 1 represents the wheel speed, even given an increasing air gap. Comparator 5101 checks the bridge voltage signal amplitude, in that a relatively high threshold of e.g., 60 mV is set in this comparator. If the distance between the ring gear and the Wheatstone bridge, the air gap, is sufficiently small, the amplitude of the bridge voltage signal is greater than the threshold of comparator 5101 . The output signal of comparator 5101 is shown, as can be seen in lower signal curve K 2 in FIG. 7 , in regular operation with a time delay of signal K 1 compared to signal K 1 . However, if comparator signal K 2 fails to appear, the bridge-voltage signal amplitude decreases, which indicates an excessive air gap.
The absence of signal K 2 is detected in unit (e.g., detector) 5102 and results in generation of signal LS. Unit 5102 is indicated in FIGS. 3 a and 3 b with the same reference numbers.
In summary regarding air gap recognition, it can be stated that the speed signals of a wheel are detected by using an active sensor, e.g., Hall sensor or magneto-resistive sensor. The sensors have a Wheatstone bridge that is unbalanced by a changing magnetic field. The speed signal is obtained from this unbalance. The amount of unbalance has a fixed relationship to the magnitude of the magnetic-field difference between the two halves of the bridge. Among other things, the magnetic-field difference is a function of the distance of the sensor from the magnet wheel. If the amount of bridge unbalance is evaluated, a statement can be made on the air gap between sensor and magnet wheel, and thus on the signal quality of the speed signal. This evaluation can be carried out with comparator 5101 , which has a greater hysteresis (U H =60 mV) than the normal useful signal comparator 5031 (U H =40 mV). If the air gap is small, both the comparators switch, but if the air gap is too large only the useful signal comparator 5031 switches. This provides an early warning system for an air gap that is too large without simultaneously losing the wheel speed information. This information can be used, for example, as an end-of-the-line check during vehicle manufacturing, in the shop or while driving.
As FIG. 3 a shows, transistor 5032 is triggered as a function of comparator 5031 described in FIGS. 6 and 7 . If transistor 1029 is blocked, current level i 1 (low level) and [i 1 +i 2 ] (high level), whose frequency indicates the wheel speed, are periodically present at output 105 ′ of sensor unit 102 ′.
By triggering transistor 1029 , current source i 3 is superimposed on current level [i 1 +i 2 ] if either signal LS (unit 5102 / FIG. 6 ) represents an air gap that has to be displayed “or” signal BBV represents a brake pad wear that has to be displayed. The logical “or” operation occurs in logical OR gate 1028 . If transistor 1029 is switched to transmission (forward), the high level of the speed signal increases at output 105 ′ to the level [i 1 +i 2 +i 3 ] (high level′). Output 105 ′ is connected to input 1031 b of the controller i.e., of evaluation unit 103 ′.
Depending on the switching status of transistor 1029 and as a function of signal BBV “or” signal LS, input amplifier 1036 ′, with the help of input resistor R, detects the voltage values corresponding to the above-mentioned current levels
U Low =R*i 1
U High =R *( i 1 +i 2 )
or
U High ′=R *( i 1 +i 2 +i 3 )],
depending on whether a brake pad wear that needs to be displayed or an air gap that needs to be displayed has been recognized (U High ′) or not (U High ).
In addition to typical curve 301 already described with additional power source 1014 switched off, upper signal line 302 in FIG. 4 shows the signal curve with power source i 3 switched on. The upper signal level (high′-level) is thus shifted by offset (R*i 3 ) compared to lower signal level 301 (high-level).
Desired wheel speed N is obtained by evaluating the frequency of these signals shown in signal line 301 or 302 in block 1034 of FIG. 3 c . Speed N can then be supplied to the actual brake-, drive- or other closed loop/open loop control 1035 . In the case of brake or drive closed loop/open loop control, wheel brakes 11 a-d are driven (signals 14 a-d ) as a function of the speeds detected. Frequency evaluation 1034 is designed in such a way that the frequency of signal lines 301 and 302 is determined independently of the offset caused by the position of switch 1041 mentioned above. In this manner, speed detection is always ensured independently of recognized brake pad wear that is too great or a recognized air gap that is too large. This is important for system availability.
In addition to evaluation 1034 mentioned above regarding wheel speeds, signals 301 and/or 302 are supplied to threshold comparator 1032 . This threshold comparator 1032 recognizes whether the offset caused by switch 1029 (R*i 3 ) is present at the high level or not. The threshold in unit 1032 lies between levels [R*(i 1 +i 2 )] and [R*(i 1 +i 2 +i 3 )].
Therefore, on the output side of threshold comparator 1032 , a signal M on/off is present which gives information on whether either a brake pad wear that needs to be displayed and/or an air gap that needs to be displayed are present (signal value M on ) or not (signal value M off ). Signal M with the signal value M on or M off is supplied to block 1033 , the function of which will be described in more detail using FIG. 8 . In addition, output signal BLS of one brake light switch 1037 and signal V (block 1036 ) representing the longitudinal vehicle velocity are supplied to block 1033 .
Block 1037 represents a switch that, in a known manner, senses an actuation of the brakes in such a way that the switch is connected to the brake pedal that can be actuated by the driver. Such a switch (brake light switch) is generally present on the vehicle for actuation of the brake light. Signal BLS can naturally also be generated as an alternative or as a supplement to the brake light switch in block 1037 as a function of the momentary brake pressure. A signal representing the momentary brake pressure is available in many braking systems (anti-lock braking systems, traction control systems or driving dynamics systems) in a known way in the corresponding controller.
Signal V representing the longitudinal vehicle velocity can be formed in a known manner from the wheel movements of one or several wheels and is also generally present as a reference speed, as it is called, in many braking systems (anti-lock braking systems, traction control systems or driving dynamics systems) (dotted line to brake, drive or other closed loop/open loop control 1035 ).
In FIG. 8 , after start step 801 , signal value M on/off that is currently present at block 1033 and the current value of signal BLS on/off and V are input in step 802 . There is an inquiry in step 803 of whether signal M has the value M on , value M on being output by block 1032 if the speed signal high level is increased.
If there is no increase in the high level of the speed signal, value M off is output, which means that switch 1029 ( FIG. 3 a ) is open and consequently neither an air gap that needs to be displayed (signal LS, FIG. 3 a ), nor a brake pad wear that needs to be displayed (signal BBV, FIG. 3 a ) is present. In this case, processing moves on immediately to final step 807 .
If there is an increase in the speed signal high level, after step 803 the processing goes over to step 804 in which a determination is made of whether signal M on is correlated in time with brake actuation signal BLS on . This can mean there is a determination of whether signal value M on only occurs if a brake actuation is simultaneously displayed due to signal BLS on . Such a correlation can occur due to the one-time simultaneous occurrence of values M on and BLS on , but it can also be set so that determination occurs only after a predefinable repetition frequency of such a correlation.
If in step 804 a correlation is found between the occurrence of signal values M on and BLS on , this means that a change in the speed signal occurs through switching on the power source i 3 whenever a brake actuation occurs. As described previously, excessive brake pad wear is detected only by contact with the brake disc of the contact pin embedded in the brake pad, i.e., only during a brake actuation. A possible air gap that is too large between sensor element 5030 ( FIG. 3 a ) and ring gear 101 ( FIG. 3 a ) is, on the other hand, independent of brake actuation. A correlation in time between the occurrence of signal values M on and BLS on thus means that excessive brake pad wear is present. In step 805 , this brake pad wear is displayed in display 110 a by outputting signal 18 a.
If in step 804 no correlation is determined between the occurrence of signal values M on and BLS on , this means that a change in the speed signal by switching on power source i 3 is present, independently of brake actuation. This indicates an air gap that is too large (defective quality of the speed signal) between sensor element 5030 ( FIG. 3 a ) and ring gear 101 ( FIG. 3 a ). If there is now another (optional) inquiry in step 808 of whether the vehicle longitudinal speed exceeds a predefinable threshold value SW, it means that if a threshold value is exceeded, an excessive air gap is present. In step 805 , this defective signal quality is displayed in display 110 b by outputting signal 18 b . If the vehicle is standing or only moving slowly, end step 807 will be triggered immediately.
While the embodiment shown in FIG. 3 c has separate displays 110 a and 110 b for displaying excessive brake pad wear and defective quality of the speed signal, respectively, a single display can also be provided since both errors can be rated equivalent in severity in driving operation and require immediate shop service. The cause of such a display being activated can be clearly diagnosed using appropriate service instructions.
In the embodiment shown in FIG. 3 a , in the presence of excessive brake pad wear and/or an excessively large air gap, each speed-signal high level is increased. In the following variation, on the other hand, only every nth high level is increased, in the concrete example, every fourth high level. This minimizes the loss of power caused by the offset. In addition, this version of the invention has the advantage during transmission of the brake pad wear that possible bounce in the brake pad wear switch will not result in incorrect display, since the offset is only initiated after the occurrence of n high levels.
FIG. 3 b shows this second embodiment variation of the present invention. In it, reference number 502 designates a unit which, similar to unit 102 ′ described above ( FIG. 3 a ), combines the actual speed detection and parts of the brake pad wear detection. Unit 502 is connected by connections 5051 and 5052 to inputs 1031 a and 1031 b of a controller not shown in FIG. 3 b . This controller corresponds basically to unit 103 ′ explained in FIG. 3 c.
In addition, unit 502 is connected by connections 5053 and 5054 to brake pad switch S 1 (corresponds to switch 1041 in FIGS. 2 and 3 a ). Switch S 1 is closed in the normal case in this embodiment (no brake pad wear needing to be displayed). In addition, FIG. 3 b shows block 5102 that generates signal LS (air gap/signal quality), which was already described using FIGS. 6 and 7 .
The actual speed detection is carried out analogously to the manner described using FIGS. 2 and/or 3 a.
If the brake pad reaches a specific degree of wear, switch S 1 is opened. Because of the open position of switch S 1 , the upper input of logical OR gate 5055 shown in FIG. 3 b will be at low level; with switch S 1 closed, the corresponding input of logical OR gate 5055 will be at high level. If an excessively large air gap is found in block 5102 , OR gate 5055 at the corresponding input will be assigned a low level. Therefore on the output side of OR gate 5055 , high level is always present if neither a brake pad wear that needs to be displayed nor an excessively large air gap is detected. Otherwise there is a low signal present at the output side of OR gate 5055 .
The triggering signal of transistor 5032 is supplied, inverted, to the lower input of logical AND gate 5021 . This means that a triggering of transistor 5032 (power source i 2 switched on, speed signal at high level) is present as low level (inverted) at the logical AND gate 5021 . When power source i 2 is switched off by the transistor (low level at transistor 5032 ) it results, because of the inversion, in the presence of a high level at the lower input of AND gate 5021 . On the output side, a high level is present at AND gate 5021 if neither brake pad wear that needs to be displayed (switch S 1 closed, upper input of OR gate 5055 at high level) nor an air gap that needs to be displayed (lower input of OR gate at high level) is present and at the same time power source i 2 is switched off. Otherwise, the AND gate output is at low level.
The output of AND gate 5021 is applied to the input of logical OR gate 5022 . In addition, comparators K 1 and K 2 are connected to the other two inputs of OR gate 5022 .
Comparator K 1 compares input voltage VCC of sensor unit 502 with a predefinable threshold value REF.K 1 . This is done by detecting low voltages, which can impair proper operation of unit 502 . If a low voltage such as this occurs, thus if VCC is lower than REF.K 1 , a high level will be present at the upper input of OR gate 5022 . Otherwise, this input is at low level.
Comparator K 2 compares the temperature detected by temperature sensor 5025 with predefinable threshold value REF.K 2 . This means temperature sensor 5025 measures the temperature to which sensor unit 502 is subject. In this context, temperature sensor 5025 is integrated directly in a known manner into the integrated circuit (IC) of sensor unit 502 , e.g., as a diode, whose temperature-dependent flux voltage is measured. The basis of temperature measurement is that sensor unit 502 is generally near the wheel, i.e., also installed in the proximity of the brake discs. The heat coming from the brake discs can heat sensor unit 502 in such a way that proper operation of unit 502 is impaired. If overheating of this type occurs, thus if the temperature measured is greater than REF.K 2 , a high level will be present at the lower input of OR gate 5022 . Otherwise, this input is at low level.
Therefore, a high signal is present at the output side of OR gate 5022 if at least one of the three inputs is at high level, thus if
either overheating of sensor unit 502 or low voltage or no brake pad wear that needs to be displayed and no air gap that needs to be displayed are present and, at the same time, power source i 2 is switched off.
Otherwise, the OR gate output is at low level.
The output of OR gate 5022 is connected to reset input R of counter 5023 . Counter 5023 is reset when there is a high signal at input R. Clock input C of counter 5023 is connected to the control signal for transistor 5032 . Input C thus receives a high level if power source i 2 is switched on and a low level if power source i 2 is switched off. Counter 5023 , designed in a known way as a flip-flop switch, is therefore always switched when power source i 2 is switched on or off. Counter 5023 has three outputs, which are at high level when the level present at clock input C has changed from low to high the first, second and fourth time. This means that three high levels are thus present at AND gate 5024 , to which the outputs of counter 5023 are supplied, when power source i 2 is switched on for the fourth time. In this case (all three inputs of AND gate 5024 are at high), the AND gate supplies a high level at its output side, after which third power source i 3 is switched on. Current i 3 from power source i 3 is then superimposed on the current that is present at this time (i 1 +i 2 ), which leads to a total current (i 1 +i 2 +i 3 ) at output 5052 . Power source i 3 can be switched on by a transistor that is not shown in FIG. 3 b which is connected in series to this power source i 3 . This would then occur similarly to switching power source i 3 on and off with transistor 1029 shown in FIG. 3 a.
FIG. 5 a shows the signal present at output 5052 if switch S 1 is closed (no brake pad wear that needs to be displayed) and no air gap that needs to be displayed are present. The upper input of AND gate 5052 shown in the lower signal line of FIG. 5 a is then set high. Counter 5023 (input R) is always reset by OR gate 5022 if power source i 2 is switched off. This ensures that third power source i 3 remains switched off if no brake pad wear that needs to be displayed and no air gap that needs to be displayed are present. In controller 103 ′ (input 1031 b ), the signal present at output 5052 is then converted via resistor R into a voltage, whereupon wheel speed N is determined by frequency analysis 1034 already described.
FIG. 5 b shows the curve of the signal present at output 5052 when switch S 1 is open (brake pad wear that needs to be displayed) and/or an air gap that needs to be displayed is present. The upper input of AND gate 5052 that is shown in lower signal line of FIG. 5 b is then set low. Counter 5023 (input R) is only reset by OR gate 5022 if a low voltage (comparator K 1 ) or excess temperature (comparator K 2 ) is present. In the normal case (neither over-voltage nor excess temperature) input R of counter 5023 is at low, whereupon power source i 3 is switched on each fourth time power source i 2 is switched on. This results in the speed signal curve shown in the upper part of FIG. 5 b.
As already described using FIG. 3 c , the signal present at output 5052 is converted into a voltage via resistor R in controller 103 ′ (input 1031 b ), whereupon wheel speed N is determined by frequency analysis 1034 already described. In addition, threshold value comparison 1032 recognizes whether level R*(i 1 +i 2 ) has been exceeded. In the case of a brake pad wear that needs to be displayed or an air gap that needs to be displayed, this is given by the increase of the fourth high level of the speed signal and is then evaluated by forming signal M on in unit 1022 as already described. | A system for a transmission of several additional pieces of information by a single modification of a speed signal. In addition to the modification of the speed signal in the area near the wheel (modified speed sensor), the system provides the special evaluation of the speed signal, modified, at a distance from the wheel (controller). In addition, the system naturally also includes the combination of the special speed sensor and the controller. | 1 |
This application is a continuation of application Ser. No. 07/890,380, filed May 26, 1992, now abandoned, which is a continuation of application Ser. No. 07/686,307, filed Apr. 16, 1991, now abandoned, which is a continuation of application Ser. No. 07/413,907, filed Sep. 27, 1989, now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to a motorcycle and, more particularly, to a motorcycle, principally of the scooter type, in which a fuel tank and an engine unit are carried between the front and rear wheels.
In such motorcycles of the prior art, a cylinder portion of the engine unit is generally provided to rise at a considerable angle. In contrast with this, from Japanese Patent Laid-Open No. 60-154964 (No. 154964/1985) it is known that the cylinder portion of the engine unit can be made to extend horizontally so as to dispose the fuel tank and the engine unit between the front and rear wheels in a substantially horizontal and rectilinear manner. In the prior art motorcycles, the wheel base is shortened, but the cylinder portion is a hindrance in that the space between the cylinder portion and the seat is reduced. In the motorcycle of Japanese Laid-Open No. 154964/1985, however, because the fuel tank and the engine unit are arranged rectilinearly, a large space is formed between the upper portion of the engine unit and the lower portion of the seat. This advantage is obtained at the cost of having a longer wheel base.
Also, as evidenced by the aforementioned Japanese Patent Laid-Open No. 154964/1985, in motorcycles of the concerned type it is characteristic to provide a chamber beneath the seat that is capable of containing a helmet. Such chambers, however, are typically incapable of containing two helmets beneath the seat. For example, in two seater motorcycles, when a helmet-containing chamber is arranged beneath the seat in order to utilize the lower space of the seat for containing two helmets, one of which is a large sized helmet for driver, there is the inconvenience that the seat height from the ground increases and the vehicle body becomes larger. Also, when a large sized longitudinally extensive containment chamber is provided beneath the seat and it extends over substantially the full length of the seat, if such a motorcycle runs with only one helmet contained in the chamber, there is the problem that the helmet is loose in the chamber and, thus, is shaken during running and thereby becomes damaged.
It is to the amelioration of these problems, therefore, that the present invention is directed.
SUMMARY OF THE INVENTION
It is one object of the present invention, therefore, to provide a motorcycle which seeks to improve the utilizable space in the region above the engine cylinder without having to lengthen the wheel base. In order to attain this object, according to the present invention, there is provided a motorcycle with a fuel tank and an engine unit carried between longitudinally spaced front and rear wheels, characterized in that the fuel tank is formed with a forwardly extending recessed portion on an upper part of the rear wall thereof, and that the engine unit is inclined in a forwardly rising manner so that a front cylinder portion of the engine unit faces the recessed portion at the front end of the cylinder head.
Since the cylinder portion of the engine unit is inclined in a forwardly rising manner and is adapted to face the forward recessed portion formed on the upper part of the fuel tank rear wall positioned forwardly of the engine unit, and the front end of the cylinder portion of the engine unit is positioned lower than the upper surface of the fuel tank, the utilizable space above the cylinder portion is increased. Also, with the engine unit positioned close to the fuel tank, the length of the wheel base is reduced.
It is another object of the present invention to provide a device for containing helmets in a motorcycle wherein the height from the ground to the front portion of the seat is reduced, as is the amount of space required to contain two helmets, and to improve, as a whole, the space efficiency for containing two helmets beneath the seat.
In order to attain the above-mentioned object, the present invention is characterized in that a device for containing helmets in the motorcycle comprises a helmet-containing chamber which is provided beneath the seat and extends over substantially the entire length of the seat to be capable of containing two helmets in longitudinally spaced relation, the helmet-containing chamber having a front containment portion and a rear containment portion and the helmet adapted for containment in the front containment portion being smaller than the helmet contained in the rear containment portion.
According to this aspect of the invention, since the helmet-containing chamber is divided into a front containment portion and a rear containment portion, with the front containment portion capable of containing a small sized helmet and a large sized helmet being adapted for storage in the rear containment portion, the height from the ground to the front portion of the seat is reduced, and the required length of the containment chamber beneath the seat shortened, whereby the need to make the vehicle body larger is avoided.
For a better understanding of the invention, its operating advantages and the specific objectives obtained by its use, reference should be made to the accompanying drawings and description which relate to a preferred embodiment thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partial sectional elevational view of a scooter-type motorcycle embodying the present invention;
FIG. 2 is a sectional view taken along line II--II of FIG. 1;
FIG. 3 is an exploded perspective view illustrating certain elemental parts of the motorcycle of FIG. 1;
FIG. 4 is a side elevational view of another embodiment of a scooter-type motorcycle embodying the present invention;
FIG. 5 is a plan view illustrating the helmet containment chamber of the motorcycle of FIG. 1;
FIG. 6 is a sectional view taken along line VI--VI of FIG. 1;
FIG. 7 is a sectional view taken along line VII--VII of FIG. 1;
FIG. 8 is a sectional view taken along line VIII--VIII of FIG. 1; and
FIG. 9 is a partial exploded view illustrating a lock device for the helmet containment chamber.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings, reference numeral 1 generally indicates a vehicle body which is provided with a front wheel 2 and a rear wheel 3 at the front and rear portions, respectively, thereof. A fuel tank 4 is carried on a middle lower portion between the front and the rear wheels 2 and 3, and an engine unit. 5 is positioned adjacent the rear portion of the fuel tank 4. A seat 6 of a two seater-type vehicle is mounted on a rear upper portion of the vehicle body. Reference numeral 7 generally indicates a vehicle body frame which, as shown in FIG. 3, is provided with a down tube 7b extending downwardly from a head pipe 7a; a pair of lower frames 7c, 7c which diverge in left and right directions from a lower end of the down tube 7b and which extend rearwardly; center frames 7d, 7d which are offset from the lower frames 7c, 7c to rise obliquely upwardly; and rear frames 7e, 7e which are offset from upper ends of the center frames 7d, 7d to extend rearwardly. Each of the left and right lower frames 7c, 7c is connected by a first cross pipe 7f at a rear end portion of the lower frame 7c, by a second cross pipe 7g at an upper end portion of the center frame 7d, and by a third pipe 7h at a rear portion of the rear frame 7e. Also, from the middle portions of the rising frames 7d, 7d is projected in the forward direction an inverted "U"-shaped sub-frame 7i. Further, between the sub-frame 7i and the down tube 7b extend a pair of angle pipes 7j, 7 j in the forward direction of the sub-frame 7i. The angle pipes 7j, 7j are detachably fixed to the sub-frame 7i and the down tube 7b at their front and rear positions, respectively, by means of threaded screws 7k, 7k.
The fuel tank 4 is formed in a generally square shape by welding both upper and lower half bodies 4a, 4b at a flange portion 4c and is fixed to the lower frames 7c, 7c at the flange portion 4c thereof through the intermediary of fixtures 8. Thus, the fuel tank 4 is protected at both sides by both lower frame 7c, 7c which, as shown in FIG. 1, have their lowermost portion below the bottom surface of the fuel tank. At its upper region the fuel tank 4 is protected by the angle pipes 7j, 7j. The tank, thus protected, is surrounded by an upper vehicle body cover 9 forming steps 9a, 9a at its both sides and by a lower cover 10.
A recessed portion 4d is formed in the fuel tank 4, which portion consists of a slanted surface formed in a forwardly rising manner on an upper portion of the rear wall of the fuel tank 4. A cylinder portion 5a located at the front end of the engine unit 5 is provided in a somewhat forwardly rising manner so that the front end 5c of the cylinder head of the cylinder portion 5a faces the recessed portion 4d, whereby the engine unit is adapted to be adjacent to the fuel tank 4 with a clearance C1.
Also, as shown in FIG. 2, the fuel tank 4 has a portion 4a projecting upwardly inside steps 9a, 9a, and refilling port 4e is provided on an upper surface of the projecting portion and covered by a cover 9c provided on the vehicle body 9.
The engine unit 5 consists of a cylinder portion 5a and a unit body 5b which extends rearwardly thereof and which is formed integrally with a crank case and a transmission case. The unit body 5b is supported at a rear portion thereof by a shaft 3a of the rear wheel 3. At its upper middle portion the unit body 5b is pivotally attached to the center frames 7d, 7d through the intermediary of an articulated link 11. At its rear end the unit body 5b is supported by the rear frame 7e through the intermediary of a cushion damper 12, whereby a so-called swing engine unit is constituted. By inclining the cylinder portion 5a in a lower space, as mentioned above, the cylinder portion 5a can be conveniently positioned rearwardly of the fuel tank 4 together with a water pump W that is located in the lower portion of the engine, and engine connections 14a, 14a of a pair of radiator hoses 14, 14 which are connected to a radiator 13 provided in the front portion of the vehicle body 1. These radiator hoses 14, 14 are fixed by means of threaded screws, or the like, to floor stays 9b, 9b supported in front and rear directions by tank securing fixtures 8, 8. Fuel from the fuel tank 4 is supplied through fuel pipes 15a, 15b to a carburetor 19 which is connected. to an air cleaner 24 connected at an upper portion of the engine unit 5 through the intermediary of a filter 16 and a fuel pump 17. To the latter also is connected an air hose 20 which introduces pulsating pressures as a driving source and the fuel pump 17 that is fixed to the floor stay 9b, as shown in FIG. 2.
According to one aspect of the invention, the cylinder portion 5a is arranged to accommodate a helmet containment box 21 between the space between the cylinder portion 5a and the seat 6. The helmet containment box 21 utilizes the seat 6 as its cover and is provided at its front portion with a forward containment box portion 21" which contains a jet-type of helmet H1 disposed to face backwardly, and at its rear portion with a rear containment box portion 21" which contains a large-sized full-face type of helmet H2 also disposed backwardly. The forward portion 21' is positioned above the sub-frame 7i and the rear portion 21" is arranged to fit between the rear frame 7e, 7e, whereby the helmet-containing box 21 is mounted at front and rear portions of its bottom wall 21a by means of screws 7m in mounting bores 7n, 7n provided in the sub-frames 7i and mounting bores 7p, 7p fixed to the rear ends of the rear frames 7e, 7e. The helmet-containment box 21 is provided with a portion 21h which is concave upwardly at a front left side of the bottom plate 21a, the portion 21h being arranged in a positional relationship so that it faces toward the open face portion H1a of the helmet H1 when the latter is contained in the forward portion 21'. The carburetor 19 is arranged beneath the concave portion 21h. The bottom plate 21a is further provided with a concave recess extending upwardly to constitute a partition 21b which divides the helmet-containment box 21 into the front containment portion 21' and the rear containment portion 21". The partition 21b permits the helmets H1, H2 to be contained snugly in the respective compartments 21' and 21" so as not to deviate in the front and rear directions. In the space existing beneath the partition 21b are arranged and provided the second cross pipe 7g and the front and rear stoppers 11a of the link 11. The bottom plate 21a lying beneath the helmet H2 in compartment 21" is provided with a recessed portion 21i sized to avoid the rear wheel 3. Also, as shown in FIG. 8, a battery case 22 is mounted on a middle portion of one of the side walls from outside through the intermediary of a retaining member 17 mounted on the rear frame 7e, whereby a battery B is permitted to be removably attached thereto from an inner opening portion 21d. Further, the air cleaner 24, as shown in FIG. 8, is arranged in a convex shape from between the vehicle body cover 9 and the containment box 21 over the lower surface of the box.
Furthermore, as shown in FIGS. 2 and 9, the seat 6 is adapted to be opened and closed by a hinge 18 which is provided on the front end of the helmet containment box 21, and to be locked by means of a locking device 23 which is provided at the rear end of the containment box, whereby the entire seat 6 is supported by the helmet box.
FIG. 4 shows a scooter-type motorcycle having another structure embodying the present invention. In this embodiment, so as to constitute a vehicle body having a low seat height, the seat 6 is made low by omitting the helmet-containing portion in the aforesaid embodiment provided in the space over the cylinder portion 5a of the engine unit 5. The helmet-containment box 21 in this embodiment is arranged to contain only one helmet H3 rearwardly the seat 6.
The embodiment of the fuel tank 4 shown in FIG. 4 is designed to contain a recessed portion 4e which is provided in a part of the upper wall of the fuel tank facing the lower surface of the forward portion of the cylinder portion 5a of the engine. This part of the cylinder portion 5a is L-shaped in cross section in a direction toward the rear wheel and provides a clearance C2 between the concave portion 4e of the fuel tank 4 and the front end of the cylinder portion 5a. Under the cylinder portion 5a is arranged an extension 4f of the fuel tank 4 with an overlapping length L.
Also, in FIG. 4, the letter, "E", indicates an exhaust tube which is arranged in the space provided rearwardly of the fuel tank 4 and under the cylinder 5a.
According to the first aspect of the present invention, therefore, the described motorcycle has the advantageous effect that the cylinder portion of the engine can be disposed in a low position without having to extend the length of the wheel base.
According to the second aspect of the present invention, on the other hand, since the containment chamber disposed beneath the seat is capable of containing in divided compartments, a small sized helmet in the front portion and a large sized helmet in the rear portion, the containment chamber can contain two helmets without extending its longitudinal length and, moreover, with a reduced height from the ground to a position forwardly of the seat whereby the motorcycle has improved stability during its operation.
It should be further understood that, although a preferred embodiment of the invention has been illustrated and described herein, changes and modifications can be made in the described arrangement without departing from the scope of the appended claims. | A motorcycle of the scooter-type is provided with a frame body supporting an engine unit whose cylinder portion is inclined forwardly. According to one aspect of the invention the frame body is provided with oppositely spaced frame members that mount a fuel tank, the surface of which is recessed to provide a clearance space for reception of the cylinder portion of the engine unit thereby to reduce the effective length required for the vehicle. According to another aspect of the invention a box-like construction forms a helmet-containment chamber for disposition on the frame body between the engine unit and the seat. The construction is particularly adapted to retain a pair of helmets without increasing the effective length of the vehicle by providing a partition that divides the chamber into separate compartments each of which is capable of snugly retaining one of the helmets. | 1 |
FIELD OF THE INVENTION
This invention relates to new RAR selective retinoid agonists, to the use of such retinoic acid receptor agonists, particularly retinoic acid receptor γ selective agonists (RARγ-selective) for the treatment of emphysema.
BACKGROUND OF THE INVENTION
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, ranking third and fourth as the leading cause of death in the European Union and North America respectively. COPD is characterized by reduced maximum expiratory flow, which does not change over several months and which persists for 2 or more consecutive years. Patients with the most severe form of COPD generally present with a significant degree of emphysema. Emphysema is defined anatomically by permanent airspace enlargement distal to the terminal bronchioles. It is characterized by gradual loss of lung recoil, alveolar destruction, decreased alveolar surface area and gas exchange, leading to a reduced FEV1. These two features, impaired gas exchange and reduction in expiratory flow, are characteristic physiological abnormalities from which patients with emphysema suffer. The main symptom of patients with severe emphysema is shortness of breath during minimal physical activity.
The most common cause of emphysema is cigarette smoking although other potential environmental toxins may also contribute. These various insulting agents activate destructive processes in the lung including release of active proteases and free radical oxidants in excess of protective mechanisms. The imbalance in protease/anti-protease levels leads to destruction of the elastin matrix, loss of elastic recoil, tissue damage and continuous decline in lung function. Removing the injurious agents (i.e. quit smoking) slows the rate of damage, however, the damaged alveolar structures do not repair and lung function is not regained.
Retinoic acid is a multifunctional modulator of cellular behavior, having the potential to alter both extracellular matrix metabolism and normal epithelial differentiation. In lung, retinoic acid has been shown to modulate various aspects of lung differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Coordinated activation of RARβ and RARγ has been associated with lung branching and alveolization/septation. During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls and RARγ expression in the lung peaks. Depletion of these retinyl-ester stores parallels the deposition of new elastin matrix and septation. In support of this concept, Massaro et al., Am. J. Physiol., 1996, 270, L305-L310, demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RARβ mRNA and subsequent alveolar septation in developing rat lung was abrogated by all-trans retinoic acid.
Recent studies demonstrated that all-trans retinoic acid can induce formation of new alveoli and return elastic recoil to near normal in animal models of emphysema, D. Massaro et el., Nature Medicine, 1997, 3, 675. However, the mechanism by which this occurs remains unclear.
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3-4 didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lung. Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the steroid/thyroid receptor superfamily. The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (α, β, and γ). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with approximately equal affinity to all the three RAR subtypes, but does not bind to the RXR receptors for which 9-cis retinoic acid is the natural ligand.
In many non-pulmonary tissues, retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis. A limitation in the therapeutic use of retinoids outside of cancer has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective and therefore have pleiotropic effects throughout the body, which are often toxic. Recently various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (α, β, γ) within a class.
SUMMARY OF THE INVENTION
This invention provides new RAR selective retinoid agonists of formula I
wherein
one of R 4 and R 5 is hydrogen and the other is
R 1 is hydrogen, lower alkyl;
R 2 is lower alkyl;
R 3 is lower alkyl or H;
X is oxygen or sulfur;
n is 1 or 2; and
wherein the dotted bond is optional;
and pharmaceutically active salts of carboxylic acids of formula I.
The compounds of formula I contain a chiral carbon (to which R 2 is bound). These compounds may be present as a racemic mixture, i.e. (RS) or in the pure enantiomeric form as (S) or (R) isomer.
Activation of RAR has been associated with lung branching and alveolization. The retinoids according to the invention possess RAR agonist activity in vitro. Therefore such compounds would be useful for the treatment of emphysema and related pulmonary diseases. They may also be useful for the therapy and prophylaxis of dermatological disorders which are accompanied by epithelial lesions, e.g. acne and psoriasis, light- and age-damaged skin; as well as for the promotion of wound healing, for example of incised wounds, such as surgical wounds, wounds caused by burns and other wounds caused by cutaneous trauma; and for the therapy and prophylaxis of malignant and premalignant epithelial lesions, tumours and precancerous changes of the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
DETAILED DESCRIPTION OF THE INVENTION
When the dotted bond is present, a triple bond is meant, when the dotted bond is absent a double bond. Where the “dotted bond” is absent, the double bond may be “E” or “Z” configurated. The terms “E” and “Z” are used herein as defined in Pure and Applied Chem. 1976, 54, 12.
The term “lower alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, amyl and 3-pentyl.
The term “substantially free” of one or another isomer means that the ratio of the desired isomer to the undesired isomer is at least 95:5, more preferably at least 98:2. Resolution of the racemic mixture into either enantiomeric form can be performed in accordance with conventional techniques.
The compounds of formula I, wherein R 1 is hydrogen forms salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, and ammonium or substituted ammonium salts such as trimethylammonium salts which are within the scope of this invention.
Preferred compounds of formula I are the compounds of formula IA
wherein X, R 1 , R 2 , R 3 , n and the dotted bond are defined as above; and pharmaceutically active salts of carboxylic acids of formula IA.
Especially preferred compounds of formula IA are the compounds, wherein X is oxygen and n is 2, particularly compounds:
A 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydro-1-benzo[b]oxepin-8-yl-ethynyl)-benzoic acid
B 4-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
C 4-(5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
D (E)-4-[2-(5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid
E (E)-4-[2-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid
F (E)-4-[2-(5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid.
Further especially preferred are compounds of formula IA, wherein X is sulfur and n is 2, in particular the compounds:
G 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid
H 4-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid
I (E)-4-[2-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid
J (E)-4-[2-(5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid.
A further preferred group of compounds are the compounds of formula IB
wherein X, R 1 , R 2 , R 3 , n and the dotted bond are as defined above; and
pharmaceutically active salts of carboxylic acids of formula IB.
Especially preferred compounds of formula IB are those wherein n is 1 and X is oxygen, for example the compounds:
K 4-(4-methoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid
L (E)-4-[2-(4-methoxymethyl-4-methyl-chroman-6-yl)-vinyl]-benzoic acid.
The compounds according to the invention can be prepared in a manner known in the art. Compounds of formula IA, wherein n is 1 or 2 and the dotted bond is present may be prepared according to the method depicted in scheme 1.
wherein the symbols are as defined above and Hal is halogen such as iodine, bromine or chlorine.
Reaction Step 1a
A dihydrobenzo[b]oxepine- or dihydrobenzo[b]thiepine-one (1) is submitted to a Wittig-reaction with (methoxymethyl)triphenylphosphonium chloride in presence of a strong base, e.g. n-butyllithium, to form after acidic hydrolysis the aldehyde (2), the reaction is preferably carried out in a solvent as e.g. tetrahydrofuran (THF) at temperatures of about −78° to 0° C.
Reaction Step 1b
The carbaldehyde is then alkylated to (3) with an appropriate alkylhalogenide, preferably an alkyliodide in presence of a base as e.g. potassium tert.-butylate in a polar solvent, preferably in tert.-butanol. O-Alkylated side products can be separated and recycled if desired.
Reaction Step 1c
The reduction of the alkylated carbaldehyde (3) is preferably performed with sodium borohydride. The primary alcohol (4) obtained by this reduction is submitted to step 1d.
Reaction Step 1d
This etherification is preferably performed by deprotonation with a strong base as e.g. sodium hydride is a polar solvent, preferably N,N-dimethylformamide (DMF), and subsequent alkylation with an alkylhalogenide, preferably an alkyliodide.
Reaction Steps 1e, 1f and 1g
The halogenated tetrahydro-oxepine or -thiepine (5) is coupled with trimethylsilyl-acetylene in the presence of a base like piperidine or triethylamine and catalytic amounts of CuI, triphenylphosphine and bis(triphenylphoshpine) palladium (II) chloride or tetrakis-(triphenylphosphine)-palladium (0) to form the ethinylated derivative (6) (reaction step 1e).
After desilylation with catalytic amounts of sodium methylate in methanol to form compound (7) (reaction step 1f) alkyl-4-iodo-benzoate is attached by means of a second Sonogashira-coupling in the presence of a base like triethylamine and catalytic amounts of copper iodide, triphenylphosphine and bis(triphenylphosphine) palladium(II) chloride to yield the compound IA, wherein n is 2.
Reaction Step 1h
In the alternative shortcut, the halogenated tetrahydro-oxepine and -thiepine, respectively, (5) can be reacted directly with alkyl (4-ethynyl)benzoate as described in reaction step 1e in the presence of CuI, triphenylphosphine and tetrakis-(triphenylphosphine)-palladium (0) or bis-(triphenylphosphine)palladium (II) chloride to afford compound IA. However, if Hal is Br, the yields are satisfactory in the sulfur series only.
Compounds of formula IA, wherein the dotted bond is absent may be prepared according to the method depicted in scheme 2
Reaction Step 2a
The halogenated tetrahydro-oxepine or -thiepine, respectively, (5) is reacted subsequently with butyllithium and dimethyl formamide at −78° C. to yield after work-up with ammonium chloride the desired aldehyde (8).
Reaction Step 2b
The aldehyde (8) is then further elaborated via Wittig-Horner-reaction with the appropriate benzylic phosphonate in a polar aprotic solvent, preferably N,N-dimethylformamide or dimethylsulfoxide, in the presence of a strong base like sodium hydride, to afford trans-olefin IA. The Wittig-Horner reaction is highly “E” selective, and Schemes 2 and 4 illustrate synthesis of the “E” isomer. The corresponding “Z” isomer may be prepared in accordance with Scheme 1 or 3, followed by Lindlar reduction of the triple bond.
Compounds of formula IB, wherein n is 1 or 2 may be prepared according to the methods depicted in reaction schemes 3 and 4.
Whereas the compounds of formula IA can be prepared starting from meta-halogenated compounds (1), readily accessible from commercially available m-bromo-phenol and m-bromo-thiophenol, respectively; the compounds of formula IB are prepared starting from the not halogenated compounds (10), (prepared starting from phenol and thiophenol, respectively) which are functionalized at a later stage by conventional halogenation methods, see reaction step 3d. If R 3 =H in compounds of formulae 1A and 1B, the primary hydroxy group must be suitably protected as e.g. acetate throughout the synthesis. Finally, the ester group COOR 1 of compounds of formula IA and IB can be hydrolyzed to the free acids according to standard conditions, e.g. with sodium hydroxide in THF/ethanol/acetone.
The starting compounds (1) and (10) can be made as illustrated in Scheme 5, or in analogy thereto.
In another aspect, this invention is concerned with the use of RAR selective agonist with systemic administration being a preferred mode of delivery for treating emphysema and associated pulmonary diseases. It is thus concerned with a method for treating emphysema and associated pulmonary diseases by treatment of a mammal with a RAR selective agonist with systemic administration being a preferred mode of delivery.
A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The RARγ agonist selectivity of a compound can be determined by routine ligand binding assays known to one of skill in the art such as described in C. Apfel et al. Proc. Nat. Sci. Acad. (USA), 89:7129-7133 (1992); M. Teng et al., J. Med. Chem., 40:2445-2451 (1997); and PCT Publication WO 96/30009.
The use of RAR agonists disclosed herein may be used for promoting the repair of damaged alveoli and septation of new alveoli, particularly for the treatment emphysema. Treatment with RAR agonists, particularly RARγ selective agonists, is useful to promote repair of alveolar matrix and septation. As such, the methods disclosed herein are useful for treating diseases such as emphysema.
Typically, the dosage will range between about 0.01 and 1.0 mg/kg body weight per day, preferably from about 0.05 to about 0.5 mg/kg body weight per day.
In particular dosage of a RAR selective agonist required to treat lung emphysema will depend on the severity of the condition. This dosage may be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results. Dosing will continue for as long as is medically indicated, which depending on the severity of the disease and may range from a few weeks to several months.
Typically, a pharmaceutically acceptable composition, such as a salt, of the RAR agonist of formula I in a pharmaceutically acceptable carrier or diluent is administered. In the context of the present invention, pharmaceutically acceptable salts include any chemically suitable salt known in the art of retinoid agonists as applicable for administration to human patients. Examples of conventional salts known in the art include the alkali metal salts such as sodium and potassium salts, the alkaline earth metal salts such as calcium and magnesium salts, and ammonium and alkyl ammonium salts.
Representative delivery regimens include oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal, buccal (including sublingual), transdermal, pulmonary and intranasal. One method of pulmonary administration involves aerosolization of an aqueous solution of an RAR agonist. Aerosolized compositions may include the compound packaged in reverse micelles or liposomes. Typical pulmonary and respiratory delivery systems are described in U.S. Pat. Nos. 5,607,915, 5,238,683, 5,292,499, and 5,364,615.
The treatment methods of this invention also include systemic administration of RAR agonists in simultaneous or sequential combination with a further active ingredient.
RAR agonists will typically be administered as pharmaceutical compositions in admixture with a pharmaceutically acceptable, non toxic carrier. As mentioned above, such compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration. Any conventional carrier material can be employed. The carrier material can be any organic or inorganic carrier material, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, polyalkylene glycols, petroleum jelly and the like.
Liquid formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. They may employ slightly acidic buffers in pH ranges of about 4 to about 6. Suitable buffers include acetate, ascorbate and citrate at concentrations ranging from about 5 mM to about 50 mM. For oral administration, the formulation can be enhanced by the addition of bile salts or acylcarnitines.
Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. Particular nasal formulations include dry powders suitable for conventional dry powder inhalers (DPI's), liquid solutions or suspensions suitable for nebulization and propellant formulations suitable for use in metered dose inhalers (MDI's). For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration, the absorption across the nasal mucous membrane may be enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, cyclodextrins and the like in an amount in the range between about 0.2 and 15 weight percent, preferably between about 0.5 and 4 weight percent, most preferably about 2 weight percent.
Solid forms for oral administration include tablets, hard and soft gelatin capsules. pills, sachets, powders, granules and the like. Each tablet, pill or sachet may contain from about 1 to about 50 mg, preferably from 5 to about 10 mg of RAR agonist of formula I. Preferred solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular interest because they provide distinct advantages over the other two forms (see Seager, H., “Soft gelatin capsules: a solution to many tableting problems”; Pharmaceutical Technology, 9, (1985)). Some of the advantages of using SEG capsules are: a) dose-content uniformity is optimized in SEG capsules because the drug is dissolved or dispersed in a liquid that can be dosed into the capsules accurately b) drugs formulated as SEG capsules show good bioavailability because the drug is dissolved, solubilized or dispersed in an aqueous-miscible or oily liquid and therefore when released in the body the solutions dissolve or are emulsified to produce drug dispersions of high surface area and c) degradation of drugs that are sensitive to oxidation during long-term storage is prevented due to the dry shell.
Delivery of the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year, may be accomplished by a single administration of a controlled release system containing sufficient active ingredient for the desired release period. Various controlled release systems, such as monolithic or reservoir type microcapsules, depot implants, osmotic pumps, vesicles, micelles, liposomes, transdermal patches, iontophoretic devices and alternative injectable dosage forms may be utilized for this purpose. Localization at the site to which delivery of the active ingredient is desired is an additional feature of some controlled release devices, which may prove beneficial in the treatment of certain disorders.
The following are representative pharmaceutical formulations for using RAR selective agonists as described herein for promoting elastin mediated matrix repair and alveolar septation.
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.
Quantity per Ingredient
tablet, mg
RAR agonist of formula I
10
cornstarch
50
croscarmellose sodium
25
lactose
120
magnesium stearate
5
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient
Quantity per capsule, mg
RAR agonist of formula I
5
lactose, spray-dried
148
magnesium stearate
2
Suspension Formulation
The following ingredients are mixed to form a suspension for oral administration.
Ingredient
Amount
RAR agonist of formula I
1.0
g
fumaric acid
0.5
g
sodium chloride
2.0
g
methyl paraben
0.15
g
propyl paraben
0.05
g
granulated sugar
25.5
g
sorbitol (70% solution)
12.85
g
Veegum K (Vanderbilt Co.)
1.0
g
flavoring
0.035
ml
colorings
0.5
mg
distilled water
q.s. to 100
ml
Injectable Formulation
The following ingredients are mixed to form an injectable formulation.
Ingredient
Amount
RAR agonist
0.2
g
sodium acetate buffer solution, 0.4 M
2.0
ml
HCl (1 N) or NaOH (1 N)
q.s. to suitable pH
water (distilled, sterile)
q.s. to
20 ml
Nasal Formulation
The following ingredients are mixed to form a suspension for nasal administration.
Ingredient
Amount
RAR agonist
20
mg/ml
citric acid
0.2
mg/ml
sodium citrate
2.6
mg/ml
benzalkonium chloride
0.2
mg/ml
sorbitol
35
mg/ml
sodium taurocholate or glycocholate
10
mg/ml
The compounds prepared in the following examples have been prepared as racemic mixtures. However, the racemic mixtures can be easily resolved into the respective enantiomers according to well established methods, e.g. at the stage of the 2,3,4,5-tetrahydrobenzo[b]oxepinyl-methanol or 2,3,4,5-tetrahydrobenzo[b]thiepinyl-methanol, respectively. Such methods include separation by HPLC on a chiral column, e.g. a chiral NUCLEOSIL column; or separation by derivatization with a chiral acid, e.g. Mosher's acid, separation of the corresponding diastereomers by conventional techniques followed by reductive or hydrolytic cleavage of the ester.
EXAMPLE 1
1.1. Preparation of 4-(5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
a] 8-Bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde
14.27 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 50 ml of abs. THF and deprotonated at a temperature of −10° C. and −5° C. by adding via syringe 25.2 ml of 1.6 M n-butyllithium (1.55 eq., in hexane). The resultant red ylide solution was cooled to −75° C. and treated with 6.20 g (26.0 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one dissolved in 13 ml of abs. THF. The mixture was then kept for 0.2 h at −78° C. and for 1 h at room temperature, poured onto crushed ice and extracted with diethylether. The organic phase was washed with water and dried over magnesium sulfate, filtrated and the solvent evaporated to yield a crude product which was purified by flash chromatography (SiO 2 , hexane/ethylacetate=95/5). Thereby, 5.85 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]oxepine was obtained as E/Z-mixture which was hydrolyzed as follows:
This enolether (21.7 mmol) was dissolved in 30 ml of THF and then treated with 31.5 ml of 35% HClO 4 . After stirring for 16 h, the resultant mixture was distributed between ice-cold water and diethylether. The organic layer washed with Na 2 CO 3 (pH ca.10) and water, dried over magnesium sulfate, filtrated and the solvent evaporated to afford 4.63 g of the title compound as colorless oil (96% pure according to GC (gas chromatography)).
b] 8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde
2.59 g (10.2 mmol) of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde was dissolved in 25 ml of abs. tert.-butanol. At 0° C. 2.28 g (2 eq.) of potassium tert.-butylate was added, followed by 1.58 ml (2.5 eq.) of methyliodide after 0.3 h. Stirring was continued at room temperature until TLC (thin layer chromatography) indicated the disappearance of starting material. The reaction mixture was then poured onto crushed ice and extracted twice with diethylether. The organic phase was washed with water, dried over magnesium sulfate, filtrated and the solvent evaporated under reduced pressure. Flash chromatography (SiO 2 , hexane/ethylacetate 97/3) gave 1.85 g of the title compound as colorless oil (98% pure according to GC).
c] (8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-methanol
20.6 g (76.5 mmol) of 8-bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde was dissolved in 100 ml of abs. ethanol and cooled to 0° C. 2.896 g (1 mol-eq.) of NaBH 4 was added in several portions and the reaction allowed to proceed for 0.5 h at 0° C. and for 0.5 h at room temperature. The reaction mixture was poured onto crushed ice and extracted with diethylether. The organic phase was washed with water, dried over sodium sulfate and the solvent evaporated. Thereby were obtained 21.5 g of the title compound as colorless oil, sufficiently pure for the next step.
d] 8-Bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine
The above obtained primary alcohol (˜76.5 mmol) was dissolved in 100 ml of abs. DMF and treated at −10° C. with 2.40 g of NaH (ca. 50% in mineral oil, ca. 1.3 eq.). Deprotonation was allowed to proceed at room temperature. When evolution of hydrogen had ceased, the mixture was cooled to 0° C., treated with 6.24 ml of methyliodide (1.3 eq.) and then kept for 0.2 h at 0° C. and for 0.75 h at room temperature (white precipitate of Nal formed). Hydrolysis with cold water, extraction with diethylether, washing the organic phase with NH 4 Cl-solution, drying over sodium sulfate, filtration and evaporation of the solvent left a crude product, which was purified by filtration over SiO 2 (hexane/ethylacetate 95/5) to afford 22.5 g of the title product as colorless oil (96.5% pure according to GC).
e] (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-trimethylsilane
To 22.5 g (<76.5 mmol) of 8-bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydro-benzo[b]oxepine, dissolved in 50 ml of piperidine, was added successively 291 mg (0.02 eq.) of CuI, 401 mg (0.02 eq.) of triphenylphoshine (Ph 3 P), and 884 mg (0.01 eq.) of (Ph 3 P) 4 Pd. After heating to 80° C., a solution of 26.5 ml (2.5 eq.) of trimethylsilylacetylene in 25 ml of piperidine was added within 1 h via dropping funnel. Since GC-analysis indicated, that 6% of starting material was still remaining, an additional amount of 3 ml of trimethylsilylacetylene was added in two portions. After cooling, the reaction mixture was poured onto crushed ice, extracted with diethylether, the organic phase washed with HCl dil., dried over sodium sulfate, filtrated and evaporated to dryness. Flash chromatography (SiO 2 , hexane/ethylacetate 95/5) yielded 26.3 g of the title compound as yellowish oil, sufficiently pure for the next step (91% pure according to GC).
f] 8-Ethynyl-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine
A small piece of sodium was dissolved in 100 ml of abs. methanol. The sodium methylate solution was added in one portion to 26.3 g (<76 mmol) of the above prepared 5-methoxy -methyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-trimethylsilane at 0° C. and then kept for 0.75 h at room temperature. The reaction mixture was poured on an aqueous saturated ammonium chloride solution and extracted with diethylether, the organic phase was separated, dried over sodium sulfate, filtrated and the solvents were removed. Flash chromatography (SiO 2 , hexane/ethylacetate 96/4) yielded 15.60 g of the title compound as a pale yellow oil (96.5% pure according to GC).
g] 4-(5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid methyl ester
In 165 ml of abs. DMF was successively dissolved 20.96 g (1.25 eq.) of methyl 4-iodo-benzoate, 2.29 g (0.04 eq.) of bis (triphenylphosphine)palladium(II) chloride, 1.86 g (0.12 eq.) of CuI, and 27.9 ml (2.5 eq.) of triethylamine. 14.67 g (63.7 mmol) of the above prepared 8-ethynyl-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine, dissolved in 60 ml of abs. DMF, was added within 0.75 h via dropping funnel, 0.25 h later, the reaction was quenched by pouring the reaction mixture onto crushed ice/ HCl, extracted with diethylether; the organic phase was washed with water, dried over sodium sulfate, filtrated and evaporated to dryness. Flash chromatography (SiO 2 , hexane/ethylacetate 91/9) produced, after crystallization from the same solvent mixture, 19.5 g of the title compound as white crystals of m.p. 111.5-112.5° C.
h] 4-(5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
20.06 g (55.04 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 100 ml of THF/ethanol (1/1) and treated with 8.81 g (4 eq.) of NaOH, dissolved in 50 ml of water. The reaction flask was kept in the dark and stirring continued for 42 h at room temperature. The mixture was then poured onto crushed ice/60 ml of 25% HCl, extracted twice with ethylacetate; the organic phase was washed with a small amount of water, dried over sodium sulfate, filtrated, and evaporated to dryness. Crystallization from hexane/ethylacetate yielded 18.90 g of the title product as pale yellow crystals of m.p. 205-206° C.
Elemental Analysis: C 22 H 22 O 4 Calculated: C75.41% H6.33% Found: C75.31% H6.17%.
NMR: (1H, δ, TMS, CDCl 3 ) 1.40 (s, 3H), 1.59 (m, 1H), 1.9-2.15 (m, 3H), 3.36 (s, 3H), 3.37 (d, J=9, 1H), 3.83 (d, J=9, 1H), 3.85 (m, 1H), 4.10 (m, 1H), 7.18 (d, J=1, 1H), 7.23 (dxd, J=8, J=1, 1H), 7.28 (d, J=8, 1H), 7.60 (d, J=8.5, 2H), 8.09 (d, J=8.5, 2H).
1.2. Preparation of 4-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
This compound was prepared in analogy to example 1.1. but using in step d] ethyliodide instead of methyliodide. White crystals of m.p. 170-171° C. were obtained. MS: (M) + 364, (M—CH 2 OC 2 H 5 ) + 305.
1.3. Preparation of 4-(5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid
This compound was prepared in analogy to example 1.1. but using in step d] propyl iodide instead of methyl iodide. Off-white crystals of m.p. 148-149° C. were obtained.
MS: (M) + 378, (M-CH 2 OC 3 H 7 ) + 305.
EXAMPLE 2
2.1. Preparation of 4-[2-(5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl) -vinyl]-benzoic acid
a] 5-Allyl-8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde
0.55 g (2.18 mmol) of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde (see example 1, step a]) was dissolved in 5 ml of abs. THF and 1 ml of abs. tert.-butanol. At 0° C. 0.490 g (2 eq.) of potassium tert.-butylate was added, followed by 0.552 ml (3 eq.) of allylbromide 0.1 h later. Stirring was continued at the same temperature until TLC (thin layer chromatography) indicated the disappearance of starting material. The reaction mixture was then poured onto crushed ice/NH 4 Cl-solution, extracted twice with diethylether, the organic phase was washed with water, dried over sodium sulfate, filtrated and the solvents were removed. Flash chromatography (SiO2, hexane/ethylacetate 95/5) gave 0.224 g of the title compound as colorless oil (98% pure according to GC).
b] (5-Allyl-8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-methanol
0.216 g (0.732 mmol) of 5-allyl-8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepine-5-carbaldehyde was dissolved in 7 ml of abs. ethanol and cooled to 0° C. 0.028 g (1 mol-eq.) of NaBH 4 was added at once and the reaction allowed to proceed for 0.5 h at 0° C. Pouring onto crushed ice, twofold extraction with diethylether, washing the organic phase with water, and drying over sodium sulfate, filtrating and removing the solvent left 0.230 g of the title compound as colorless oil, sufficiently pure for the next step (96% pure according to GC).
c] (8-Bromo-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-methanol
0.230 g of the above prepared (5-allyl-8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl) -methanol was dissolved in 10 ml of ethylacetate and hydrogenated over 0.20 g of 5% Pd/C during 0.5 h at room temperature and 1.01×10 5 Pa of H 2 . The progress of the reaction must be followed carefully in order to avoid reductive removal of the bromine! After filtration over a pad of Celite the solvent was removed. Flash chromatography (SiO 2 , hexane/ethylacetate 8/2) produced 0.191 g of the title compound as colorless oil (GC-purity 91%).
In principle, this intermediate can also be prepared as described in example 1, step b] by using propyliodide for the alkylation. However, the yields are distinctively lower.
d] 8-Bromo-5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepine
0.191 g (0.638 mmol) of (8-bromo-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-methanol) was dissolved in 3 ml of abs. DMF and treated at 0° C. with 0.061 g of NaH (ca. 50% in mineral oil, ca. 2 eq.). Deprotonation was allowed to proceed at room temperature for 0.2 h. The mixture was cooled to 0° C., treated with 0.079 ml of methyliodide (2 eq.) and then kept for 1 h at room temperature. Hydrolysis with cold water, acidification with NTH 4 Cl-solution, extraction with diethylether, drying the organic phase over sodium sulfate, filtration and evaporation of the solvents left a crude product, which was purified by flash chromatography (SiO2, hexane/ethylacetate 96/4) to give 0.179 g of the title compound as colorless oil (93% pure according to GC).
e] 5-Methoxymethyl-5-propyl -2,3,4,5-tetrahydrobenzo[b]oxepine-8-carbaldehyde
0.179 g (0.571 mmol) of 8-bromo-5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b] oxepine was dissolved in 5 ml of abs. THF and cooled to −78°. 0.447 ml of n-butyllithium (1.5M, hexane) was slowly added and the temperature maintained for 0.2 h. 0.141 ml (3.2 eq.) of abs. DMF was introduced via syringe and stirring continued for 0.25 h. Warming to room temperature, pouring onto crushed ice/ NH 4 Cl-solution, twofold extraction with diethylether, and drying the organic phase over sodium sulfate, filtration and evaporation of the solvent left 0.18 g of a crude product, which was purified by flash chromatography (SiO 2 , hexane/ethylacetate 9/1) to give 0.125 g of the title compound as colorless oil (98% pure according to GC).
f] (E)-4-[2-(5-Methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid ethyl ester
0.048 g of NaH (50% in mineral oil) was suspended in 3 ml of abs. DMF. 0.27 g of 4-(diethoxyphosphorylmethyl)-benzoic acid ethyl ester was added at 0° C. The mixture was stirred at room temperature, until H 2 -formation had ceased. After cooling to −10° C., 0.119 g (0.454 mmol) of 5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b] oxepine-8-carbaldehyde, dissolved in 2 ml of DMF, was added and allowed to react for 0.2 h at −10° C. and for 1 h at room temperature The mixture was then poured onto crushed ice/ NH 4 Cl-solution, extracted with diethylether, the organic phase was washed with water, dried over sodium sulfate, filtrated and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/ethylacetate 9/1) left finally 0.088 g of pure, colorless title compound which solidified spontaneously.
g] 4-[2-(5-Methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid
0.081 g (0.198 mmol) of (E)-4-[2-(5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid ethyl ester was dissolved in 1 ml of THF/ethanol (1/1) and treated with 0.33 ml of 3N NaOH (5 eq). The reaction flask was kept in the dark and stirring continued for 20 h at room temperature. The mixture was then poured onto crushed ice/diluted HCl, extracted twice with ethylacetate, the organic phase was washed with water, dried over sodium sulfate, filtrated and evaporated to dryness. Crystallization from hexane/ethylacetate yielded 0.46 g of the title product as white crystals of m.p. 157-159° C.
MS: (M) + 380, (M-CH 2 OCH 3 ) + 335.
NMR: (1H, δ, TMS, DMSO)) 0.81 (t, J=7, 3H), 0.9-1.25 (m, 2H), 1.6-2.05 (m, 6H), 3.30 (s, 3H), 3.44 (d, J=9, 1H), 3.66 (d, J=9, 1H), 3.72 (m, 1H), 4.11 (m, 1H), 7.17 (d, J=8, 1H), 7.21 (d, J=1, 1H), 7.28 (dxt, J=8, J=1, 1H), 7.31 (br s, 2H), 7.70 (d, J=8, 2H), 7.93 (d, J=8, 2H), 12.91 (br s, COOH).
2.2. Preparation of (E)-4-[2-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid
This compound was prepared in analogy to example 2.1., but using in step e] 8-bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepine instead of the propyl-analogue. Colorless crystals of m.p. 194-96° C. were obtained.
CI−MS: (M−H) + 351.
IR(cm −1 ): 2667, 2546, 1688, 1606, 1567, 1419, 1291, 1238, 1179, 1080, 958, 871, 768.
NMR: (1H, δ, TMS, CDCl 3 ) 1.41 (s,3H), 1.59 (m, 1H), 1.9-2.15 (m, 3H), 3.37 (s,3H), 3.37 (d, J=9, 1H), 3.84 (d, J=9, 1H), 3.86 (m, 1H), 4.12 (m, 1H), 7.08-7.28 (m, 5H), 7.58 (d, J=8.2, 2H), 8.09 (d, J=8.2, 2H).
2.3. Preparation of (E)-4-[2-(5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)-vinyl]-benzoic acid
was prepared in analogy to example 2.1., but using in step e] 8-bromo-5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo[b] oxepine instead of 8-bromo-5-methoxymethyl- 5-propyl-2,3,4,5-tetrahydrobenzo[b]oxepine. Colorless crystals of m.p. 164-65° C. were obtained.
MS: (M) + 380, (M-CH 2 OC 3 H 7 ) + 307.
2.4. Preparation of (E)-4-[2-(4-methoxymethyl-4-methyl-chroman-6-yl)-vinyl]-benzoic acid
was prepared in analogy to Example 2.1., but using in step e] instead of 8-bromo-5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b] oxepine 6-bromo-4-methoxymethyl-4-methyl-chroman, synthesis is described in Example 5 d]. Yellowish crystals of m.p. 209-210° C. were obtained.
NMR: (1H, δ, TMS, DMSO) 1.30 (s, 3H), 1.68 (dxdxd, 1H), 2.04 (dxdxd, 1H), 3.27 (s, 3H), 3.41 (d, J=9, 1H), 3.51 (d, J=9, 1H), 4.17 (m, 2H), ,6.77 (d, J=8, 1H), 7.18 (d, J=16, 1H) 7.32 (d, J=16, 1H), 7.38 (dxd, J=8, J=2, 1H), 7.60 (d, J=2, 1H), 7.66 (d, J=8.3, 2H) 7.91 (d, J=8.3, 2H).
CI−MS: (M−H) + 337.
EXAMPLE 3
3.1. Preparation of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid
a] 8-Bromo-2,3,4,5-tetrahydrobenzo[b]thiepine-5-carbaldehyde
16.68 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 75 ml of abs. THF and deprotonated between −15° C. and −5° C. by adding via syringe 29.5 ml of 1.6 M n-butyllithium (hexane, 1.55 eq.). The resultant red ylide solution was cooled to −75° C. and treated with 7.82 g (30.4 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]thiepin-5-one, dissolved in 15 ml of abs. THF. The mixture was then kept for 0.3 h at −78° C. and for 1.25 h at room temperature. Pouring onto crushed ice, twofold extraction with diethylether, washing the organic phase with water, drying over magnesium sulfate, filtration and evaporation of the solvents yielded a crude product which was purified by flash chromatography (SiO 2 , hexane/ethylacetate 95/5); thereby, 7.39 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]thiepine was obtained as E/Z-mixture which was hydrolyzed as follows:
This enolether (25.8 mmol) was dissolved in 37 ml of THF and then treated with 37 ml of 35% HClO 4 . After stirring for 16 h at room temperature, the resultant mixture was distributed between ice-cold water and diethylether, the organic layer was washed twice with Na 2 CO 3 (pH ca.10) and water, dried over magnesium sulfate, filtrated and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/ethylacetate 95/5) left finally 6.33 g of the title compound as colorless oil (98% pure according to GC).
MS: (M) + 270,272, (M-CO) + 242,244.
b] 8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-5-carbaldehyde
1.00 g (3.69 mmol) of 8-bromo-2,3,4,5-tetrahydrobenzo[b]thiepine-5-carbaldehyde was dissolved in 8 ml of abs. THF/abs. tert.-butanol (10/1). At 0° C. 0.828 g (2 eq.) of potassium tert.-butylate was added, followed by 0.575 ml (2.5 eq.) of methyliodide after 0.25 h. Stirring was continued for 5 h at room temperature. The reaction mixture was then poured onto crushed ice and extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and the solvent was removed. Flash chromatography (SiO2, hexane/ethylacetate 96/4) gave 0.636 g of the title compound as colorless oil.
c] (8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl)-methanol
636 mg (2.23 mmol) of 8-bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-5-carbaldehyde was dissolved in 15 ml of abs. ethanol and cooled to 0° C. 84.4 mg (1 mol-eq.) of NaBH 4 was added and the reaction allowed to proceed for 2 h at room temperature. Pouring onto crushed ice, extraction with diethylether, washing the organic phase with water, drying over magnesium sulfate, filtration and evaporation of the solvent left 628 mg of the title compound as white solid, which was used in the next step without further purification (93.5% pure according to GC).
d] 8-Bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine
628 mg (2.19 mmol) of (8-bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl) -methanol was dissolved in 12 ml of abs. DMF and treated at 0° C. with 210 mg of NaH (ca. 50% in mineral oil, ca. 2 eq.). Deprotonation was allowed to proceed at 0° C. for 1 h. The resultant solution of the corresponding sodium alkoxide was then treated with 0.204 ml of methyliodide (1.5 eq.) and kept for 2 h at room temperature. Hydrolysis with cold water, extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, filtration and evaporation of the solvent left a crude product, which was purified by filtration over SiO 2 (hexane/ethylacetate 96/4) to produce 576 mg of the title compound as colorless oil (95% pure according to GC).
MS: (M) + 300,302, (M-CH 2 OCH 3 ) + 255,257.
e] 4-(5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid methyl ester
To 478 mg (1.59 mmol) of 8-bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine, dissolved in 2.9 ml of piperidine, was added successively 4.8 mg (0.02 eq.) of CuI, 7.0 mg (0.02 eq.) of Ph 3 P, and 24.1 mg (0.01 eq.) of (Ph 3 P) 4 Pd. After heating to 80° C., a solution of 508 mg (2 eq.) of 4-ethynyl-benzoic acid methyl ester in 2.8 ml of piperidine was added within 2 h via dropping funnel and then kept at this temperature for 3 additional h. After cooling, the reaction mixture was poured onto crushed ice/ HCl diluted, extracted with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness. Flash chromatography (SiO 2 , hexane/ethylacetate 95/5) yielded 270 mg of the title compound as colorless oil.
MS: (M) + 380, (M-CH 2 OCH 3 ) 335.
f] 4-(5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid
316 mg (0.83 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 8 ml of THF/EtOH (1/1) and treated with 1.38 ml of 3N NaOH (5 eq.). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/ HCl, extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and evaporated to dryness. Crystallization of the residue from hexane/ethylacetate yielded 282 mg of the title product as white crystals of m.p. 182-183° C.
NMR: (1H, δ, TMS, CDCl 3 ) 1.51 (s, 3H), 1.74 (m, 1H), 1.99 (m, 1H), 2.13 (m, 2H), 2.77 (t, J=6, 2H), 3.37 (s, 3H), 3.65 (d, J=9, 1H), 3.95 (d, J=9, 1H), 7.38 (s, 2H), 7.60 (d, J=8.4, 2H), 7.72 (s, 1H), 8.09 (d, J=8.4, 2H).
MS: (M) + 366, (M-CH 2 OCH 3 ) + 321.
3.2. Preparation of 4-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-ylethynyl)-benzoic acid
This compound was prepared in analogy to Example 3.1., but using in step e] 8-bromo-5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine instead of the 5-methoxymethyl -derivative. White crystals of m.p. 154-155° C. were obtained.
MS: (M) + 380, (M-CH 2 OC 2 H 5 ) + 321.
EXAMPLE 4
4.1. Preparation of (E)-4-[2-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid
a] 8-Bromo-5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine
917 mg (3.19 mmol) of (8-bromo-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-5-yl) -methanol (Example 3.1. c]) was dissolved in 17 ml of abs. DMF and treated at 0° C. with 309 mg of NaH (ca. 50% in mineral oil, ca. 2 eq.). Deprotonation was allowed to proceed at 0° C. for 0.25 h. The resultant solution of the corresponding sodium alkoxide was then treated with 0.389 ml of ethyliodide (1.5 eq.) and kept for 1 h at room temperature. Hydrolysis with cold water, extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, filtration and evaporation of the solvent left a crude product, which was purified by filtration over SiO 2 (hexane/ethylacetate 95/5) to produce 966 mg of the title compound as colorless oil (98% pure according to GC).
b] 5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde
431 mg (1.37 mmol) of 8-bromo-5-ethoxymethyl-5-methyl-2,3,4,3-tetrahydrobenzo[b]thiepine was dissolved in 3.5 ml of abs. THF and cooled to −78° C. 0.97 ml of n-butyllithium (1.55M, hexane) was slowly added and the temperature maintained for 0.3 h. 0.316 ml (3eq.) of abs. DMF was introduced via syringe and stirring continued for 0.1 h at −78° C. Warming the reaction mixture to room temperature, pouring it onto crushed ice, and extract it with diethylether, washing the organic phase with water, and drying it over sodium sulfate left after filtration and evaporation of the solvent a crude product, which was purified by flash chromatography (SiO 2 , hexane/ethylacetate 95/5) to give 0.339 g of the title compound as colorless oil (99% pure according to GC).
c] (E)-4-]2-(5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]benzoic acid methyl ester
85 mg of NaH (ca. 1.4 eq., 50% in mineral oil) was added to a solution of 534 mg (1.4 eq.) of 4-(diethoxyphosphorylmethyl)-benzoic acid ethyl ester in 1.9 ml of abs. DMF at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 1.5 h. After cooling to 0° C., 336 mg (1.27 mmol) of 5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde, dissolved in 1 ml of DMF, was added and allowed to react for 2 h at room temperature. The mixture was then poured onto crushed ice, extracted twice with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane/ethylacetate 95/5) afforded 409 mg of pure, colorless title compound.
d] (E)-4-[2-(5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]benzoic acid
406 mg (0.99 mmol) of (E)-4-[2-(5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid methyl ester was dissolved in 4 ml of THF/ethanol=1/1 and treated with 1.32 ml of 3N NaOH(4 eq). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/diluted HCl, extracted twice with ethylacetate, the organic phase was washed with a small amount of water, dried over magnesium sulfate, filtrated and the solvent evaporated. Crystallization of the residue from hexane/ethylacetate (8/2) yielded 337 mg of the title compound as white crystals of m.p. 186-187° C.
NMR: (1 H, δ, TMS, DMSO) 1.10 (t, J=7, 3H), 1.43 (s, 3H), 1.65-2.15 (m,4H),, 2.79 (m, 2H), 3.46 (m, 2H), 3.61 (d, J=9, 1H), 3.88 (d, J=9, 1H), 7.33 (s, 2H), 7.42 (d, J=8, 1H), 7.50 (br d, J=S, 1H), 7.68 (br s, 1H), 7.71 (d, J=8.3, 2H), 7.93 (d, J=8.3, 2H), 12.92 (br s, COOH).
MS: (M) + 382, (M-CH 2 OC 2 H 5 ) + 323.
4.2. Preparation of (E)-4-[2-(5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)-vinyl]-benzoic acid
This compound was prepared in analogy to Example 4.1.; White crystals of m.p. 169-170° were obtained, but using in step c] 5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde instead of 5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]thiepine-8-carbaldehyde. The former had been prepared in analogy to Example 2.1., a]-d], but starting the whole reaction sequence with 8-bromo-3,4-dihydro-2 H-benzo[b]thiepin-5-one instead of the oxa-analogue. White crystals of m.p. 169-170° were obtained.
CI−MS: (M−H) + 395.
EXAMPLE 5
5.1. Preparation of 4-(4-methoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid
a] 4-Methyl-chroman-4-carbaldehyde
5.28 g (32.55 mmol) of chroman-4-carbaldehyde was dissolved in 100 ml of abs. THF/abs. tert.-butanol (5/1). At −10° C., 7.31 g (2 eq.) of potassium tert.-butylate was added, followed after 0.25 h by 4.05 ml (2.0 eq.) of methyliodide. Stirring was continued at room temperature over night. The reaction mixture was then poured onto crushed ice and extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and the solvent was removed. Flash chromatography (SiO 2 , hexane/ethylacetate 9/1) yielded 4.29 g of the title compound as colorless oil (96.5% pure according to GC).
MS: (M) + 176, (M-HCO) + 147.
b] (4-Methyl-chroman-4-yl)-methanol
4.29 g (24.3 mmol) of 4-methyl-chroman-4-carbaldehyde was dissolved in 160 ml of abs. ethanol and cooled to 0° C. 0.921 g (1 mol-eq.) of NaBH 4 was added in several portions and the reaction allowed to proceed for 16 h at room temperature. Pouring onto crushed ice, twofold extraction with diethylether, washing the organic phase with water, and drying it over magnesium sulfate left, after filtration and evaporation of the solvent, 4,41 g of the title compound as pale yellow oil, sufficiently pure for the next step (GC:>97%).
c] 4-Methoxymethyl-4-methyl-chroman
2.00 g (11.2 mmol) of (4-methyl-chroman-4-yl)-methanol was dissolved in 60 ml of abs. DMF and treated at 0° with 1.08 g of NaH (ca. 50% in mineral oil, ca. 2 eq.). Deprotonation was allowed to proceed at 0° C. for 0.75 h. When evolution of hydrogen had ceased, the mixture was treated with 1.05 ml of methyliodide (1.5 eq.) and then kept for 0.2 h at 0° C. and for 0.5 h at room temperature. Careful hydrolysis with cold water, twofold extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, left, after filtration and evaporation of the solvent, a crude product, which was purified by flash chromatography over SiO 2 (hexane/ethylacetate 9/1) to give 2.01 g of the title compound as colorless oil (97% pure according to GC).
MS: (M) + 192, (M-CH 2 OCH 3 ) + 147.
d] 6-Bromo-4-methoxymethyl-4-methyl-chroman
2.00 g (10.4 mmol) of 4-methoxymethyl-4-methyl-chroman was dissolved in 25 ml of abs. CH 2 Cl 2 and treated with a catalytic amount of Fe-powder and Na 2 CO 3 . After cooling to 0° C., 1.21 m of bromine (1.1 eq.) was added and the mixture kept for 0.6 h at this temperature. Pouring onto crushed ice, extraction with diethylether, washing the organic phase with water, drying it over magnesium sulfate, filtration and evaporation of the solvents, and ensuing flash chromatography over SiO 2 (hexane/ethylacetate 95/5) yielded 1.676 g of pure title compound as colorless oil (GC>95%).
MS: (M) + 270,272, (M-CH 2 OCH 3 ) + 225,227.
e] (4-Methoxymethyl-4-methyl-chroman-6-ylethynyl)-trimethylsilane
To 1.67 g (6.16 mmol) of 6-bromo-4-methoxymethyl-4-methyl-chroman, dissolved in 11.5 ml of piperidine, was added successively 19 mg (0.02 eq.) of CuI, 27.5 mg (0.02 eq.) of triphenylphosphine (Ph 3 P), and 93 mg (0.01 eq.) of (Ph 3 P) 4 Pd. After heating to 80° C., a solution of 4.27 ml (5 eq.) of trimethylsilyl-acetylene in 19 ml of piperidine was added within 2.5 h via dropping funnel. After cooling, the reaction mixture was poured onto crushed ice, extracted with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and the solvent was evaporated. Flash chromatography (SiO 2 , hexane/ethylacetate 95/5) of the residue afforded 1.44 g of the title compound as colorless oil, sufficiently pure for the next step.
f] 6-Ethynyl-4-methoxymethyl-4-methyl-chroman
A catalytic amount of sodium was dissolved in 22 ml of abs. methanol. To the resultant solution of sodium methylate was then added in one portion the above prepared (4-methoxymethyl-4-methyl-chroman-6-ylethynyl)-trimethylsilane (1.44g, 4.99 mmol), dissolved in a small amount of methanol, at 0° C. and then kept for 1 h at room temperature. The reaction mixture was poured onto crushed ice, extracted twice with diethylether, the organic phase was dried over magnesium sulfate, filtrated and the solvents were removed. Flash chromatography (SiO 2 , hexane/ethylacetate 96/4) yielded 0.704 g of the title compound as a pale yellow oil, >94% pure according to GC.
MS: (M) + 216, (M-CH 2 OCH 3 ) + 171.
g] 4-(4-Methoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid methyl ester
In 11 ml of abs. DMF was successively dissolved 1.061 g (1.25 eq.) of methyl 4-iodo-benzoate, 114 mg (0.05 eq.) of bis (triphenylphosphine)palladium(II) chloride, 74.1 mg (0.12 eq.) of CuI, and 1.13 ml (2.5 eq.) of triethylamine. 701 mg (3.24 mmol) of the above prepared 6-ethynyl-4-methoxymethyl-4-methyl-chroman, dissolved in 2.7 ml of abs. DMF, was added within 1 h via dropping funnel. After 0.25 h, the reaction was quenched by pouring the reaction mixture onto crushed ice/ HCl. Extraction with diethylether, washing the organic phase twice with water, drying it over magnesium sulfate, filtration and evaporation of the solvent yielded after flash chromatography (SiO 2 , hexane/ ethylacetate 92/8) 630 mg of the title compound as yellowish oil.
h] 4-(4-Methoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid
625 mg (1.78 mmol) of 4-(4-methoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid methyl ester was dissolved in 9 ml of THF/ethanol (1/1) and treated with 2.34 ml of 3N NaOH (4 eq.). The reaction flask was kept in the dark and stirring continued for 18 h at room temperature. The mixture was then poured onto crushed ice/ HCl, extracted twice with diethylether, the organic phase was washed with water, dried over magnesium sulfate, filtrated and the solvent was evaporated. Crystallization from ethylacetate yielded 545 mg of the title product as white crystals of m.p. 202-203° C.
NMR: (1H, δ, TMS, DMSO) 1.27 (s, 3H), 1.66 (dxdxd, 1H), 2.02 (dxdxd, 1H), 3.26 (s,3H), 3.39 (d, J=9, 1H), 3.50 (d, J=9, 1H), 4.19 (m, 2H), 6.80 (d, J=8.4, 1H), 7.30 (dxd, J=8.4, J=2, 1H), 7.57 (d, J=2, 1H), 7.63 (d, J=8.3, 2H), 7.95 (d, J=8.3, 2H), 13.14 (br s, COOH).
MS: (M) + 336, (M-CH 2 OCH 3 ) + 291.
EXAMPLE 6
6.1. Preparation of (E)-4-(4-hydroxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid
a] Acetic acid 4-methyl-chroman-4-ylmethyl ester
1.00 g (5.61 mmol) of (4-methyl-chroman-4-yl)-methanol was dissolved in 6 ml of abs. CH 2 Cl 2 , treated at 0° C. with 1.17 ml (1.5 eq. ) of triethylamine and 0.518 ml (1.3 eq.) of acetylchloride and then kept for 0.5 h at room temperature. The reaction mixture was poured onto crushed ice and extracted twice with diethylether; the organic phase was washed with water, dried over sodium sulfate, filtrated and the solvents were removed. Flash chromatography (SiO2, hexane/ethylacetate 9/1) gave 1.082 g of pure title compound as colorless oil.
MS: (M) + 220, (M-CH 2 OAc) + 147.
b] Acetic acid 6-bromo-4-methyl-chroman-4-ylmethyl ester
Was prepared in analogy to Example 5d], by bromination of the above prepared acetic acid 4-methyl-chroman-4-ylmethyl ester.
MS: (M) + 298,300 (M-CH 2 OAc) + 225,227.
NMR: (1 H, δ, TMS, DMSO) 1.29 (s, 3H), 1.69 (dxdxd, 1H), 1.99 (dxdxd, 1H), 4.08-4.2 (m, 4H),, 6.73 (d, J=8.7, 1H), 7.25 (dxd, J=8.7, J=2.4, 1H) 7.53 (d, J=2.4, 1H).
c] Acetic acid 4-methyl-6-trimethylsilanylethynyl-chroman-4-ylmethyl ester
Was prepared in analogy to Example 5e] from acetic acid 6-bromo-4-methyl-chroman-4-ylmethyl ester.
MS: (M) + 316 (M-CH 2 OAc) + 243.
d] Acetic acid 6-ethynyl-4-methyl-chroman-4-ylmethyl ester
Was prepared in analogy to Example 5f] from acetic acid 4-methyl-6-trimethylsilanyl ethynyl-chroman-4-ylmethyl ester.
MS: (M) + 244 (M-CH 2 OAc) + 171.
e] 4-(4-Acetoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid methyl ester
Was prepared in analogy to Example 5g] from acetic acid 6-ethynyl-4-methyl-chroman-4-ylmethyl ester.
MS: (M) + 378, (M-CH 3 O) + 347, (M-CH 2 OAc) + 305.
f] 4-(4-Hydroxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid
498 mg (1.32 mmol) of 4-(4-acetoxymethyl-4-methyl-chroman-6-ylethynyl)-benzoic acid methyl ester was dissolved in 7 ml of THF/ethanol (1/1) and treated with 1.75 ml of 3N NaOH (4 eq.). The reaction flask was kept in the dark and stirring continued for 4 h at room temperature. The mixture was then poured onto crushed ice/ HCl, extracted twice with diethylether, the organic phase was washed with brine, dried over magnesium sulfate, filtrated and the solvent evaporated. Crystallization from ethylacetate at −30° C. yielded 334 mg of the title compound as off-white crystals of m.p. 234-235° C.
MS: (M) + 322, (M-CH 2 OH) + 291.
IR(cm −1 ): 2924, 2854, 1678, 1602, 1564, 1490, 1429, 1317, 1377, 1294, 1228, 1173, 1018, 828, 771.
NMR: (1 H, δ, TMS, DMSO) 1.24 (s, 3H), 1.62 (dxdxd, 1H), 2.02 (dxdxd, 1H), 3.46 (dxd, 1H), 3.55 (dxd, 1H), 4.20 (m, 2H), 4.91 (br t, OH), 6.79 (d, J=8.4, 1H), 7.27 (dxd, J=8.4, J=2, 1H) 7.54 (d, J=2, 1H), 7.62 (d, J=8.3, 2H), 7.95 (d, J=8.3, 2H), 13.15 (br s, COOH).
EXAMPLE 7
Effects of RAR Selective Retinoids on Repair of Alveoli in Elastase-induced Emphysema
RAR selective agonists were evaluated for its effects on alveolar repair in the rat model of elastase-induced emphysema in rats (Massaro et al. Nature (Medicine, 1997, 3, 675)). Animals were divided into treatment groups of approximately eight. Lung inflammation and alveolar damage was induced in male Sprague Dawley rats by a single instillation of pancreatic elastase(porcine derived, Calbiochem) 2 U/gram body mass. Three weeks post injury all-trans retinoic acid or RAR agonist was dissolved in dimethylsulfoxide (20 mg/ml) and stored at −20 C. Fresh working stocks were prepared fresh daily by dilution in PBS to a final concentration of 2 mg/ml. Animals treated with all-trans retinoic acid (0.5 mg/Kg ip) were dosed once daily by intraperitoneal injection, starting 21 days post injury. Control groups were challenged with elastase and 21 days later treated with Vehicle (DMSO/PBS) for 14 days. Animals were sacrificed 24 hours after the last dose of by exsanguination under deep anesthesia.
The lungs were inflated with 10% neutral buffered formalin by intratracheal instillation at a constant rate (1 ml/gram body mass/min). The lung was excised and immersed in fixative for 24 hours prior to processing. Standard methods were used to prepare 5 um paraffin sections. Sections were stained with Hematoxylin and Eosin (H%E). Computerized Morphometric analysis was performed to determine the average alveolar size and alveolar number (Table 1).
TABLE 1
Dose [mg/kg]
% repair area
compound
0.5
i.p.
58
A
0.1
p.o.
45.2
A
0.3
p.o.
51.3
A
i.p. intraperitoneal
p.o. per os
The foregoing invention has been described in some detail by way of illustration and example, for the purposes of clarity and understanding. It will be obvious to one of ordinary skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.
The patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. The contents of European Patent Application No. 99116603.4, filed Aug. 25, 1999, are incorporated herein by reference. | This invention relates to new selective retinoid acid receptor agonists of formula I
wherein the symbols are as defined in the specification to their pharmaceutically acceptable salts, individual isomers or to a racemic or non-racemic mixture; to pharmaceutical compositions containing them, and to methods for their use as therapeutic agents. | 2 |
BACKGROUND OF THE INVENTION
[0001] The present invention relates generally to multi-player video games, and more particularly to out-of-game play presentations supporting equipping of video game characters.
[0002] Video games are enjoyed by many, often allowing video game players to virtually participate in otherwise unavailable activities, whether due to requirements of skill, experience, or equipment availability, or simply due to inherent dangers of the activities.
[0003] In many games a video game player may control a video game character, who may have various skills and powers, and who may be equipped with various items, whether for use in the video game or merely for purposes of visual appearance in a virtual world of the game. Some games may allow for personalization of equipping of video game characters. The personalization, which may be termed equipping, may relate to clothing worn by a video game character, whether for function or fashion, and what may be broadly termed accessories. The accessories may be tools or other usable equipment carried by the video game character for the video game character's use. The personalization may also, in some embodiments, relate to the video game character's skills or capabilities, capabilities which include an ability to call upon assistance provided by capabilities of others.
[0004] In some video games some personalizations may be more desirable than others. For example, some personalizations may be appropriate for some virtual worlds, but not others. Similarly, in the context of multi-player games, some personalizations may be more desirable over others depending on the personalizations of opponents or teammates.
[0005] Unfortunately, a desired personalization of a video game character may not be known until game play commences, and depending on the nature of game play, changes in personalization during game play may not be possible, or if possible not prudent if success during game play is desired.
[0006] Traditionally, video games were generally monetized through sales of the games themselves, either as a packaged item or through an online download. These transactions were typically one-time transactions between a buyer and a seller (e.g., retailer, video game publisher, or video game developer). More recently, new monetization models have developed. For example, instead of, or in addition to, the traditional sale of the video game itself, some sellers are now monetizing video games through multiple, small, in-game transactions called microtransactions or micropayments. In some cases, users of video games may obtain the personalizations described above through such microtransactions, for free, or through some combination of microtransactions and free transactions. One challenge facing video game sellers who use microtransactions is to find effective and non-intrusive ways to further incentivize users to purchase microtransactions.
BRIEF SUMMARY OF THE INVENTION
[0007] One aspect of the invention provides a computer implemented method useful for video game play, comprising: determining identities and equipment of at least some game characters for participation in game play; in a time period outside of game play, providing information for rendering the game characters with their equipment in a scene having visual characteristics of a virtual world for game play; and providing for game play including the game characters.
[0008] Another aspect of the invention provides a system for providing for changes to equipment of a game character prior to play of a video game, comprising: a plurality of compute devices coupled by a network to a server, the compute devices and server configured to: prior to commencement of game play including game characters assigned to teams, provide for display of a team of game characters with their equipment in a scene having visual characteristics of a virtual world for game play; provide an option for change of equipment of the team of game characters, the option accessible during display of the team of game characters with their equipment in the scene having visual characteristics of a virtual world for game play prior to commencement of game play; provide for further display of the team of game characters with their equipment, as changed, in the scene having visual characteristics of a virtual world for game play prior to commencement of game play; and provide for game play.
[0009] Another aspect of the invention provides a system for recommending equipment suitable for a game character prior to play of a video game, comprising: a plurality of compute devices coupled by a network to a server, the compute devices and server configured to: prior to commencement of game play including game characters, provide for display of the game characters with their equipment in a scene having visual characteristics of a virtual world for game play; provide a recommendation for one or more pieces of equipment suitable for a game character, said recommendation being based on the characteristics of the virtual world for game play; provide an option for purchase of at least one of the recommended pieces of equipment, the option accessible during display of the game characters with their equipment in the scene having visual characteristics of a virtual world for game play prior to commencement of game play; and provide for game play.
[0010] Another aspect of the invention provides a computer implemented method for purchasing items in a video game, comprising: determining identities and equipment of at least some game characters for participation in game play; in a time period outside of game play, providing information for rendering the game characters with their equipment in a scene having visual characteristics of a virtual world for game play; upon request, providing a description of the equipment of at least one of the game characters; allowing a user to purchase the described equipment; and providing for game play including the game characters.
[0011] These and other aspects of the invention are more fully comprehended upon review of this disclosure.
BRIEF DESCRIPTION OF THE FIGURES
[0012] FIG. 1 is a block diagram of a system in accordance with aspects of the invention.
[0013] FIG. 2 is a flow chart of a process in accordance with aspects of the invention.
[0014] FIG. 3 is a screen shot of a portion of a lobby in accordance with aspects of the invention.
[0015] FIG. 4 is a screen shot including a lobby in accordance with aspects of the invention.
[0016] FIG. 5 is a flow chart of a process including a pre-game equipment change option in accordance with aspects of the invention.
[0017] FIG. 6 is a flow chart of a process for providing game play in accordance with aspects of the invention.
[0018] FIG. 7 is a flow chart of a process including a post-game equipment change option in accordance with aspects of the invention.
[0019] FIG. 8 is a further screen shot including a lobby in accordance with aspects of the invention.
[0020] FIG. 9 is a further screen shot including a lobby in accordance with aspects of the invention.
DETAILED DESCRIPTION
[0021] FIG. 1 illustrates a system in accordance with aspects of the invention. A first game console 113 and a second game console 114 , each with associated monitor and game controller, are each configured for play of a video game. Although only two game consoles are explicitly shown in FIG. 1 , in many embodiments the system of FIG. 1 includes many game consoles. The game console may be any suitable compute device (e.g., Xbox, PlayStation, Wii, personal computers, laptops, tablets, smartphones, etc.). The game consoles are coupled to a network 115 . The network may be a broad area network, for example the Internet.
[0022] In addition to the game consoles, compute devices (which have for example at least one processor and memory), such as a smartphone 117 , and a personal computer, shown in the form a laptop computer 119 may also be coupled to the network. In some embodiments, some or all of these other compute devices each may be configured for play of the video game. The smartphone is generally coupled to the Internet by way of a wireless cellular communications system, which may include wired communications links in addition to wireless communication channels. The server, laptop, and smartphone, of course, each have one or more processors, memory, communication circuitry, and associated hardware.
[0023] Also coupled to the network is a server 111 . The server may be for example be part of a server farm, including multiple servers, some of which may provide similar functions, and the server farm may be located at a co-location facility or other facility providing security, environmental conditioning, and wired Internet connections. The server may be for example be part of a server farm, including multiple servers, some of which may provide similar functions, and the server farm may be located at a co-location facility or other facility providing security, environmental conditioning, and wired Internet connections.
[0024] During game play the compute devices, which include at least one processor, computer memory, communication circuitry, and associated other hardware, execute program instructions to provide for play of the video game, generally in conjunction with the server. Video game players provide game play inputs using their respective input devices, for example game controllers, and the associated monitors display game play events. In various embodiments the video game may be an action game, for example a fighting game or a first-person shooter game, a role playing game, or a vehicle simulator game.
[0025] The server, in addition to possibly other functions, performs functions related to video game play amongst users of the compute devices. In some embodiments the server may distribute game state and/or action information received from the compute devices to allow for coordinated game play amongst multiple game players, and in some embodiments the server may also determine game states based on information received from the compute devices regarding actions taken during game play. In some embodiments, one or more compute devices may act as the server, thus allowing users of the compute devices to host multiplayer games.
[0026] In various embodiments, prior to and/or after game play, the system of FIG. 1 provides information regarding game characters and a virtual world in which the game occurs or is to occur by way of rendered images including the game players and a scene of, or representative of, the virtual world. The rendered images, in many embodiments, include the game characters in the scene of the virtual world, equipped and ready to play the game, or as equipped at the end of the game. In some embodiments the rendered images may be still images, or a sequence of images providing a video presentation of game characters moving about the scene, or assuming various poses in the scene.
[0027] In many embodiments the rendered images are displayed in conjunction with an option to change equipment of, or purchase equipment for, a game character. For example, a game player may realize the equipment could be improved considering the nature of the virtual world or the equipment of the other game characters, who may be teammates during game play. For example, the game character could be dressed in clothing that stands out in the virtual world, when camouflage is desired. Similarly, the game character could be dressed differently than the other teammates when similarity of dress is desired, or vice versa. In addition, a game player may realize that the combination of equipment of the teammates is lacking, or that another game player has particular equipment also desired. As another example, a game player observe the equipment or accessories of one or more other game players and desire to acquire one or more of the observed items.
[0028] In some embodiments, a game player can only view game characters, and their equipment, or load out, on their team. In another embodiment each game player can see the equipment loadout of game players from all teams. In this embodiment game player's equipment choices can be influenced by the choices made by the opposing team. Such information regarding the other team's equipment loadout adds a strategic element before game play begins. It also provides the game player an additional opportunity to purchase and use new equipment before game play begins.
[0029] Accordingly, selection of the option to purchase and/or change equipment allows a game player to modify equipment selections for the game player's game character. In some embodiments, selection of the option causes the system to present displays relating to and allowing for purchase of equipment or for change of equipment selection, with the system causing return to display of the rendered images after equipment purchase and/or selection is completed.
[0030] In some embodiments the rendered images are also displayed in conjunction with message boxes showing communications between game players.
[0031] FIG. 2 is a flow chart of a process in accordance with aspects of the invention. The process may be performed by the system of FIG. 1 , or portions of the system of FIG. 1 .
[0032] In block 211 , the process provides pre-game play presentation information for display of video game characters, equipped for game play, in a scene having visual characteristics of a virtual world in which game play is to take place. The scene may be termed a lobby. The lobby may provide an opportunity for game players, who may be physically remote from one another, to interact, for example by way of text communications. In one embodiment, a background of the lobby is scenery of the virtual world in which game play will take place. In another embodiment, the background has visual characteristics of a generic facility suitable considering the nature of the game play, for example a generic military equipment storage facility, in the case of a warfare video game. In one embodiment the lobby includes chatroom functionality for game player to game player communication. In some embodiments, the process provides for game players to make changes to the equipment of the video game characters, for example tools, possibly including weapons, clothing, and other items to be carried, used, or called upon by or for the video game characters. For example, more equipment may be available than game play allows a game character to employ, with selection of particular equipment to be used made by the game player. Accordingly, individual game players may switch equipment for a game character prior to game play. In some embodiments, the process allows for game players to obtain a description of the equipment and items used by one or more other players. The description may, in some embodiments, include the purchase price of the items. In some embodiments, the process allows the game player to purchase additional equipment, including the equipment described for the one or more other players. In some embodiments, the process enables one or more of the chatroom functionality, equipment change functionality, and purchase functionality. In addition, for a given game player, the process may make only a subset of other game players viewable in the lobby (e.g., only the given game player's teammates).
[0033] In some embodiments, the operations of block 211 are performed by a server, and the presentation information comprises rendered images. In some embodiments, the operations of block 211 are performed by a compute device configured for game play, and the presentation information comprises rendered images. In many, perhaps most embodiments, the operations of block 211 are performed by a combination of a server and a compute device configured for game play, with the server providing information for a compute device configured for game play to use, in conjunction with information possessed by the compute device, to render images comprising the presentation information.
[0034] In block 213 , the process provides for game play. During game play the compute devices and/or server determine game states based on user inputs to the compute device in accordance with program instructions providing for game play, and determine game play presentations based on the game states, also in accordance with program instructions. In some embodiments, game play may be time based, with game play ending after a designated amount of time has passed, and in some embodiments game play may be event based, with game play ending after occurrence of one or more specific events takes place in game play.
[0035] As illustrated in FIG. 2 , the process thereafter returns. In some embodiments, however, the process may return to block 211 upon completion of game play, for example to provide for additional interaction involving the game players or to allow the game players to consider or make further equipment changes for the future, while being able to view the equipment of the other game characters.
[0036] FIG. 3 is a screen shot of a portion of a lobby in accordance with aspects of the invention. The screen shot of FIG. 3 shows a background scene 311 having visual characteristics of a virtual world in which game play is to take place. In some embodiments, the screen shot may be one of the images of a lobby presented as discussed with respect to the process of FIG. 2 .
[0037] As shown in FIG. 3 , the scene may be considered to include an interior of a partially enclosed structure in a semi-rural mid-latitude environment. A plurality of game characters, equipped for game play, are shown in the screen shot. For example, a first game character 313 is shown, along with substantial portions of a second game character 315 . The first game character is shown wearing dark pants 327 and holding an assault weapon with launcher tube 317 . The second game character is shown wearing lighter colored pants 325 , a camouflage headwrap 321 , and a light bandana 323 over the character's face and holding an assault rifle 319 . The background, the characters, and the equipment are a rendered image in the screen shot of FIG. 3 . In most embodiments, the scene is dynamic, in that the characters may move, and in some embodiments portions of the background as well, and the image of the screenshot is of a stream of images providing a video presentation.
[0038] A game player, for example a game player who controls or is to control the first game character, may decide upon viewing the scene that the game player's character has deficient equipment in some manner. For example, the game characters may be part of a team of game players, and it may be desired that all the team members have a common item of clothing, for example a bandana such as the bandana of the second game character. Alternatively or in addition, the first game player may consider that the combination of weapons carried by the team members is lacking, and that the first game character should be equipped with some other weapon.
[0039] FIG. 4 is a screen shot including a lobby in accordance with aspects of the invention. The screen shot of FIG. 4 includes a background scene 411 having visual characteristics of a virtual world in which game play is to take place. In some embodiments the screen shot include one of the images of a lobby presented as discussed with respect to the process of FIG. 2 .
[0040] As shown in FIG. 4 , a plurality of game characters are present in the scene, for example game characters 413 and 415 . In some embodiments, only a subset of game characters are shown to a given game player (e.g., the given game player's teammates, or the given player's friends or clan members). The scene itself is bounded by a border, which may include selectable options relating to a video game. Inset within the scene is a message box 419 , for display of messages between game players who control or are to control the game characters. Also inset is an image of a particular location 417 within the virtual world, which may have some importance to game play in some embodiments. Also inset are selectable options 421 for performing equipment changes to, or purchasing equipment for, a game character. In some embodiments, selection of such a selectable option results in display of a different screen allowing for equipment changes and/or purchases. In some embodiments, selection of such a selectable option may result in an immediate change in equipment selection for a game character, with the game character then shown in the scene with the changed equipment. In some embodiments selection of such a selectable option results in display of screens allowing for purchase of an option to expand equipment available for selection. In some embodiments the selectable options, or a selectable option, for performing equipment changes, which may involve other presentation screens, may be otherwise provided. For example, a link available on the display may instead be available, and the selectable options 421 may instead be a list 421 of team members, or opposing team members, or both. In such embodiments, the process may provide for display of further information regarding a particular team member, for example if a game player scrolls or points to a particular team member using an input device of a compute device. The further information may be, for example, a listing of equipment of that team member. In addition, in some embodiments a selectable option allowing a game player to switch to an opposing team may be provided.
[0041] FIG. 5 is a flow chart of a process including a pre-game equipment change option in accordance with aspects of the invention in accordance with aspects of the invention. The process may be performed by the system of FIG. 1 , or portions of the system of FIG. 1 .
[0042] In block 511 , the process determines initial personnel and equipment for play in a video game. Personnel are game characters, for example avatars in some embodiments, generally controlled by game players. The game characters may be assigned to a team, and may be assigned to a team for a particular online game play session. Equipment includes, in various embodiments, in-game weapons, associated tactical gear, clothing worn by, or available to, the avatar, or some or all of the foregoing, during game play.
[0043] In block 513 , the process provides display information for images or for use in generating images showing game characters with their equipment in a background scene of or having characteristics of the virtual world in which game play will take place. In one embodiment, equipment is displayed as graphical recreation of the piece of equipment, either held by the game character, about the game character, or placed on the game character's person. In a further embodiment, the equipment is displayed partly as a graphical recreation and partly as text on the screen. In some embodiments, the display information is the display information for the screen shots of FIGS. 3 and/or 4 , or display information for images similar in nature to those screen shots. In some embodiments, the process provides a description of one or more game character's equipment. In some embodiments, the description includes a purchase price for the one or more items. In some embodiments, the process only displays to a given game player a subset of other game players (e.g., the given game player's teammates, friends, or clan members).
[0044] In block 515 , the process determines if game play should begin. In some embodiments game play begins at a predefined time. In some embodiments game play begins when some or all game players provide an indication, using their compute devices for example, that game play should begin. If game play should begin, the process continues to block 521 , which provides for game play for the course of the game, and then returns. Otherwise the process continues to block 517 .
[0045] Often, a game character's profile will include more equipment than game play allows the game character to employ. Based on the game play scenario, the mix of equipment the game players have equipped, or loaded out, for their game characters could be considered by the game players to be less than ideal. Similarly, a game player may observe another game player's load out and decide that the other player's load out is advantageous to the game player scenario. In such instances, or other instances, individual game players may switch and/or purchase equipment so that the equipment may be utilized during gameplay. Accordingly, in block 517 , the process determines if a game player has requested an equipment change and/or purchase for the game player's game character. In some embodiments, the process determines if a game player has requested an equipment change and/or purchase if the process receives an indication that a compute device of a game player has received an input requesting an equipment change and/or purchase.
[0046] In block 519 , the process changes equipment and/or transacts a purchase for a game character. In some embodiments the process changes and/or transacts a purchase for equipment for the game character based on menu selections, determined by a compute device based on game player inputs. In one embodiment, available equipment is displayed graphically, and equipment changes effected by receipt of compute device inputs, controlled by the game player, resulting in movement of equipment from an unused state to an in use state. In another embodiment, the equipment available is displayed and selectable in a check box type fashion. In another embodiment, the process allows for the purchase of another game player's entire loadout in one transaction. Once the equipment change or purchase has been made, the process returns to block 513 and displays the lobby and game characters with their then current equipment.
[0047] FIG. 6 is a flow chart of a process for providing video game play in accordance with aspects of the invention. The process may be performed by the system of FIG. 1 , or portions thereof, in various embodiments.
[0048] In block 611 the process processes compute device inputs. The compute device inputs are generally controlled by game players operating input devices of or associated with the compute devices.
[0049] In block 613 the process determines a new game state. In most embodiments the process determines a new game state based on the compute device inputs, in accordance with programming instructions of the video game. Generally the game state includes information regarding game character position and posture within a virtual game world, and may include bone information of the game character, an action being taken by the game character, a result of an action taken by other game characters, and other game information.
[0050] In block 615 the process provides the game state information, or portions of the game state information, for display purposes, for example for generation of displays on display elements of or associated with compute devices of game players.
[0051] The process thereafter returns, generally to repeat until a conclusion of game play.
[0052] FIG. 7 is a flow chart of a process including a post-game equipment change option in accordance with aspects of the invention. The process may be performed by the system of FIG. 1 , or portions thereof in various embodiments.
[0053] In block 711 , the process determines game players' end of game equipment in a video game. Equipment includes, in various embodiments, in-game weapons, associated tactical gear, clothing worn by, or available to, the game character, or some or all of the foregoing.
[0054] In block 713 , the process, in a manner similar to that of block 513 of the process of FIG. 5 , provides display information for images or for use in generating images showing game characters with their equipment in a background scene of or having characteristics of the virtual world in which game play will take place. The display information can be considered display information for a lobby including the game characters. In one embodiment equipment is displayed as graphical recreation of the piece of equipment, either held by the game character, about the game character, or placed on the game character's person. In a further embodiment, the equipment is displayed partly as a graphical recreation and partly as text on the screen. In some embodiments the display information is the display information for the screen shots of FIGS. 3 and/or 4 , or display information for images similar in nature to those screen shots. In some embodiments, only a subset of game players are displayed. For example, only the top performers of the game are displayed. As another example, the top performers of the game may be displayed alongside the worst performers of the game, with the top performers assuming victorious poses while the worst performers assume dejected poses. As another example, only the winning team may be displayed. Of course, these examples are merely illustrative, and any combination of players may be displayed.
[0055] In block 715 , the process determines if a game player has requested an equipment change and/or purchase for the game player's game character. In some embodiments, the process determines if a game player has requested an equipment change and/or purchase if the process receives an indication that a compute device of a game player has received an input requesting an equipment change and/or purchase.
[0056] In block 717 , the process changes and/or transacts a purchase of equipment for a game character. In some embodiments the process changes and/or transacts a purchase of equipment for the game character based on menu selections, determined by a compute device based on game player inputs. In one embodiment, available equipment is displayed graphically, and equipment changes and/or purchases effected by receipt of compute device inputs, controlled by the game player, resulting in movement of equipment from an unused state to an in-use state. In another embodiment, the equipment available is displayed and selectable in a check box type fashion. Once the equipment change and/or purchase has been made, the process returns to block 713 and displays the lobby and game characters with their then current equipment.
[0057] FIG. 8 shows a portion of screen shot of a post-game lobby in accordance with aspects of the invention. In various embodiments, the post-game lobby may as be discussed with respect to the pre-game lobbies of FIGS. 3 and 4 . The lobby of FIG. 8 shows game characters, with their equipment, in a scene of or having characteristics of the virtual world of the preceding game play.
[0058] FIG. 9 shows a further screen shot in accordance with aspects of the invention. In some embodiments the screen shot may include or represent a lobby as discussed herein. The screen shot of FIG. 9 includes a background scene having visual characteristics of a virtual world in which game play is to or has taken place. A game character 912 is shown in the context of the background.
[0059] The screen shot includes a team member listing 913 and an opposing team member listing 915 . In some embodiments additional information regarding a particular team member or opposing team member may be displayed if a game player points to or selects one of such teammates, for example using an input device of a compute device. The additional information may be, for example, equipment of that team member or opposing team member. In addition to show a listing of members of the teams, the screen shot also shows a selectable option 921 allowing a game character of the game player to switch teams.
[0060] As with the screenshot of FIG. 4 , the screenshot of FIG. 9 also shows an image of a scene from the virtual world of game play, which may be a scene that may have game importance in during game play, as well as a message box 919 for displaying messages between game players.
[0061] Although the invention has been discussed with respect to various embodiments, it should be recognized that the invention comprises the novel and non-obvious claims supported by this disclosure. | Systems and methods for pre-game and post-game video game character presentation and equipping are disclosed. According to one aspect of the invention, a computer implemented method useful for video game play comprises: determining identities and equipment of at least some game characters for participation in game play; in a time period outside of game play, providing information for rendering the game characters with their equipment in a scene having visual characteristics of a virtual world for game play; providing game players the opportunity to change and/or purchase equipment for their game characters; and providing for game play including the game characters. | 0 |
RELATED APPLICATION
This application is a continuation application of application Ser. No. 13/362,416, filed Jan. 31, 2012. The entire content of this application is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present disclosure relates generally to systems and methods for authentication of mobile devices and, more particularly, to the authentication of a mobile electric device using a charging pattern of the mobile device.
BACKGROUND OF THE INVENTION
Many different electronic and mechanical devices include battery storage, which are connected to the electric utility grid for recharge. Generally, costs for the energy used to recharge such mobile devices are assessed to the owner or provider of the outlet used for charging the mobile device, and are billed based on meter reading at the owner's meter associated with the outlet used for charging.
SUMMARY OF THE DISCLOSURE
In accordance with embodiments disclosed herein, the cost associated with the recharging of a mobile device can be allocated to the owner of the device, rather than the premises where the outlet is located, through a procedure for authenticating the device owner at the time of recharging the device. The mobile device communicates with an authenticator affiliated with the recharging facility, to identify itself. To confirm that the mobile device is connected to the correct facility, the mobile device draws a charge according to a pattern that is recognized by the authenticator. Upon detecting a charge being drawn according to that pattern, the authenticator has confirmation that an identified device is connected to the facility, and permits the recharging to proceed. The amount of electricity drawn during the recharging procedure can be metered, or otherwise determined and then billed to a party associated with the identified mobile device.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:
FIG. 1 is a schematic diagram illustrating a system for authenticating a pairing of a power source and mobile device in accordance with an exemplary embodiment of the present invention;
FIG. 2 is a flowchart illustrating a method of authentication of a mobile device in accordance with a first exemplary embodiment;
FIG. 3 is a graph illustrating a load pattern used in systems and methods in accordance with exemplary embodiments of the present invention;
FIG. 4 is a timing diagram illustrating communications between or among a mobile device and authenticators in accordance with a second exemplary embodiment;
FIG. 5 is a flowchart illustrating a method of managing a charging session in accordance with the second exemplary embodiment;
FIG. 6 is timing diagram illustrating communications between or among a mobile device and authenticators in accordance with a third exemplary embodiment.
DETAILED DESCRIPTION OF THE INVENTION
Mobile electric devices such as plug-in electric cars, laptop computers, notebook computers, PDAs, and cell phones, among others, are proliferating with the advent of a more mobile society. The ability to recharge such devices may be limited to electrical outlets associated with an owner of the mobile electric devices (e.g., where the billing account associated with electrical outlet and the owner of the mobile device are the same entity) or where the billing account owner associated with the electrical outlet allows the owner of the mobile device to recharge the mobile device at no charge. The owner associated with an electrical outlet generally refers to the individual or entity who is financially obligated to pay for the electricity consumed at the electrical outlet, which may include the owner of the electrical outlet or a third party responsible for such payments.
In various exemplary embodiments, a mobile electronic device may be authenticated to the electrical outlet, power connection or power source used for charging. By authenticating to such an outlet, power connection or power source, the billing account associated with the mobile device may be billed for the cost of recharging of the mobile device.
In certain exemplary embodiments, an authenticator may negotiate or specify a load pattern used by the mobile electronic device to identify its pairing with the electrical outlet, the power source or the power connection.
To facilitate an understanding of the concepts that underlie the invention, exemplary embodiments are described in which the mobile device is a plug-in electric vehicle. It will be appreciated, however, that the mobile electric device may be any device which is mobile and capable of recharge from any power source such as the electric grid, a generator, or another mobile device, among others.
FIG. 1 is a schematic diagram illustrating a system 100 for authenticating a pairing of a power source 122 a and mobile electrical device 110 in accordance with exemplary embodiments disclosed herein. Referring thereto, system 100 may include mobile electric device 110 , first electric supply site 120 a , second electric supply site 120 b , first authenticator 130 a , second authenticator 130 b and electric grid 140 . The apparatus and functions associated with first electric supply site 120 a are substantially the same as those of second electric supply site 120 b.
First electric supply site 120 a may include first power source 122 a and first connector 124 a . First electric power source 122 a may be connected to utility grid 140 for supply of electric power to first connector 124 a , or may be a stand alone power source for generating electrical power.
Although first electric power supply 122 a is shown connected to electric grid 140 , it is contemplated that any power source may be used, including both alternating current (AC) and direct current (DC) power sources such as batteries, fuel cells, photovoltaics, and electric generators, among others. First electric power source 122 a may include a meter/sensor 126 a and a load switch 128 a.
Meter/sensor 126 a may measure current draw through first electric power source 122 a . Meter sensor 126 a may be coupled to first authenticator 130 a . First authenticator 130 a may be located at the first electric supply site or may be located remotely, for example, in a vicinity of a plurality of electric metering sites or in the vicinity of back office 150 .
Although first authenticator 130 a is shown coupled to meter/sensor 122 a , it is contemplated that first authenticator 130 a may be coupled to any number of meters/sensors to measure the charge (e.g., current) drawn at a plurality of electric meter sites for authentication of the electrical outlets, power sources or power connections with mobile devices. In certain exemplary embodiments, one authenticator may measure charge drawn from electric meter sites associated with a specified geographic area (e.g., a parking lot, a plurality of parking spots, or a recharging center, among others). In other exemplary embodiments, such an authenticator may be associated with or located at back office 150 and may measure charge draw associated with electric meter sites associated with back office 150 .
Load switch 128 a may be controlled by first authenticator 130 a to connect or disconnect electric utility grid 140 or power source 120 a from mobile device 110 . Although load switch 128 a is shown to connect or disconnect power entirely to/from mobile device 110 , it is contemplated that load switch 128 a may only connect or disconnect a portion of the load of mobile device 110 (e.g., charging circuits of mobile device 110 ) from power source 122 a or electric utility grid 140 . For example, electric meter site 120 a may continue to enable power supply to mobile device 110 for functions such as communications with first authenticator 130 a and other processing functions of mobile device 110 using a low power connection via first connector 124 a.
Although load switch 128 a is shown as a single-pole single-throw switching device, it is contemplated that load switch 128 a may include other configurations to connect or disconnect other connections including, for example a ground connection, a communications connection, and/or a presence detection circuit, among others.
First authenticator 130 a may include a current sensor 131 a , a controller 132 a , a transceiver 134 a , a memory 136 a and an antenna 138 a . Mobile device 110 may include a network interface 112 having a controller 114 , transceiver 116 , memory 118 , and antenna 119 . Controller 132 a and controller 114 may establish a communication session (e.g., an internet protocol (IP) session) via transceiver 134 a and antenna 138 a of first authenticator 130 a and transceiver 116 and antenna 119 of network interface 112 . Controller 132 a may receive information (including measurements, meter readings and/or sensor readings, among others) from meter/sensor 126 a of first electric metering site 120 a . First connector 124 a of first electric metering site 120 a may connect to connector 115 of mobile device 110 to electrically connect power source 122 a and/or utility grid 140 to mobile device 110 .
Although a converter is not shown in FIG. 1 , mobile device 110 may include a converter to convert AC power to DC power. It is also contemplated that such a converter may be disposed between utility grid 140 and mobile device 110 .
System 100 may include back office 150 in communication with a plurality of authenticators (e.g., first and second authenticators 130 a and 130 b ) via communication network 160 . Back office 150 may include a controller 152 , a transceiver 154 , and a memory 155 (e.g., including authentication tables 156 ). Controller 152 may control the operation of back office 150 . Transceiver 154 may receive and send information via communication network 160 to first and/or second authenticators 130 a and 130 b . Memory 155 may include data structures used to uniquely identify load patterns monitored by first or second authenticator 130 a or 130 b with a mobile device identifier. Authentication tables 156 may include account and billing information associated with mobile devices in system 100 .
In one embodiment, authentication tables 150 may include records having unique identifiers associated with each mobile device. When mobile device 110 connects to first electric metering site 120 a via first connector 124 a , first authenticator 130 a may monitor for a current draw at first connector 124 a . The current draw may have a unique load pattern that identifies mobile device 110 . For example, network interface 112 may have a media access control (MAC) address (e.g., a unique address) that is associated with network interface 112 . The MAC address may be encoded as a unique load pattern associated with mobile device 110 .
In an alternate embodiment, rather than employ a public address or the like as the identifier of the mobile device, a secure value, such as a secret key, that is stored at both the authenticator and the mobile device can be employed as the unique identifier of the mobile device. Furthermore, the same identification credentials can be employed by a group of users. For instance, all of the members of a family who charge to the same billing account can share the secret key, and use it to identify their mobile devices to the authenticator. In a similar manner, a group address or other such form of shared credential can be employed to identify, and authenticate, all of the members of a group.
First authenticator 130 a may monitor for the unique load pattern of mobile device 110 and may authenticate the pairing of mobile device 110 with the first electric metering site 120 a (and/or first power source 122 a ) in response to the unique load pattern being detected. First authenticator 130 a may continuously monitor first electric metering site 120 a via meter/sensor 126 a to determine current draw from connector 124 a . First authenticator 130 a may determine the start of a unique load pattern based on current draw at first connector 124 a which is below a threshold level for a specified period of time (e.g., for greater than one minute) followed by a series of loads (the load pattern) which exceeds the threshold level during at least a portion of an authentication period.
First authenticator 130 a may determine an end to the unique load pattern based on the same or similar criteria as the start of the unique load pattern. That is, during the unique load pattern, load may exceed a threshold level to generate a sequence of load values above and below a load reference value, which will dynamically change based on at least a unique identifier of mobile device 110 (e.g., based on a MAC address, a unique identifier, or some other predetermined unique identifier of mobile device 110 and associated with network interface 112 ). First authenticator 130 a may request validation from back office 150 using authentication tables 156 to validate the unique load pattern of mobile device 110 . For example, controller 132 a may convert the unique load pattern detected from meter/sensor 126 a to a digital code and may request validation of the converted code from back office 150 .
Back office 150 may validate the converted code from first authenticator 130 a and may provide a message indicating the authentication of mobile device 110 . Controller 132 a of first authenticator 130 a , upon receiving the message authenticating mobile device 110 , may control load switch 128 a to maintain a connection between power source 122 a and mobile device 110 .
In certain exemplary embodiments, first authenticator 130 a may include memory 135 a for storing program code executable by controller 132 a and for storing information sent from authentication tables 156 for local authentication. For example, once mobile device 110 is authenticated (e.g., paired) with first electric metering site 120 a , authentication information associated with mobile device 110 (e.g., the unique load pattern of mobile device 110 ) and an identifier included in authentication tables 156 to identify mobile device 110 may be stored locally in memory 135 a of first authenticator 130 a , such that first authenticator 130 a may authenticate the same mobile device in a subsequent authentication process (without back office 150 ) based on rules established by back office 150 (e.g., when the planned current draw by mobile device 110 is below a threshold, when mobile device is of a certain type (e.g., a laptop, a PDA, a cell phone, or a plug-in vehicle) or may be set as a flag in memory 135 a from back office 150 based on criteria set by back office 150 ).
Mobile device may include an energy storage unit 170 and a energy management device 180 . Energy management device 180 may include a controller 182 and a metering unit 184 . Controller 182 of energy management device 180 may control charging and discharging of energy storage unit 170 to power, for example, mobile device 110 .
In certain exemplary embodiments, the energy management device 180 may be integral to a vehicle management system. In other exemplary embodiments, the energy management device 180 may be separate from and in communications with the vehicle management system.
FIG. 2 is a flowchart of the pairing authentication in accordance with the first embodiment. At step 210 , mobile device 110 is connected to a power source (e.g., first electric metering site 120 a ). At step 215 , mobile device 110 may initiate a sequence of charge draws. At step 220 , first authenticator 130 a may determine whether a predetermined time has elapsed since the connection of mobile device 110 to first electric metering site 120 a . At step 225 , responsive to the predetermined time being exceeded, mobile device 110 may be disconnected from first electric metering site 120 a via load switch 122 a . At step 230 , responsive to the predetermined time not being exceeded, first authenticator 130 a may monitor for the sequence of charge draws. At step 235 , first authenticator 130 a may determine whether the identity of mobile device 110 is recognizable from the sequence of charge draws. For example, first authenticator 130 a may match the sequence of charge draws with a unique identifier of mobile device 110 . In certain exemplary embodiments, the unique identifier of mobile device 110 may be stored in authentication tables 158 of back office 150 . In such exemplary embodiments, first authenticator 130 a may request via communication network 160 authentication information stored in authentication tables 158 . The request for authentication information may be sent via transceiver 134 a of first authenticator 130 a , communication network 160 and transceiver 154 of back office 150 . In alternate exemplary embodiments, first authenticator 130 a may include authentication tables (not shown) for authentication locally (without communication with back office 150 ).
In other alternative exemplary embodiments, first authenticator 130 a may send a logical series of bits corresponding to the sequence of charge draws to back office 150 via communication network 160 and back office 150 may determine and direct first authenticator 130 a regarding the recognition of the identity of the mobile device from the sequence of charge draws. Responsive to the first authenticator 130 a and/or back office 150 not recognizing the identity of the mobile device from the sequence of charge draws, processing is sent to step 220 to determine whether a predetermined amount of time has elapsed since connection by mobile device 110 . If the predetermined amount of time has elapsed, the mobile device is disconnected at step 225 , to thereby prevent a rogue device from continuing to draw current via the authentication process.
Responsive to first authenticator 130 a and/or back office 150 recognizing the identity of the mobile device from the sequence of charge draws, back office 150 may validate at step 240 whether the recognized mobile device has permission to draw power. For example, back office 150 may correlate the recognized identity of mobile device 110 with a billing account and it may determine, based on billing activity, payment terms, arrearages, among others, whether to permit the draw of power. If the back office does not permit the draw of power, back office 150 may send a message to first authenticator 130 a to block a charging session. For example, first authenticator 130 a may control load switch 128 a to disconnect mobile device 110 , at step 245 . At step 250 , responsive to the recognized mobile device having permission to draw power, the first authenticator 130 a may authenticate mobile device 110 and initiate a charge session. At step 255 , first authenticator 130 a may determine whether a predetermined time has elapsed since the beginning of the charge session. Responsive to the predetermined time having elapsed, mobile device 110 may be disconnected from first electric metering site 120 a using load switch 128 a . Responsive to the predetermined time not having elapsed, first authenticator 130 a may monitor for an indication that the charge session has ended. For example, first authenticator 130 a may monitor for a current draw below a threshold level for a specified period to indicate the end of a charge session.
If the end of a charge session is indicated, first authenticator 130 a may control load switch 128 a to disconnect mobile device 110 at step 265 . If the end of a charging session is not indicated by the monitored charge draw, at step 260 , processing is transferred to step 255 to determine if a predetermined time has elapsed since the beginning of the charge session.
FIG. 3 is a graph of one example of a possible load pattern. The graph includes load history 310 and filtered data 320 which corresponds to load history data with high frequency components (e.g., components above a threshold frequency) removed. The load history represents a series of load patterns provided by mobile device 110 . Prior to sending its unique identification, the mobile device may first draw current according to a generic pattern that indicates an intent to draw power, during an initial period 340 . The load pattern during the initial period 340 may indicate that mobile device 110 is connected to the utility grid via first electrical metering site 120 a , and alerts the authenticator 130 a to begin looking for a load pattern that indicates a unique identifier. Thereafter, the mobile device 110 sends its identifier during an authentication period 350 . The load pattern associated with mobile device 110 presents a binary pattern 330 that is derived from filtered data 320 .
In response to detection and authentication of a specified load pattern, the first authenticator 120 a may enable the initiation of a charging period 360 . If a valid load pattern is not detected, the first authenticator 120 a may control the load switch 128 a to open and disconnect the mobile device from the external power source. That is, the first authenticator 120 a blocks charging of the mobile device 110 .
In one implementation of the first embodiment, the unique identifier of the mobile device may be a secret that is shared between the mobile device and the authenticator, rather than being transmitted in the clear. For example, each of the authenticator and the mobile device may store an algorithm that is seeded by the identifier of the mobile device and an identifier of the authenticator, such as its MAC address. When the mobile device initiates the generic load pattern during the initial period 340 , the authenticator can respond with its identifier, by varying any parameter of the power that is capable of being detected by the mobile device. For instance, the authenticator may cause the power source 122 a to vary the voltage, phase or current of the power, or simply turn the power on and off, so as to encode the identifier in the power received via the connectors 115 and 124 a . In response to receiving this identifier, the mobile device can execute the algorithm, using the received identifier and its own unique identifier as inputs, to obtain a result value. This result value is sent to the authenticator during the authentication period. Applying an inverse of the algorithm to the received result value, the authenticator can then derive the unique identifier of the mobile device. This derived identifier can then be checked against the table of authorized identifiers to authenticate the mobile device.
In the first embodiment described above, the communication between the mobile device and the authenticator are carried out via the power line connection, through current draws or other forms of modulation of the power delivered to the mobile device. In a second embodiment described hereinafter, wireless RF communication can be employed to transmit at least some of the information that is exchanged between the mobile device and one or more authenticators.
Now referring to FIG. 4 , at step 410 , when the mobile device 110 is plugged into a power outlet, it may broadcast a message to authenticators within operational range (e.g., authenticators 130 a and 130 b ) via the network interface 112 and antenna 119 . The broadcast message may advertise an intent for mobile device 110 to charge. First authenticator 130 a and second authenticator 130 b may each send a response message to mobile device 110 to initiate a load pattern, at steps 420 and 430 , respectively. The load pattern may be specific to each authenticator, and/or a time stamp. Alternatively, the pattern may be specific to mobile device 110 , a fixed pattern, or portions of the load pattern may be a combination thereof. In certain exemplary embodiments, the load pattern may be based on a unique identifier of the mobile device 110 and may be obscured by hashing the unique identifier with a hash algorithm.
Responsive to receiving one or more response messages from first authenticator 130 a and second authenticator 130 b , at step 440 mobile device 110 may determine which one of the authenticators in its operational range (e.g., first authenticator 130 a or second authenticator 130 b ) to select for authentication. The selection of authenticator 130 a or authenticator 130 b may be based on the authenticator having the highest signal strength. Alternatively, or in addition, the mobile device may store a list of known addresses, and select an authenticator based on an address included in the responses from the authenticators. Mobile device 110 may draw charge according to the load pattern established with the selected authenticator (e.g., first authenticator 130 a ).
Although first authenticator 130 a and second authenticator 130 b are shown in the timing diagram of FIG. 4 , it is contemplated that more or fewer authenticators may be within operating range of mobile device 110 and each authenticator may send a response message and monitor for charge draw. In certain exemplary embodiments, the selection of the authenticator may be improper (i.e., mobile device 110 may choose an authenticator associated with an electric metering site not connected to mobile device 110 ). FIG. 4 depicts a situation in which the mobile device 110 selects the second authenticator 130 b , but it is connected to the power source associated with the first authenticator 130 a . At step 450 , the authenticator which discovers a load draw after sending a response message to mobile device 110 (in this case authenticator 130 a ) may send a further response message to indicate to mobile device 110 that the authenticator has monitored a charge draw and also indicating the proper load pattern for the mobile device 110 . At step 460 , mobile device 110 may then determine the proper authenticator and draw charge according to the load pattern established with the proper authenticator.
At step 470 , based on the monitoring at step 420 , first authenticator 130 a (as the selected authenticator) determines that mobile device 110 is drawing charge according to the load pattern indicated in the response message at step 420 . First authenticator 130 a may send an acknowledgment of the pairing of mobile device 110 with first electric metering site 120 a and may enable the initiation of a charge session for mobile device 110 based on the detected load pattern (e.g., when responsive to the load pattern being detected).
In certain embodiments the reselection of an authenticator may be eliminated if the load pattern is based on only the unique identification associated with mobile device 110 , such as a Mac address or other unique identifier.
Now referring to FIG. 5 , at step 510 , the charging system of mobile device 110 (e.g., a plug-in vehicle) may be prepared for charging. At step 520 , the mobile device's network interface (e.g., the plug-in vehicle's network interface card) may advertise to all authenticators (e.g., all meter network interface cards) stored in the mobile device's memory 117 (e.g., as a neighborhood table in memory 117 ) the plug-in vehicle's intent to charge. At step 525 , the mobile device's network interface receives acknowledgement from the neighboring NICs in response to the advertisement, indicating their readiness to detect a message. At step 530 , the charging system 111 of plug-in vehicle 110 may initiate a series of loading following a pattern indicative of third party electrical loads. At step 540 , neighboring meter network interface cards that acknowledge vehicle advertisement monitor the load registers of their respective meters at a predetermined interval. For example, the sampling interval for load registers associated with meters that may be used for charging the plug-in vehicle's charging system may be increased from a normal sample range of about 30 seconds to about five minutes, to a faster range of about five seconds to about one minute, depending on the metering unit 126 a used. At step 550 , the neighboring meter network interface card may determine whether to acknowledge the load pattern. Responsive to the neighboring meter network interface controller 132 a acknowledging the load pattern of the third party load, at step 570 , the load pairing of first electric metering site 120 a and plug-in vehicle 110 are verified using any of the previously disclosed authentication processes. At step 560 , if the neighboring meter network interface controller does not acknowledge the load pattern of the third party load, the monitoring of the load registers of the neighboring meter (e.g., meter unit 126 a ) may resume normal operations. For example, the sampling interval of the meter registers may be adjusted to a normal interval.
At step 575 , if the load pairing of the first electric metering site 120 a and plug-in electric vehicle 110 is validated, the meter seal of the plug-in vehicle 110 is validated. At step 580 , if the load pairing is not verified at step 570 , the vehicle charging system is locked out. For example, the load switch 128 a of first electric metering site 120 a may be disconnected by meter network interface controller 132 a . Further, if the meter seal of plug-in vehicle 110 is not validated, the vehicle charging system of plug-in vehicle 110 may be locked out at step 580 . If the meter seal of plug-in vehicle 110 is validated at step 575 , the back office determines whether the customer account associated with the plug-in vehicle is valid at step 585 . For example, the back office 150 may determine that the customer account has sufficient pre-paid funds or that a valid credit account is associated with the customer account. If the customer account is validated, the back office may send a charging commencement message to the meter network interface controller 132 to commence charging at step 590 . If the customer account is determined to be invalid by back office 150 , the back office may send an invalid account message to meter network interface controller 132 a at step 580 to cause vehicle charging system of plug-in vehicle 110 to be locked out.
In another embodiment, the mobile device may first attempt to discover potential hosts within its communication range. Referring to FIG. 6 , at step 610 , mobile device 110 may broadcast a message to discover other communication nodes in operational range (e.g., one-hop nodes or neighboring nodes). For example, mobile device 110 may broadcast a message to first authenticator 130 a and second authenticator 130 b . Any neighboring node (authenticator) receiving the broadcast message directly from mobile device 110 may respond by sending a response message establishing the respective node (authenticator) as a neighboring or one-hop node. For example, at step 620 , first authenticator 130 a may receive directly from mobile device 110 the broadcast message, and may reply with a response message indicating that authenticator 130 a is a neighboring or one-hop node of mobile device 110 . This response may include instructions to initiate a general charge pattern. At step 630 , second authenticator 130 b may receive the broadcast message directly from mobile device 110 and may send a response message with instructions to for a charge pattern, establishing second authenticator 130 b as a neighboring or one-hop node as well.
Mobile device 110 may receive the response messages from the authenticators which neighbor the mobile device. At step 640 , the mobile device may send a message to the established neighboring nodes that mobile device 110 is initiating a series of current draws. In certain exemplary embodiments the current draws may be below a threshold level and/or may be a predetermined/fixed series of charge draws that are generic to third-party connections. At step 650 , mobile device 110 may initiate a series of charge draws according to the instructed pattern, and at steps 660 and 670 first authenticator 130 a and second authenticator 130 b may monitor for the series of charge draws, respectively. In the example of FIG. 6 , the mobile device is connected to the power source 122 a associated with authenticator 130 a . First authenticator 130 a , upon detecting the current draw, may send an acknowledgment message instructing the mobile device to draw charge based on a unique, predetermined, specified, or negotiated load pattern and may monitor for charge draw according to the instructed load pattern, at step 680 . Mobile device 110 may receive the acknowledgment message and may draw charge according to the instructed load pattern, at step 690 . At step 695 , the authenticator may enable a charge session for mobile device 110 upon detection of the instructed load pattern and verification through the back office system.
From the foregoing, therefore, it can be seen that the disclosed embodiments provide techniques for associating and authenticating a mobile device with external power sources that can be used to charge the device. Communication between the mobile device and the power source is carried out via the manner in which the device draws power from the source. In some embodiments, wireless communication between the mobile device and the power source are used to enhance the capabilities for pairing the mobile device with the power source, and authenticating the device.
Once the pairing and authentication have been achieved, various approaches can be employed to quantify the amount of charge delivered to the mobile device. In one implementation, a standard rate of charge draw can be established for a given category of device. By measuring the duration of the charging period, the authenticator at the location of the power source can determine the amount of charge delivered, and report it to the back office 150 , for debiting the account of the device owner.
In another implementation, a sealed, tamper-proof meter can be installed in the mobile device and connected to its wireless network interface 112 . Once the pairing has been established, the authenticator or the back office can send a command via the network interface, to begin measuring the current draw, and report back, either during the transaction period or upon completion of the period.
If metering is possible at both the site of the source and within the mobile device, the charge amount measured at each location can be checked against one another for confirmation. In addition, the amount measured at the source can be employed to check the calibration, and/or detect tampering, of the meter in the mobile device.
Thus, it will be appreciated by those skilled in the art that the present invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The presently disclosed embodiments are therefore considered in all respects to be illustrative and not restricted. The scope of the invention is indicated by the appended claims rather than the foregoing description and all changes that come within the meaning and range and equivalence thereof are intended to be embraced therein. | A mobile device communicates with an authenticator affiliated with a recharging facility, to identify itself. To confirm that the mobile device is connected to the correct facility, the authenticator instructs the mobile device to draw electrical charge according to an identifiable pattern. Upon detecting a charge being drawn according to that pattern, the authenticator has confirmation that the identified device is connected to the facility, and permits the charging to proceed. The amount of electricity drawn during the charging procedure can be metered, and then billed to a party associated with the identified mobile device. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
This Application is a divisional of application Ser. No. 12/395,450, filed on Feb. 27, 2009, now U.S. Pat. No. 8,096,246, which is a divisional of application Ser. No. 11/444,154, filed on May 31, 2006, now U.S. Pat. No. 7,503,266, incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
This invention relates generally to folding, collapsible structures, and more particularly relates to a modular folding table having a truss framework, a folding table top and a folding utility shelf.
Folding card tables and heavy work tables having individual legs or pairs of legs that are pivotally connected to a table top to swing down from a concealed position to lock into a set up position are well known. The portability of such tables is generally limited by the size of the table top. The lighter card table style tables are generally not strong enough or stable enough to support modern video or computer types of displays that are currently used in traveling presentations. The heavier, folding work style tables are generally quite large and heavy, making them impractical for use as a portable display table in presentations, often requiring the use of a truck for transporting video or computer display equipment and appropriate display tables. A display table offering one or more utility shelves would also be useful for providing an efficient use of space for display equipment, but conventional tables providing one or more utility shelves have also generally not been collapsible and easily portable.
In order to provide such a collapsible display table that is expandable both horizontally as well as vertically, it would be desirable to provide a modular folding table with a collapsible truss framework that supports a folding table top and a folding utility shelf to offer a larger and more efficient use of table space, and having improved strength and stability, to support relatively large, heavy equipment and displays such as video display monitors, video or film display equipment, and the like. The present invention fulfills these needs.
SUMMARY OF THE INVENTION
Briefly and in general terms, the present invention provides for a modular folding table with a collapsible truss framework that supports a folding table top and a folding utility shelf, with the truss framework connected to a plurality of legs that can be connected horizontally or vertically to the legs of one or more similar modular folding tables, to provide desired table and shelf space with a structure that is foldable, strong and stable.
The present invention accordingly provides for a modular folding table, including a plurality of vertically disposed legs, each of the legs having an upper end and a lower end, and a truss framework connected to each of the legs. The truss framework includes a plurality of truss pairs of link members, each of the truss pairs including first and second link members having upper and lower ends. The first and second link members are pivotally connected together at a midpoint between the upper and lower ends, the first end of the first link member is pivotally connected to the upper end of one of the legs, and the second end of the first link member is slidably connected to an adjacent one of the legs. The first end of the second link member is similarly pivotally connected to the upper end of one of the legs, the second end of the first link member is slidably connected to an adjacent one of the legs, and the first and second link members are pivotally connected together in a scissors configuration so as to be extendable horizontally from a collapsed configuration to an extended configuration. Each of the first and second link members advantageously includes a table top support bracket mounted between the midpoint and the upper ends of the link members. A plurality of slider members are slidably mounted to each of the plurality of vertically disposed legs, respectively, and the second ends of the link members are connected to corresponding slider members, respectively, for slidably connecting adjacent second link members of adjacent sides to corresponding vertically disposed legs, respectively. A table top is removably disposed on the upper ends of the legs and rests on the table top support brackets of the truss pairs of link members in the extended configuration.
In one presently preferred aspect, the upper ends of the legs include a land for supporting the table top, and the upper ends of the legs include a recess for receiving a lower end of a leg of a second modular folding table for vertically stacking the second modular folding table on the modular folding table. In another presently preferred aspect, an upper leg connector bracket is provided for connecting one the recess of one of the legs of the modular folding table to an adjacent recess in an upper end of a leg of a second modular folding table for horizontally connecting the modular folding table and the second modular folding table together. A lower leg connector bracket may also be provided for connecting one of the legs of the modular folding table to an adjacent leg of a second modular folding table for horizontally connecting the modular folding table and the second modular folding table together. A latch may also be provided for latching at least one of the slider members in a fixed position on at least one of the legs.
In another presently preferred aspect, each of the legs further includes a telescoping foot extension, and the legs may include means for fixing the foot extension in a retracted position or in an extended position. The upper ends of the legs along at least one side of the modular folding table may also include a socket for receiving a table top support bar. A second modular folding table may also be provided, wherein the upper ends of the legs along at least one side of the second modular folding table include a land for supporting the second table top and a socket for receiving the table top support bar. In another presently preferred aspect, the table top includes a plurality of segments connected together by at least one hinge, so as to be foldable. In another presently preferred aspect, the table top comprises at least three segments connected together by at least two hinges each including a pair of flat plate portions connected to adjoining segments of the table top, the pair of flat plate portions being pivotally connected together by a pivot pin, and the at least two hinges having the flat plate portions connected to the pivot pin at positions at different distances from the flat plate portions so that the table top is foldable. In another presently preferred aspect, the table top includes a plurality of notches at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
In another presently preferred aspect, the modular folding table includes at least two shelf support arms each having first and second ends, and means for removably attaching the first and second ends between adjacent legs for supporting a lower shelf, which may be disposed on the at least two shelf support arms. In another presently preferred aspect, the lower shelf includes a plurality of segments hingedly connected together so as to be foldable. The lower shelf may, for example, include at least three segments connected together by at least two hinges, the at least two hinges each including a pair of flat plate portions connected to adjoining segments of the lower shelf, the pair of flat plate portions being pivotally connected together by a pivot pin, and the at least two hinges having the flat plate portions connected to the pivot pin at positions at different distances from the flat plate portions, so that the lower shelf is foldable. In another presently preferred aspect, the lower shelf includes a plurality of notches at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
Other features and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiments in conjunction with the accompanying drawings, which illustrate, by way of example, the operation of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a first embodiment of the modular folding table in a disassembled, collapsed configuration according to the present invention.
FIG. 2 is a perspective view of the modular folding table of FIG. 1 in an extended configuration prior to assembly with the table top.
FIG. 3 is a perspective view of the modular folding table of FIG. 1 in an assembled, extended configuration.
FIG. 4 is a perspective view of the modular folding table of FIG. 1 in an extended configuration with the legs extended, prior to assembly with the table top.
FIG. 5 is a perspective view of the underside of the table top and upper end of a leg of the modular folding table of FIG. 1 .
FIG. 6 is a perspective view of the upper end of a leg of the modular folding table of FIG. 1 .
FIG. 7 is a perspective view of a corner of the upper side of the table top and upper end of a leg of the modular folding table of FIG. 1 .
FIG. 8 is a perspective view of the underside of the table top showing the hinges of the table top of FIG. 1 .
FIG. 9 is a perspective view of the underside of the table top illustrating the folding of the table top of FIG. 1 .
FIG. 10 is a perspective view of the modular folding table of FIG. 1 in an assembled, extended configuration, with shelf support arms added.
FIG. 11 is a perspective view of the modular folding table of FIG. 1 in an extended configuration, with shelf support arms added, prior to assembly with the table top.
FIG. 12 is a perspective view of a shelf support bracket mounted to a leg of the modular folding table of FIG. 1 .
FIG. 13 is another perspective view of a shelf support bracket mounted to a leg of the modular folding table of FIG. 1 .
FIG. 14 is a perspective view of the modular folding table of FIG. 1 horizontally connected to a second modular folding table by a lower leg connector bracket.
FIG. 15 is a perspective view of the upper end of a leg of the modular folding table of FIG. 1 placed adjacent to the upper end of a leg of a second modular folding table showing the placement of the upper recesses of the adjacent legs together.
FIG. 16 is a perspective view of the upper ends of the legs of the first and second modular folding tables of FIG. 15 horizontally connected together with an upper leg connecting bracket connecting the upper recesses of the adjacent legs together.
FIG. 17 is a perspective view of the lower end of a leg of the modular folding table of FIG. 1 placed adjacent to the lower end of a leg of a second modular folding table.
FIG. 18 is a perspective view of the lower ends of the legs of the first and second modular folding tables of FIG. 17 with a lower leg connecting bracket connecting the lower legs together.
FIG. 19 is a perspective view of a second embodiment of the modular folding table in a disassembled, extended configuration, prior to assembly with a table top, according to the present invention.
FIG. 20 is an enlarged view of an upper leg of the modular folding table of FIG. 19 , showing the upper leg pivotally connected to the upper ends of three link members of the truss framework, and a slider mounted on the leg pivotally connected to the lower ends of three link member of the truss framework.
FIG. 21 is a perspective view of the modular folding table of FIG. 19 in an assembled, extended configuration.
FIG. 22 is a perspective view of the modular folding table of FIG. 19 in an assembled, extended configuration, and connected by upper and lower leg connector brackets to a second modular folding table.
FIG. 23 is a perspective view of a third embodiment of the modular folding table including table top support bars, shown in an assembled, extended configuration, with a variant of the second embodiment connected by table top support bars to a second modular folding table, which is a variant of the first embodiment, including shelf support arms.
FIG. 24 is another perspective view of the modular folding table of FIG. 23 .
FIG. 25 is a perspective view of the modular folding table of FIG. 23 , including a lower shelf installed on shelf support arms.
FIG. 26 is another perspective view of the modular folding table of FIG. 23 , showing a table top placed on the table top support bars.
FIG. 27 is a perspective view of an underside of a table top and an upper end of a leg of the modular folding table of FIG. 26 , showing a socket for receiving a table top support bar.
FIG. 28 is another perspective view of a table top and an upper end of a leg of the modular folding table of FIG. 26 , showing a socket for receiving a table top support bar.
FIG. 29 is a perspective view of a lower modular folding table of FIG. 1 with a second modular folding table vertically stacked on top, with the legs of the second modular folding table connected in the upper recesses of the legs of the lower modular folding table.
FIG. 30 is a perspective view of a lower modular folding table of FIG. 19 with a second modular folding table vertically stacked on top, with the legs of the second modular folding table connected in a portion of the upper recesses of the legs of the lower modular folding table.
FIG. 31 is an enlarged view of a portion of the view of FIG. 30 , showing the lower modular folding table of FIG. 19 with a second modular folding table vertically stacked on top, with the legs of the second modular folding table connected in a portion of the upper recesses of the legs of the lower modular folding table.
FIG. 32 is a perspective view of a lower modular folding table of FIG. 19 with a second modular folding table vertically stacked on top, with the legs of the second modular folding table connected in a portion of the upper recesses of the legs of the lower modular folding table, with a lower shelf mounted on lower shelf support arms of the upper, second modular folding table.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings, which are provided for purposes of illustration and by way of example, the present invention provides for a modular folding table 20 , including a plurality of legs 22 , and a truss framework 24 connected to each of the legs, shown in a disassembled, collapsed configuration in FIG. 1 . As is shown in FIG. 2 , the truss framework includes a plurality of truss pairs of link members 26 , with each of the truss pairs including first link members 28 and second link members 30 , each having upper ends 32 and lower ends 34 . A table top 38 , shown in FIGS. 1 and 3 , can be removably disposed on the upper ends of the legs. The first and second link members are pivotally connected together at a midpoint 36 between the upper and lower ends in a scissors configuration so as to be extendable horizontally from a collapsed configuration to an extended configuration. Referring to FIGS. 2 and 3 , in a presently preferred aspect, each of the first and second link members also includes a table top support bracket 39 mounted between the midpoint and the upper ends of the link members for contacting and supporting the table top when it is placed on the upper ends of the legs.
Each of the legs has an upper end 40 and a lower end 42 , and the upper end of the first link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs. Likewise, the upper end of the second link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs.
With reference to FIGS. 6 and 7 , in a presently preferred aspect, the upper ends of the legs include a land 44 for supporting the table top. In another presently preferred aspect, the upper ends of the legs include a recess 46 for receiving a lower end of a leg 22 ′ of a second modular folding table 20 ′, for stacking the second modular folding table on the modular folding table, as is illustrated in FIG. 29 , or for horizontally connecting an adjacent second modular folding table 20 ′, as is illustrated in FIG. 14 , described further below.
Referring to FIG. 5 , each the leg preferably includes a slider member 50 slidably mounted to the leg for slidably connecting the lower ends of the first and second link members to corresponding ones of the legs. As is illustrated in FIG. 6 , in a presently preferred aspect, at least one of the legs includes latch means 54 for latching at least one of the slider members in a fixed position on the leg. Referring to FIGS. 2 and 4 , each of the legs preferably includes a telescoping foot extension 56 , and each of the legs preferably includes means 58 for fixing the foot extension in a retracted position and for fixing the foot extension in an extended position, such as spring loaded detent pins and corresponding latching holes in the leg, for example.
As is shown in FIGS. 8 and 9 , the table top comprises a plurality of segments 72 a , 72 b , 72 c , connected together by at least one hinge 74 so that the table top segments are foldable. Typically, the table top comprises at least three segments connected together by at least two hinges, 74 a , 74 b , each of which includes a pair of flat plate portions 76 connected to adjoining segments of the table top. The pair of flat plate portions of each hinge are pivotally connected together by a pivot pin 78 , and preferably the flat plate portions of at least one of the hinges are connected to the pivot pin by right angle members 80 a , 80 b extending transversely from the flat plat portions, so that the table top segments are foldable. In another presently preferred aspect, shown in FIGS. 7 and 9 , for example, the table top includes a plurality of notches 82 at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
Referring to FIGS. 10-13 , in another presently preferred aspect, the modular folding table may be provided with at least two shelf support arms 84 each having a first end 86 and a second end 88 connected between a pair of legs, so that a lower shelf 90 , shown in FIG. 11 , may thus be removably disposed on the shelf support arms. The lower shelf typically includes a plurality of segments hingedly connected together so as to be foldable, such as at least three segments 92 a , 92 b , 92 c connected together by at least two hinges, for example. The hinges of the shelf typically also each include a pair of flat plate portions connected to adjoining segments of the lower shelf, and the pair of flat plate portions are pivotally connected together by a pivot pin 98 . Preferably the flat plate portions of at least one of the hinges are connected to the pivot pin by right angle members 100 a , 100 b extending transversely from the flat portions, so that the lower shelf segments are foldable. In another preferred aspect, the lower shelf includes a plurality of notches 102 at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
Referring to FIGS. 14-16 , an upper leg connector bracket 48 , such as a two plug cap, for example, may also be provided for connecting a recess 46 of one of the legs of the modular folding table to an adjacent recess 46 ′ in an upper end 40 ′ of a leg 22 ′ of a second modular folding table 20 ′ for connecting the modular folding table 20 and the second modular folding table 20 ′ together. As is illustrated in FIGS. 14 , 17 and 18 , a lower leg connector bracket 52 , such as a two plug cap, for example, may also be provided for connecting sockets 51 of female connector brackets 53 attached to the lower leg portions may also be provided for connecting one of the legs 22 of the modular folding table to an adjacent leg 22 ′ of a second modular folding table 20 ′ for connecting the modular folding table and the second modular folding table together.
Referring to FIGS. 19-21 , in which like reference numbers denote like elements, in a second embodiment of the modular folding table according to the present invention, the modular folding table 120 includes a plurality of legs 122 , and a truss framework 124 connected to each of the legs. The truss framework includes a plurality of truss pairs of link members 126 , with each of the truss pairs including first link members 128 and second link members 130 , each having upper ends 132 and lower ends 134 . A plurality of table tops 138 can be removably disposed on the upper ends of the legs. The first and second link members are pivotally connected together at a midpoint 136 between the upper and lower ends in a scissors configuration so as to be extendable horizontally from a collapsed configuration to an extended configuration. Each of the first and second link members includes a table top support bracket 139 mounted between the midpoint and the upper ends of the link members for contacting and supporting the table top when it is placed on the upper ends of the legs.
Each of the legs has an upper end 140 and a lower end 142 , and the upper end of the first link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs. Likewise, the upper end of the second link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs.
The upper ends of the legs include a pair of lands 144 for supporting the plurality of table tops. Each leg preferably includes a slider member 150 slidably mounted to the leg for slidably connecting the lower ends of the first and second link members to corresponding ones of the legs. In a presently preferred aspect, at least one of the legs includes latch means for latching at least one of the slider members in a fixed position on the leg. Each of the legs preferably includes a telescoping foot extension, and each of the legs preferably includes means, such as a spring loaded detent pin and corresponding latching hole in the leg, for example, for fixing the foot extension in a retracted position, and means, such as another spring loaded detent pin and corresponding latching hole in the leg, for fixing the foot extension in an extended position. The table top preferably includes a plurality of notches 182 at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
As is illustrated in FIG. 22 , an upper leg connector bracket 148 , such as a two plug cap, for example, may also be provided for connecting a recess of one of the legs of the modular folding table to an adjacent recess in an upper end 140 ′ of a leg 122 ′ of a second modular folding table 120 ′ for connecting the modular folding table and the second modular folding table together. As is illustrated in FIG. 22 , a lower leg connector bracket 152 , such as a two plug cap, for example, may also be provided for connecting sockets of female connector brackets 153 attached to the lower leg portions may also be provided for connecting one of the legs of the modular folding table to an adjacent leg 122 ′ of a second modular folding table 120 ′ for connecting the modular folding table and the second modular folding table together. In another presently preferred aspect, the upper ends of the legs include a recess 146 for receiving a lower end of a leg 122 ′ of a second modular folding table 120 ′, for stacking the second modular folding table on the modular folding table, as is illustrated in FIGS. 30-32 .
As described above, in another presently preferred aspect, the modular folding table may be provided with shelf support arms connected between a pair of legs, so that a lower shelf may thus be removably disposed on the shelf support arms. The lower shelf typically includes a plurality of segments hingedly connected together so as to be foldable, such as at least three segments connected together by at least two hinges, for example. The hinges of the shelf typically also each include a pair of flat plate portions connected to adjoining segments of the lower shelf, and the pair of flat plate portions are pivotally connected together by a pivot pin. Preferably the flat plate portions of at least one of the hinges are connected to the pivot pin by right angle members extending transversely from the flat portions, so that the lower shelf segments are foldable. In another preferred aspect, the lower shelf includes a plurality of notches at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
In a third preferred embodiment, in which like reference numbers denote like elements, as is illustrated in FIGS. 23-28 , the invention provides for a modular folding table 220 including a plurality of legs 222 , and a truss framework 224 connected to each of the legs. The truss framework includes a plurality of truss pairs of link members 226 , with each of the truss pairs including first link members 228 and second link members 230 , each having upper ends 232 and lower ends 234 . A plurality of table tops 238 can be removably disposed on the upper ends of the legs. The first and second link members are pivotally connected together at a midpoint 236 between the upper and lower ends in a scissors configuration so as to be extendable horizontally from a collapsed configuration to an extended configuration. Each of the first and second link members includes a table top support bracket 239 mounted between the midpoint and the upper ends of the link members for contacting and supporting the table top when it is placed on the upper ends of the legs.
Each of the legs has an upper end 240 and a lower end 242 , and the upper end of the first link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs. Likewise, the upper end of the second link member is pivotally connected to the upper end of one of the legs, and the lower end of the first link member is slidably connected to an adjacent one of the legs.
The upper ends of the legs include a pair of lands 244 for supporting the plurality of table tops. Each leg preferably includes a slider member 250 slidably mounted to the leg for slidably connecting the lower ends of the first and second link members to corresponding ones of the legs. As described above, in a presently preferred aspect, at least one of the legs includes latch means for latching at least one of the slider members in a fixed position on the leg. Each of the legs preferably includes a telescoping foot extension, and each of the legs preferably includes means, such as a spring loaded detent pin and corresponding latching hole in the leg, for example, for fixing the foot extension in a retracted position, and means, such as another spring loaded detent pin and corresponding latching hole in the leg, for fixing the foot extension in an extended position. The table top preferably includes a plurality of notches 282 at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
The upper ends 240 of the legs 222 along at least one side 262 of the modular folding table, and preferably along opposing sides, include a land 264 for supporting a table top, and a socket 266 for receiving a table top support bar 268 for supporting the table top, as is illustrated in FIG. 26 , for example.
Referring to FIGS. 23-26 , in another presently preferred aspect, the modular folding table may be provided with at least two shelf support arms 284 each having a first end and a second end connected between a pair of legs, so that a lower shelf 290 may thus be removably disposed on the shelf support arms. The lower shelf typically includes a plurality of segments hingedly connected together so as to be foldable, such as at least three segments connected together by at least two hinges, for example. The hinges of the shelf typically also each include a pair of flat plate portions connected to adjoining segments of the lower shelf, and the pair of flat plate portions are pivotally connected together by a pivot pin. Preferably the flat plate portions of at least one of the hinges are connected to the pivot pin by right angle members extending transversely from the flat portions, so that the lower shelf segments are foldable. In another preferred aspect, the lower shelf includes a plurality of notches at corner locations corresponding to the plurality of legs when the legs and the truss framework are in the extended configuration.
It will be appreciated that the present invention accordingly provides for a modular folding table with one or more braces added to the truss framework for supporting a table top, with legs having upper portions with recesses for receiving the legs of one or more other modular tables, so that the modular folding table of the invention is stackable. The present invention also provides for a modular folding table with brackets allowing the addition of one or more leaves of a table top to expand the table without adding base frame sections. In addition, shelves can be fixed to the legs with brackets, and the modular folding table of the invention is connectable at the base of the legs by brackets that allow two or more tables to connect with a two plug cap.
It will be apparent from the foregoing that, while particular forms of the invention have been illustrated and described, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited, except as by the appended claims. | The modular folding table includes a collapsible truss framework that supports a folding table top and a folding utility shelf, and includes legs that can be connected horizontally or vertically to the legs of one or more similar modular folding tables, to provide desired table and shelf space with a structure that is foldable, strong and stable. | 0 |
TECHNICAL FIELD
[0001] The present invention relates, in general to material movement systems and methods, and more specifically to a system and method for moving material past an obstacle and/or for moving materials in areas of limited space.
BACKGROUND OF INVENTION
[0002] Moving objects from one location to another location can be simplified with the use of some type of device, such as a hand cart, a hand truck, a dolly and the like. Such devices are often used everyday in a variety of locations for a variety of purposes, such as in factories, warehouses, offices, outdoors, homes and the like. These hand trucks and carts come in different sizes and shapes, depending on the nature of the object to be moved. For example, when large objects are moved, such as refrigerators, stoves, large boxes and the like, a mover may move the large object and position the large object on the dolly or cart so that the mover can move the large object to the desired destination with the use of the dolly or cart.
[0003] Various types of dollys may be used to move objects depending on the object to be moved. For example, a special hand dolly may be used to assist in moving various cylindrical objects such as beverage kegs, liquid filled bottles, pressurized cylinders, and the like. In such a case, the hand dolly may include some type of wall member to prevent the cylindrical object from being dislocated from the hand dolly.
[0004] While hand carts, dollys, or trucks are often used to assist a mover in relocating objects, such carts are unable to help a user move objects around or past various obstacles. For example, movement of objects around a jobsite, such as a construction worksite, may be very difficult due to various restrictions imposed by the jobsite, and ordinary hand trucks, dollys and carts provide no solution to the problem. When a building is under construction, it is often difficult to move large items throughout the building, such as moving items from a first floor to an upper floor, due to physical restrictions of the building, such as wall heights, hall way dimensions, door openings, and the like. In such instances, individuals may attempt to move items up elevators that are designed to carry people and not large items.
[0005] When individuals attempt to use hand trucks, carts, and dollys to move large items through an area characterized by physical restrictions, such as a building under construction, the individual is presented with many roadblocks and restrictions. For example, the individual attempting to move large items from lower floors of a building to upper floors of a building characterized by limited spaces, may attempt to move the large items in an elevator designed for people. However, the individual will often discover that the large item can not be transported in the limited space, such as the elevator designed for people. Accordingly, the individual ultimately has to move the larger items, to the upper floors by physically carrying the item, without the assistance of a hand truck, dolly or cart, up the stairs, which is very labor intensive, time consuming and dangerous.
[0006] Accordingly, a need exists in the art for a system and method that allows individuals to move material past obstacles, and/or for moving materials in areas of limited space, such as those presented by various physical restrictions of the location where the material is being moved.
BRIEF SUMMARY OF THE INVENTION
[0007] The present invention is directed to a system and method for moving material past an obstacle and/or for moving materials in areas of limited space. In one embodiment, the present invention provides a tilting bed cart/truck capable of carrying a load neither perpendicular nor parallel to the ground so that the area and space required to move an object is reduced. The tilting bed cart/truck may tilt the object loaded upon it so that the area needed to move an object is reduced. In one embodiment, the present invention enables objects to be moved in locations characterized by various physical restrictions such as limited height, width, and length dimensions that do not ordinarily allow for movement of larger sized objects. In another embodiment, the present invention may be configured so that as objects on the tilting bed cart/truck are tilted or moved in an upward and/or elevated direction, the load center of the object on the tilting bed cart/truck is maintained in order to provide stability to the object as the object is tilted and moved.
[0008] In one embodiment of the present invention, the tilting bed cart/truck may be configured so that it includes two base members, wheels, a lifting cylinder, a sliding member, and a holding framework. In such an embodiment, the wheels may be mounted to the two base members to allow the embodiment to be moved around. The sliding member may be configured so that it joins the two base members and allows the base members to move towards one another and allows the base members to move away from one another to ultimately change the length layout of the cart. The holding framework is configured to hold objects to be moved. Accordingly, the holding framework may take the form of any number of shapes or sizes to accommodate the moving of any number of objects, such as furniture, office cubicles, doors, refrigerators, sheet rock, plywood, paneling, and the like. The lifting cylinder may be configured so that it can be mounted to one base member and mounted to the holding framework so that it can move the holding framework in an upward and backward direction, such as tilting the object located on the holding framework in order to reduce the area needed to move an object and de-tilting the object or moving the object in a backward direction when the object has been moved around the obstacle.
[0009] The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter, which form the subject of the claims of the invention. It should be appreciated that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized that such equivalent constructions do not depart from the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying figures, in which:
[0011] FIG. 1 illustrates a rear view of an embodiment of the present invention;
[0012] FIG. 2 illustrates a side/frontal view of an embodiment of the present invention with a door located on the embodiment;
[0013] FIG. 3 illustrates a close up view of a portion of an embodiment of the present invention; and
[0014] FIG. 4 illustrates a flowchart representing one method for moving objects around obstacles and/or in limited areas according to one embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] A preferred embodiment of a tilting bed-cart/truck adapted according to the present invention is shown generally as tilting bed-cart/truck 100 in FIGS. 1 , 2 and 3 . FIG. 1 illustrates a rear view of an embodiment of the present invention, FIG. 2 illustrates a side/frontal view of an embodiment of the present invention with a door located on the embodiment, and FIG. 3 illustrates a close up view of a portion of an embodiment of the present invention. Tilting bed-cart/truck 100 includes base member 110 , wheels 111 , base member 120 , wheels 121 , lift mechanism 130 , framework support 135 , mounts 136 , mounts 138 , sliding mechanism 140 , framework 150 , framework mount 151 , mount member 152 , lifting mechanism-framework mount 153 , pump 160 , power supply 170 , and control station 180 .
[0016] As illustrated in FIGS. 1 and 2 , base members 110 and 120 are rectangular shaped. However, the present invention is not limited to this configuration as base members 110 and 120 may take the form of any number of shapes. Wheels 111 mount to base member 110 and wheels 121 mount to base member 120 . Wheels 111 and 121 may be swivel wheels, fixed position wheels, or any combination thereof. Such wheels may be of any size, such as three (3) inch diameter, four (4) inch diameter, and the like that are mounted to base members 110 and 120 by any fastening means, such as a screw, bolt, socket, cotter pin, and the like. Wheels 111 and 121 allow tilting bed-cart/truck 100 to move. The present invention may also be configured so that wheels 111 and/or wheels 121 are provided with a brake mechanism to help control movement of tilting bed-cart/truck 100 and some type of motorized device that will automatically move the wheels and thereby moving tilting bed-cart/truck 100 .
[0017] Base members 110 and 120 may also include mount blocks 112 and 122 , respectively. Mount blocks 112 and 122 may be a hollow block of material mounted to base members 110 and 120 which provide a mounting location for various items of the present invention. Mount blocks 112 provide a mounting location for mounts 136 to fasten to and mount blocks 122 provide a location for mount members 152 to fasten to. The present invention is not limited to this configuration as an embodiment may be configured without mount blocks 112 and 122 whereby mounts 136 and mount members 152 would mount directly to base members 110 and 120 .
[0018] Framework 150 is a tray like device that can receive and hold a variety of objects, such as doors, furniture, office cubicles, sheet rock, building materials, and the like that may be moved by the present invention. Framework 150 is generally a planar surface with an underside and a ledge 155 extending outward that helps keep objects from moving off of framework 150 . Framework 150 may be made of any number of various materials, such as metal, plastic, chrome, iron, stainless steel, aluminum, wood, any combination thereof, and the like. Objects that are to be moved by the present invention are placed upon framework 150 and remain on framework 150 throughout the moving process. The present invention may also include a variety of safety belts, clips, straps, and the like that are located near framework 150 , so that when an item is placed on framework 150 , the straps, belts, and or clips may be used to secure the item to framework 150 and prevent the item from inadvertently sliding off of framework 150 . For example, if the present invention were used to move a door, the door would be placed upon framework 150 whereby the door would rest upon framework 150 and may be secured to framework 150 with a safety belt, strap, and or clip until movement of the door is complete.
[0019] Framework mount 151 and mount member 152 provide a means in which framework 150 may be mounted to base member 120 . Framework mount 151 may be mounted to base member 120 with the use of mount member 152 which may be mounted to base member 120 through mount block 122 , and connecting rod 154 . Mounting member 152 may be mounted directly to base member 120 or to mount block 122 by any number of fastening means, such as a screw, bolt, socket, cotter pin, and the like. Framework mount 151 may be mounted to framework 150 by any number of fastening means, such as a screw, bolt, socket, cotter pin, and the like. In one embodiment, framework mount 151 may be a mount comprising a base that is physically attached to framework 150 with an upper portion located above the base that has a circular member that allows cylindrical devices, such as rod 154 , to fit into the circular member to allow the framework mount 151 to be attached to other objects. Mounting member 152 may be configured so that it comprises a hole to allow cylindrical devices, such as rod 154 , to slide through mounting member 152 . In one embodiment, rod 154 may be positioned through the hole in mounting member 152 and through the circular member of framework mount 151 thereby connecting mounting member 152 to framework mount 151 which in turn connects framework 150 to base member 120 with the use of rod 154 , framework mount 151 , and mounting member 152 . Framework mount 151 may also include some type of tightening device that functions to secure rod 154 within framework mount 151 so that the connection provided by rod 154 , framework mount 151 , and mounting member 152 is stable.
[0020] Lift mechanism 130 includes cylinder 130 a and rod 130 b. Lift mechanism 130 operates to lift framework 150 and any object that may be located on framework 150 . Lift mechanism 130 may be a hydraulic lift cylinder. However, the present invention is not limited to this configuration as lift mechanism 130 may be any number of devices or systems that are capable of lifting framework 150 , such as a manual screw lift device, an air lift device, a chain operated lift device, a hand operated lift device, and the like.
[0021] In one embodiment, the present invention also includes lower lift frame 131 and upper lift frame 132 as shown in FIG. 2 . Lower lift frame 131 and upper lift frame 132 provide attachment points for lift mechanism 130 that enables lift mechanism 130 to tilt framework 150 when lift mechanism 130 is operated. In one embodiment, the cylinder 130 a portion of lift mechanism 130 mounts to lower lift frame 131 and the rod 130 b portion of lift mechanism 130 mounts to upper lift frame 132 shown in FIGS. 1 and 3 , which enables the tilting of framework 150 via lift mechanism 130 .
[0022] In one embodiment, as shown in FIG. 1 , lower lift frame 131 is a rectangular shaped device comprising right member 131 a , left member 131 b , bottom member 131 c , and top member 131 d . Lower lift frame 131 may be mounted to base member 110 through bracket 113 . In one embodiment, bottom member 131 c of lower lift frame 131 may include a rod or other similar part that is mounted to base member 110 through bracket 113 . For example, bracket 113 may contain slots so that a rod member located near the bottom of lower lift frame 131 is mounted within slots of bracket 113 thereby enabling lower lift frame 131 to move when lift mechanism 130 is operated and functioning to move framework 150 . However, the present invention is not limited to the use of slots, as lower lift frame 131 may mount to base member 110 in any number of ways, such as the use of a bolt, screw, cotter pin, and the like.
[0023] In one embodiment of the present invention, lower lift frame 131 is configured so that it provides a location for lift mechanism 130 to mount to lower lift frame 131 . As illustrated in FIG. 1 , the cylinder 130 a portion of lift mechanism 130 mounts to bottom member 131 c of lower lift frame 131 with the use of some type of attachment device or method, such as a screw, a bolt, a permanent fixation by welding, and the like.
[0024] Lower lift frame 131 may also be configured in an embodiment so that top member 131 d of lower lift frame 131 includes a rod shaped member, such as rod member 131 e shown in FIGS. 1 , 2 , and 3 , that connects right member 131 a and left member 131 b . Lower lift frame 131 may also include link member 131 f , illustrated in FIGS. 2 and 3 . As illustrated in FIG. 3 , link member 131 f may be an oblong shaped cylindrical member that connects to rod shaped member 131 e and rod shaped member 133 that is connected to upper lift frame 132 as shown in FIG. 3 . Link member 13 If operates to connect lower lift frame 131 to upper lift frame 132 as shown in FIG. 3 and allows lower lift frame 131 and upper lift frame 132 to move relative to one another when lift mechanism 130 is operating, such as when it is used to move, tilt and/or de-tilt framework 150 .
[0025] In one embodiment, as shown in FIG. 1 , upper lift frame 132 may comprise connecting member 132 a , side members 132 b , and cylindrical member 132 c . Connecting member 132 a connects rod 130 b of lift mechanism 130 to upper lift frame 132 so that when lift mechanism 130 is operated, any movement by rod 130 b will result in movement to connecting member 132 a that will ultimately result in movement to any member connected to connecting member 132 a , such as upper lift frame 132 and framework 150 . Rod 130 b of lift mechanism 130 connects to one area of connecting member 132 a , and another area of connecting member 132 a connects to side members 132 b of upper lift frame 132 . Rod 130 b may be connected to connecting member 132 a by any number of ways, such as permanent welded connection, a bolt, screw, cotter pin, and the like.
[0026] As shown in FIGS. 2 and 3 , side members 132 b may be configured so that a rod shaped member, such as rod shaped member 133 , connects side members 132 b to one another and provides a manner in which link member 131 f can connect lower lift frame 131 to upper lift frame 132 .
[0027] As shown in FIG. 1 , side members 132 b may run parallel to framework 150 and connect to cylindrical member 132 c . In one embodiment, cylindrical member 132 c may be a hollow cylindrical member that is arranged so that rod member 132 d is positioned inside of cylindrical member 132 c and may extend out of cylindrical member 132 c . Rod member 132 d mounts to lifting mechanism-framework mount 153 in order to hold rod member 132 d and to keep 132 c connected between lifting mechanism-framework mounts 153 . Cylindrical member 132 c is configured so that it has a diameter larger than the diameter of rod member 132 d so that cylindrical member 132 c can move around rod member 132 d , such as when lift mechanism 130 is moving framework 150 , and so that rod member 132 d can be easily removed from cylindrical member 132 c.
[0028] Framework support 135 is a support device that adds additional support to framework 150 and helps to enable framework 150 to be moved, raised, lowered, tilted, de-tilted, and the like with the use of lift mechanism 130 , lower lift frame 131 , and upper lift frame 132 . As illustrated in FIGS. 1 and 3 , framework support 135 includes a right member 135 a and a left member 135 b . In one embodiment, one end of framework support 135 is mounted to member 110 through mounts 136 and the opposite end of framework support 135 is mounted to framework 150 through framework mounts 138 . Mounts 136 and 138 are preferably pivot mounts that allow the items connected into the mounts to pivot or move in mounts 136 and 138 . However, the present invention is not limited to this configuration as mounts 136 and/or mounts 138 may be non-pivoting mounts.
[0029] As illustrated in FIGS. 1 , 2 , and 3 , the present invention may be configured so that framework support 135 includes rods 137 and 139 that are located at each end of framework support 135 . Rods 137 and 139 may be configured to provide a mounting location for framework support 135 so that rod 137 fits into mounts 136 and rod 139 fits into mounts 138 . In one embodiment, mounts 136 and 138 are pivot mounts so that rods 137 and 139 can pivot or move in mounts 136 and 138 .
[0030] Although FIG. 1 illustrates rods 137 and 139 as extending longitudinal from one mount to another mount, the present invention is not limited to this configuration. The present invention may also be configured so that rods 137 and 139 do not extend from one mount to the other mount but the rods may be configured so that it can fit into mounts 136 and 138 but the rods do not continually extend longitudinal between mounts 136 and between mounts 138 .
[0031] An embodiment of the present invention may also include sliding mechanism 140 , clearly shown in FIG. 2 . Sliding mechanism 140 is a device that may be configured so that part of sliding mechanism 140 is connected to base member 110 and another part of sliding mechanism 140 is connected to base member 120 . Sliding mechanism 140 can expand and/or retract depending on the operation of lift mechanism 130 . Sliding mechanism 140 may comprise a sliding member 140 a , illustrated in FIG. 2 , and a receiving member 140 b , illustrated in FIG. 1 . In one embodiment sliding member 140 a and receiving member 140 b may be two separate pieces and in another embodiment sliding mechanism 140 may be configured so that sliding member 140 a and receiving member 140 b are one piece that may collapse into one another in a telescoping fashion. Sliding member 140 a may be connected to base member 120 and receiving member 140 b may connect to base member 110 . The sliding member 140 a may be an object, either hollow or solid, of any number of different shapes, such as cylindrical, rectangular, octagonal, triangular, and the like that is capable of moving into receiving member 140 b . Sliding member 140 a is not limited to any particular type of material as it may comprise any number of different materials, such as metal, wood, plastic, iron, aluminum, and the like.
[0032] Receiving member 140 b is preferably a hollow object that is capable of receiving sliding member 140 a as lift mechanism 130 operates to move framework 150 . Receiving member 140 b may also take the form of any number of shapes, such as cylindrical, rectangular, octagonal, triangular, and the like and is not limited to any particular type of material as it may comprise any number of different materials, such as metal, wood, plastic, iron, aluminum, and the like. In a preferred embodiment, receiving member 140 b will be a hollow member that is the same shape as sliding member 140 a so that when lift mechanism 130 moves framework 150 , sliding member 140 a can move into or out of receiving member 140 b with little to no friction. However, the present invention is not limited to this embodiment, as any number of configurations is permissible as long as sliding member 140 a and receiving member 140 b can move into or out of or away from one another as lift mechanism 130 operates. For example, in one embodiment, sliding member 140 a may be a hollow member that is larger than receiving member 140 b and receiving member 140 b may be a solid member smaller than sliding member 140 a whereby sliding member 140 a will slide over or outside of receiving member 140 b when lift mechanism 130 operates.
[0033] In one embodiment, when lift mechanism 130 is activated so that rod 130 b extends out of the cylinder 130 a and elevates framework 150 in an outward or titled manner, wheels 111 and 121 will move towards one another so that the length between base members 110 and 120 will decrease and sliding mechanism 140 will retract with sliding member 140 a moving into receiving member 140 b or sliding member 140 a moving over or outside of receiving member 140 b.
[0034] When lift mechanism 130 is activated so that rod 130 b retracts into cylinder 130 a , framework 150 will move in a downward direction. In such a case, wheels 111 and 121 will move apart from one another so that the length between base members 110 and 120 will increase and sliding mechanism 140 will protract with sliding member 140 a moving away from or out of receiving member 140 b . Sliding mechanism 140 will expand thereby causing base members 110 and 120 to move apart from one another.
[0035] The present invention may also include pump 160 , as illustrated in FIG. 1 . Pump 160 is utilized to operate lift mechanism 130 . Pump 160 is preferably a hydraulic pump that is used to operate lift mechanism 130 . The present invention is not limited to any particular type or size of pump as pump 160 may be any size or type of pump that can operate lift mechanism 130 .
[0036] In another embodiment, the present invention may include another machine or device instead of or in addition to pump 160 that can be used to activate lift mechanism 130 . For example, the present invention may include a motor, a self cranking device, a foot pedal, and the like that can be used to activate lift mechanism 130 .
[0037] An embodiment of the present invention also includes a power supply, such as power supply 170 illustrated in FIG. 2 . Power supply 170 may be utilized to provide power to any number of devices that may be part of, installed on, or used with tilting bed-cart/truck 100 . In one embodiment, power supply 170 provides a source of power to operate pump 160 . Power supply 170 may be a battery. However, the present invention is not limited to this configuration as power supply 170 may be any number of power supplies capable of providing power, such as a battery, a solar power supply, an electrical cord for connection to an outlet, and the like.
[0038] In one embodiment, the present invention may be configured to include carriage 165 , as shown in FIGS. 1 and 2 . Carriage 165 is a device utilized to hold pump 160 , power supply 170 , and any number of additional devices, to tilting bed-cart/truck 100 . As illustrated in FIGS. 1 and 2 , carriage 165 may be a half-box shaped device that functions to hold various items, such as pump 160 and power supply 170 . Carriage 165 is not limited to the illustrations show in FIGS. 1 and 2 as it may take the form of any number of shapes and may be made of any number of materials, such as wood, steel, iron, aluminum, chrome, plastic, and the like. Pump 160 and power supply 170 may be mounted to carriage 165 or may simply sit in carriage 165 .
[0039] The present invention may also include control station 180 as illustrated in FIG. 2 . Control station 180 may provide a means for a user to control the present invention. In one embodiment, control station 180 may include a start button and a stop button that may be used to start and stop the operation of lift mechanism 130 , to activate or de-activate any braking mechanism that may be installed on wheels 111 and 121 , to activate any motor mechanism that may move wheels 111 and 121 , and /or to activate or de-activate any braking mechanism that may be installed on lift mechanism 130 to prevent it from moving any further. Control station 180 may also be configured such that it is mounted to one of members 110 and 120 for use by a user's foot. In another embodiment, control station 180 may be configured so that it is a remote control device. In such an embodiment, the remote control may be hard wired or wireless. In a wireless configuration, control station 180 may comprise a remote device that a user may uses to send control signals and a signal receiving device for receiving the signals sent by the remote device. The signal receiving device may also operate to receive the signals and pass the signals on, either as the same signal or as a new signal, so that a user can operate and control the present invention. However, the present invention is not limited to this configuration, as the control station may be configured in any number of ways so that a user is able to control tilting bed-cart/truck 100 .
[0040] One embodiment of the present invention may also include various safety devices to assist in keeping use of the present invention safe. For example, a buzzer may be installed to make noise when framework 150 is moved, either in an elevated or de-elevated direction. A buzzer may also be installed to make a sound when tilting bed-cart/truck 100 is in the process of being rolled in either a forward or backward direction. The present invention is not limited to the foregoing safety devices as any number of safety devices may be used to increase safety, such as blinking lights, wheel brakes, brakes on lift mechanism 130 to ensure that framework 130 does not fall, a weight sensor to detect when the objects placed upon framework 150 are too heavy, a power indicator to indicate when power is low, and the like.
[0041] The present invention is not limited to any range of movement or elevation of an object on framework 150 . For example, the present invention may be configured so that lift mechanism 130 and the surrounding components can operate to move, lift, elevate, tilt, de-elevate, and/or de-tilt framework 150 and any objects on framework 150 to any number of degrees of movement, such as 30 degrees movement, 45 degrees movement, 60 degrees movement, 90 degrees of movement, 180 degrees of movement (so that framework 150 and any objects located on framework 150 are laying flat and parallel to the ground, and the like.
[0042] A technical advantage of the present invention is that as an object on framework 150 is moved, in either an elevated/ tilted direction or in a de-elevated or de-tilted direction through the activation of lift mechanism 130 , the center of the load of the object on framework 150 will continue to stay between base members 110 and 120 and between wheels 111 and 121 . The present invention will function to maintain the load center between the wheels because as an object on framework 150 is tilted and/or moved in an upward or elevated direction, base members 110 and 120 move towards one another through wheels 111 and 121 whereby the center of the load of an object on framework 150 will stay between base members 110 and 120 and wheels 111 and 121 . In addition, as an object on framework 150 is de-tilted and/or moved in an downward or de-elevated direction, base members 110 and 120 move away from one another through wheels 111 and 121 whereby the center of the load of an object on framework 150 will stay between base members 110 and 120 and wheels 111 and 121 By maintaining the load center between the base members 110 and 120 , the present invention provides load stability throughout the entire range of movement of an object on framework 150 .
[0043] Another advantage is that the overall length of tilting bed-cart/truck 100 when framework 150 is elevated to an upright limit is shorter than the overall length of tilting bed-cart/truck 100 when framework 150 and any object on framework 150 is moved to its lowest non-elevated position. By decreasing the overall length of tilting bed-cart/truck 100 , it is easier to move objects with the present invention in areas characterized by dimension restrictions, such as an elevator designed for people, hallways, door entry ways, and the like. For example, in several instances, the only way to get large flat objects, such as sheet rock, doors, plywood and the like, to the upper floors of a building is to carry these objects up the stairs. The present invention helps solve this problem as the large flat objects can be placed upon framework 150 and then framework 150 can be tilted with lift mechanism 130 so that the large flat objects are not carried parallel nor perpendicular to the ground when the objects are in the process of being moved. In tilting and/or elevating framework 150 , the floor space required to carry the large objects is reduced thereby allowing various large flat objects to be transported in, around, and through limited spaces. For example, the present invention can be utilized to tilt a 3 foot by 9 foot door so that the door can be transported in an area that only requires 7 feet of length as opposed to 9 feet of length.
[0044] The present invention may also include a locking mechanism that may increase the safety of users moving objects with the present invention. A locking mechanism may operate to lock sliding mechanism 140 to prevent sliding member 140 a and receiving member 140 b from moving into or away from one another. For example, if the present invention were in use and a door was on framework 150 and lift mechanism was unable to hold the framework in its present tilted position, a locking mechanism could be used to prevent the sliding member 140 a and receiving member 140 b from moving into or away from one another so that the present invention would be able to keep the door in its present (tilted) position.
[0045] FIG. 4 illustrates a flowchart representing one method for moving objects around obstacles according to one embodiment of the present invention. Flow 40 represents a method for moving objects around obstacles. A tilting bed-cart/truck is provided in block 400 . The tilting bed-cart/truck may comprise tilting bed-cart/truck 100 illustrated in FIGS. 1 and 2 . After the tilting bed-cart/truck is provided, flow 40 proceeds to block 410 , where an object is loaded on the tilting bed-cart/truck. For example, the object may be a door or a piece of sheet rock that is loaded on the tilting bed-cart/truck.
[0046] After the object is loaded, flow 40 proceeds to block 420 . In block 420 , the object is tilted. The object may either be tilted in either an upward or downward direction. For example, a user may be using the tilting bed-cart/truck to move large flat objects to an upper floor of a building by using an elevator designed for people. The user will load the object, such as a door or piece of sheet rock, and then tilt the object to a desired angle of elevation so that the object can be moved in the elevator. After block 420 , flow 40 proceeds to block 430 . When flow 40 proceeds to block 430 , the object may be moved to its final location where it may then be moved off of the tilting bed-cart/truck. For example, after the object, such as the door, is loaded and tilted, a user will use the tilting bed-cart/truck to move the object, via the wheels on the cart, to the desired location. When the object, such as a door, is moved via the tilting bed-cart/truck to its final destination, then the object may be unloaded and/or moved off of the tilting bed-cart/truck.
[0047] Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one will readily appreciate from the disclosure, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps. | A method and system are disclosed for moving material past an obstacle and/or for moving materials in areas of limited space. A user can move so that the area and space required to move an object is reduced. A user can utilize the system and method to load an object and then tilt the object to be moved so that the area needed to move an object is reduced. After the object has been tilted, a user can move the object in locations characterized by various physical restrictions such as limited height, width, and length dimensions that do not ordinarily allow for movement of larger sized objects. | 1 |
FIELD OF THE INVENTION
[0001] The invention relates to a topical composition that provides enhanced skin health by way of providing anti-aging benefits that are evident from visibly reduced wrinkles and under-eye dark circles.
BACKGROUND OF INVENTION
[0002] Life-style modification and age increases the probability to acquire major health problems like cardiovascular risk factors. Impairment in blood vessel flexibility is a major risk factor for the onset of such diseases, reflected as hypertension, angina and atherosclerosis. In humans, the investigation of endothelial function has centered on either the macrocirculation or the microvasculature. Microcirculation is the delivery of fresh blood to the smallest blood vessels, present in the vasculature embedded within organ tissues. This contrasts with macrocirculation, which transport blood to and from the organs. The main functions of the microcirculation include 1. regulation of blood flow and tissue perfusion 2. regulation of blood pressure, 3. regulation of tissue fluid (swelling or edema), 4. delivery of oxygen and other nutrients and removal of carbon dioxide and other metabolic waste products, 5. regulation of body temperature, and 6. reduction of sedentary aging (wrinkles, under eye dark circles). In addition to maintaining these functions for overall health benefits, microcirculation enhances skin health.
[0003] Skin microcirculation is a complex and dynamic system which is important for thermoregulation, skin metabolism and trans-cutaneous penetration. The blood supply to the skin is provided by a network of arterioles, capillaries and venules organized into a superficial and a deep plexus. Skin is exposed to environmental stressors (such as UV, chemical pollutants and particulate matter) or physiological (non-environmental) stressors (psychological stress, sedentary aging and inflammation). Such compromised blood flow leads to physiological effects such as under-eye dark circles, wrinkles, retarded wound healing and edema.
[0004] To overcome these issues, for better skin health, the present inventors have approached the problem by combining actives that regulate macro vascular and micro vascular endothelial function. They have found that a composition comprising gallated catechins and folic acid in specific ratios is able to interact synergistically to enhance skin health when applied topically.
[0005] US2009061023 discloses a nutritional supplement for inhibiting sensorineural hearing loss which includes several micronutrients selected from folic acid, green tea extract and several others like thiamin, hydroxycobalamin, magnesium, zinc, selenium, and manganese to name a few. The claimed benefit is believed to be effected by improved microcirculation among others.
[0006] US2005106263 discloses a a natural formulation for treatment of male, female and adolescent pattern hair loss comprising a combination of green tea leaf extract, polyphenols, epigallocatechin gallate (EGCG), vitamin E, folic acid, copper (as amino acid chelate), vitamin B12, zinc (as oxide), calcium pantothenate, niacin, biotin, riboflavin, thiamine, and optionally inositol, black tea extract and nettle extract.
[0007] The compositions disclosed in the above mentioned published documents do not disclose the specific ratios of gallated catechins and folic acid which the present inventors have determined to interact synergistically to improve micro and macro circulation for enhanced skin health.
[0008] It is thus an object of the present invention to provide for a topical composition that exhibits enhanced micro and/or macro-circulation for improved skin health.
SUMMARY OF THE INVENTION
[0009] According to the first aspect of the invention there is provided a topical composition comprising
(i) 0.1 to 5% folic acid; (ii) 0.1 to 5% a gallated catechin; and (iii) a cosmetically acceptable base selected from the group consisting of cream, lotion, gel and emulsion.
[0013] wherein the weight ratio of gallated catechin: folic acid is in the range of 1:1 to 10:1.
[0014] According to yet another aspect of the present invention there is provided a method of improving microcirculation of skin comprising applying to the skin a composition of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] These and other aspects, features and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. For the avoidance of doubt, any feature of one aspect of the present invention may be utilized in any other aspect of the invention. The word “comprising” is intended to mean “including” but not necessarily “consisting of” or “composed of.” In other words, the listed steps or options need not be exhaustive. It is noted that the examples given in the description below are intended to clarify the invention and are not intended to limit the invention to those examples per se. Similarly, all percentages are weight/weight percentages unless otherwise indicated. Except in the operating and comparative examples, or where otherwise explicitly indicated, all numbers in this description and claims indicating amounts of material or conditions of reaction, physical properties of materials and/or use are to be understood as modified by the word “about”. Numerical ranges expressed in the format “from x to y” are understood to include x and y. When for a specific feature multiple preferred ranges are described in the format “from x to y”, it is understood that all ranges combining the different endpoints are also contemplated.
[0016] “Topical composition” as used herein, is meant to include a composition for application to the external surface e.g. skin of mammals, especially humans for better skin health benefits. Such a composition may be generally classified as leave-on or rinse off, preferably leave-on and includes any product applied to a human body primarily for enhanced health of skin but may be used also for improving appearance, cleansing, odour control or general aesthetics. The composition of the present invention can be in the form of a liquid, lotion, cream, foam, scrub, gel, soap bar or toner, or applied with an implement or via a face mask, pad or patch. Non-limiting examples of such topical compositions include leave-on skin lotions and creams, antiperspirants, deodorants, lipsticks, foundations, mascara, sunless tanners or sunscreen lotions, and wash-off products like shampoos, conditioners, shower gels, or toilet bars. “Skin” as used herein is meant to include skin on the face and body (e.g., neck, chest, back, arms, underarms, hands, legs, buttocks and scalp) and especially to the under-eye portions of the face. The topical composition of the invention is especially useful for application on skin areas that get wrinkled or are more likely to get wrinkled especially to the sun exposed parts of the body.
[0017] The first aspect of the present invention provides for a topical composition comprising folic acid and a gallated catechin in a cosmetically acceptable base wherein the weight ratio of gallated catechin: folic acid is in the range of 1:1 to 10:1.
[0018] Folic acid is an important micronutrient. Folic acid has the structure as given below:
[0000]
[0019] Folic acid (also known as folate, vitamin M, vitamin B9, vitamin Bc (or folacin), pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid) are forms of the water-soluble vitamin B9. Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.
[0020] Vitamin B9 (folic acid and folate) is essential to numerous bodily functions. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions. It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folic acid to produce healthy red blood cells and prevent anemia.
[0021] Leafy vegetables are principal sources of folic acid, although in Western diets fortified cereals and bread may be a larger dietary source.
[0022] Foods that are high in folate include:
Fruits particularly kiwi fruit and papaya. Vegetables such as broccoli, brussel sprouts, spinach, cabbage, asparagus and parsnips. Cooked kidney and liver Oranges (including orange juice) Tinned baked beans Lettuce, peas and cauliflower Egg yolks Milk
[0031] Folic acid is present in 0.1 to 5% preferably in 0.1 to 3%, more preferably 0.1 to 2% in the composition of the invention.
[0032] Gallated catechins are present in the composition of the invention. Gallated catechins are preferably epigallo catechin gallate (EGCG) or epicatechin gallate (ECG) or catechin gallate (CG). EGCG and ECG have the structure as given below:
[0000]
[0033] These catachins are found in high amounts in green tea from which they are preferably extracted. Green tea is made from the tea plant. Tea refers to one or more plants belonging to the family of Camellia sinensis var. sinensis and/or Camellia sinensis var. assamica . Tea is the second most consumed beverage worldwide. It is rich source of monomeric and polymeric forms of the flavonoids and can account up to 10-30% flavonoids by weight.
[0034] Green tea is generally prepared from the leaves and buds of the tea plant by the process described below.
[0035] Tea ( Camellia sinensis ) is the second most consumed beverage worldwide. At harvest tea leaves contain high levels of catechins, a particular class of polyphenols. After harvest catechins may be rapidly converted by enzymatic oxidation to a complex mixture of other derivatives, thearubigins and theaflavins, responsible for the characteristic color of oolong and black tea. Green tea (GT), however, is produced by heat-treating leaves soon after harvest, thereby preserving the catechins from oxidation. The amount of catechins in a cup of GT is highly variable, depending on the precise type of tea, the ratio of dry tea to water and on the time that the leaves are infused before consumption. An average serving of 250 ml of GT contains between 50 and 100 mg of catechins. Catechins are the main bioactive constituents of green tea leaves and account for 25% to 35% of their dry weight. The polyphenolic flavonoid-type catechin are (+)-catechin (C), (−)-epicatechin (EC), (+)-gallocatechin (GC), (−)-epigallocatechin (EGC), (+)-catechin gallate (CG), (−)-epicatechin. gallate (ECG), (+)-gallocatechin gallate (GCG) and (−)-epigallocatechin gallate (EGCG). Catechins are also found in many commonly consumed fruits and beverages like apples, black, red and white currants, blueberries, chocolates, cocoa, grape seeds, and red wine.
[0036] The principle component in green tea is mentioned in the table below
[0000]
TABLE 1
Principle components of green tea
Green Tea
(% weight of extract solids)
Catechins
30-42
Flavonols
5-10
Other flavonoids
2-4
Theogallin
2-3
Other depsides
1
Ascorbic Acid
1-2
Gallic Acid
0.5
Quinic acid
2
Other organic acids
4-5
Theanine
4-6
Other amino acids
4-6
Methylxanthines
7-9
Carbohydrates
10-15
Minerals
6-8
Volatiles
0.02
[0037] Amongst the catechins the composition of different catechins in green tea are as follows.
[0038] Flavonoid Composition of Green Tea: percent by dry weight.
[0000]
Component
Gree tea
TotalFlavonoids
15-25%
Total Catechins
12-18%
(−) Epicatechin
1-3%
(−) Epicatechingallate
3-6%
(−) Epigallocatechin
3-6%
(−) Epigallocatechingallate
9-13%
Flavonols
2-3%
Theaflavins
<1%
Other polyphenols
2-4%
[0039] Gallated catechins are present in 0.1 to 5%, preferably 0.1 to 4%, more preferably 0.1 to 3% in the composition of the invention.
[0040] The gallated catechins and folic acid are included in the composition of the invention in a weight ratio of gallated catechin: folic acid is in the range of 1:1 to 10:1, preferably in range of 2.5:1 to 7.5:1.
[0041] Without wishing to be bound by theory it is believed that the problem of poor blood circulation leading to the problems of poor skin health like under-eye dark circles, wrinkles etc occur due to the mechanism described below. Further, described below is the mechanism by which the composition of the present invention is believed to work to alleviate the problem.
[0042] Skin is exposed to environmental stressors (such as UV, chemical pollutants and particulate matter) or physiological (non-environmental) stressors (psychological stress, sedentary aging and inflammation), which triggers sequential changes; thereby induce significant changes in cutaneous blood flow due to endothelial dysfunction or nitric oxide (NO) impairment. Such compromised blood flow leads to physiological effects such as under-eye dark circles, wrinkles, retarded wound healing, and edema. All these physiological functions are linked with chronic low grade inflammation and peripheral resistance (endothelial dysfunction).
[0043] The present inventors believe that this compromised state of endothelium can be reverted to gain its normal functionality, by modulating endothelial NO production, either by interfering with NO signaling or by scavenging NO dissipating free radicals.
[0044] The mechanism underlying this effect is activation of endothelial nitric oxide synthase (eNOS), which results in enhanced nitric oxide which will result in vessel dialation. EGCG, a major gallated-catechin in green tea is believed to act as pro-oxidant at higher concentrations, while its presence at lower concentrations confers antioxidant effect in different cell types. EGCG exposure to endothelial cells, invitro potentiates eNOS activation, while presence of high concentration of EGCG leads to activation of pro-oxidant milieu. The pro-oxidant milieu is characterized by increased production of superoxide. This increased superoxide production may be due to conformational change in the enzyme called as eNOS ‘uncoupling’. This enzyme is a homo-dimer under normal physiology and produces nitric oxide with stimulation (which is benefitial), and alters into its momomeric form under pro-oxidant milieu. The monomeric form produces superoxide instead of nitric oxide. The superoxide formed even scavenges minimal amount of NO in the surrounding to form peroxinitrites. Peroxinitrites are believed to cause protein nitrosylation and hamper normal signaling.
[0045] Uncoupling of eNOS is a major cause of endothelial dysfunction in both micro and macro vascular pathophysiology. At molecular level, administration of folic acid, a precursor of methyl tetrahydro folate (MTHF, co-factor to eNOS) keeps the enzyme in its coupled state (the active form). Thus folic acid pretreatment reduces superoxide production and enhances NO synthesis by the enzyme.
[0046] The present inventors have found that, when EGCG is treated in endothelial cells, it activated eNOS enzyme, but at higher concentration lead to superoxide formation. Pretreatment with folic acid abolished eNOS uncoupling, hence enhances EGCG induced NO production. Thus, a carefully selected combination of gallated catechins and folic acid produces the desired benefits which are not evident outside the selected concentration ratios.
[0047] The composition of the invention comprises a cosmetically acceptable base. The cosmetically acceptable base as per the present invention is a cream, lotion, gel or emulsion. The cosmetically acceptable base preferably comprises a fatty acid or a silicone compound. When the cosmetically acceptable base comprises fatty acid it is preferably present in 1 to 25% by weight of the composition. When the cosmetically acceptable bases are such as to have a product in a cream, lotion, or emulsion format, it generally comprises fatty acid. Of these formats, a more preferred format is a cream or lotion, further more preferably a cream. Vanishing cream base is one which comprises 3 to 25%, more preferably 5 to 20% fatty acid, which is a preferred format of the composition of the invention. In this, the base preferably comprises 0.1 to 10%, more preferably 0.1 to 3% soap. C 12 to C 20 fatty acids are especially preferred in vanishing cream bases, further more preferred being C 14 to C 18 fatty acids. In creams, the fatty acid is preferably substantially a mixture of stearic acid and palmitic acid. Soaps in the vanishing cream base include alkali metal salt of fatty acids, like sodium or potassium salts The soap is preferably the potassium salt of the fatty acid mixture. The fatty acid in vanishing cream base is often prepared using hystric acid which is substantially (generally about 90 to 95%) a mixture of stearic acid and palmitic acid (usually 55% stearic acid and 45% palmitic acid). Thus, inclusion of hystric acid and its soap to prepare the vanishing cream base is within the scope of the present invention. It is particularly preferred that the composition comprises at least 6%, preferably at least 10%, more preferably at least 12% fatty acid. The cosmetically acceptable base is usually from 10 to 99.9%, preferably from 50 to 99% by weight of the composition.
[0048] Another preferred base is a lotion. Lotions generally comprise 1 to 20% fatty acid. The cosmetically acceptable base preferably includes water. Water is preferably included in 35 to 90%, more preferably 50 to 85%, further more preferably 50 to 80% by weight of the composition.
[0049] An especially suitable cosmetically acceptable base is one which comprises a water-in-oil emulsion comprising silicone oils as the continuous phase. The water in oil emulsions preferably comprise a crosslinked silicone elastomer blend.
[0050] Inclusion of silicone elastomer blend in a water-in-oil emulsion may be used as the cosmetically acceptable base for preparing the compositions of the present invention. While silicone fluids may be used, silicone elastomers which are cross-linked, are especially preferred. The creation of cross-linkages between linear polymers, such as dimethicone, converts the linear polymer into a silicone elastomer. In contrast to silicone fluid polymers, the physical properties of elastomers are typically dependent on the number of cross-linkages, rather than molecular weight. The ability of silicone elastomers to swell makes them ideal thickeners for oil phases. The elastomers have a very smooth and soft feel when applied to skin or hair. They can also be used as delivery agents for fragrances, vitamins and other additives in cosmetic compositions.
[0051] Suitable silicone elastomer blends or gels which are commercially available and suitable for inclusion in the composition of the invention and found to provide the enhanced stability are: Dow Corning® EL-8051 IN Silicone Organic Elastomer Blend [INCI Name: Isodecyl Neopentanoate (and) Dimethicone/Bis Isobutyl PPG-20 Crosspolymer]; EL-8050 [INCI Name: Isododecane (and) Dimethicone/Bis-Isobutyl PPG 20 Crosspolymer] DC 9040, DC9041, DC9045 (Dimethicone crosspolymer); DC 9506, 9509 (Dimethicone vinyl dimethicone crosspolymer); Shin-Etsu KSG-15, KSG-16, KSG-17 (Dimethicone vinyl dimethicone crosspolymer). It is further preferred that the composition comprises 5 to 50% silicone elastomer by weight of the composition.
[0052] Useful sun-protective agents e.g. inorganic sun-blocks may be preferably used in the present invention. These include, for example, zinc oxide, iron oxide, silica, such as fumed silica, or titanium dioxide. The total amount of sun block that is preferably incorporated in the composition according to the invention is from 0.1 to 5% by weight of the composition.
[0053] The composition of the invention may additionally comprise a skin lightening agent. The skin lightening agent is preferably chosen from a vitamin B3 compound or its derivative e.g. niacin, nicotinic acid, niacinamide or other well known skin lightening agents e.g. aloe extract, ammonium lactate, azelaic acid, kojic acid, citrate esters, ellagic acid, glycolic acid, green tea extract, hydroquinone, lemon extract, linoleic acid, magnesium ascorbyl phosphate, vitamins like vitamin B6, vitamin B12, vitamin C, vitamin A, a dicarboxylic acid, resorcinol derivatives, hydroxycarboxylic acid like lactic acid and their salts e.g. sodium lactate, and mixtures thereof. Vitamin B3 compound or its derivative e.g. niacin, nicotinic acid, niacinamide are the more preferred skin lightening agent as per the invention, most preferred being niacinamide. Niacinamide, when used, is preferably present in an amount in the range of 0.1 to 10%, more preferably 0.2 to 5% by weight of the composition.
[0054] The composition according to the invention may also comprise other diluents. The diluents act as a dispersant or carrier for other materials present in the composition, so as to facilitate their distribution when the composition is applied to the skin. Diluents other than water can include liquid or solid emollients, solvents, humectants, thickeners and powders.
[0055] The composition of the invention may comprise a conventional deodourant base as the cosmetically acceptable carrier. By a deodorant is meant a product in the stick, roll-on, or propellant medium which is used for personal deodorant benefit e.g. application in the under-arm or any other area which may or may not contain anti-perspirant actives.
[0056] Deodorant compositions can generally be in the form of firm solids, soft solids, gels, creams, and liquids and are dispensed using applicators appropriate to the physical characteristics of the composition.
[0057] The compositions of the present invention can comprise a wide range of other optional components. The CTFA Cosmetic Ingredient Handbook, Second Edition, 1992, which is incorporated by reference herein in its entirety, describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples include: antioxidants, binders, biological additives, buffering agents, colorants, thickeners, polymers, astringents, fragrance, humectants, opacifying agents, conditioners, exfoliating agents, pH adjusters, preservatives, natural extracts, essential oils, skin sensates, skin soothing agents, and skin healing agents.
[0058] According to another aspect of the present invention there is provided a method of improving microcirculation of skin comprising applying to the skin a composition of the invention. The use of such a method is preferably non-therapeutic.
[0059] The invention will now be illustrated with the help of the following non-limiting examples.
EXAMPLES
[0060] The experiments were conducted using the following procedure:
Materials
[0061] DAF FM-DA was purchased from Invitrogen (Eugene, Oreg.)
[0062] DMEM, Folic acid (Cat #—F7876) and EGCG (Cat #—50299) were purchased from Sigma (St. Louis, Mo., USA).
Preparation of EA.Hy926 Cells
[0063] The cultured human endothelial cell line EA.Hy926 cells were procured from American Type Culture Collection (CRL-2922—ATCC) and were cultured in DMEM (Sigma) supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% vol/vol FBS (Gibco, Invitrogen). Cells were cultured at 37° C. in 95% humidified air with 5% CO 2 . After attaining 70-80% confluence, the cells were sub-cultured by trypsinization (0.25% Tryp-EDTA, for 2-3 min). For experimental purpose, cells were seeded onto 24 well tissue culture plates (CLS3524 Sigma). After adherence, cells were subjected to starvation in serum free low glucose DMEM for 12-14 hrs prior to any experiment, to maintain the cells in quiescent state and reduce the basal level of NO production.
Measurement of Intracellular Nitric Oxide Using Flow-Cytometry
[0064] Experimental Flow:
[0065] 1. EAHy926 (5×10 5 ) cells were seed into 24 well tissue culture plate and allowed to adhere for 12-16 hrs.
[0066] 2. After adherence, cells were treated with or without 4.41 μg/ml (10 μM) folic acid and incubated for 24 hrs in DMEM without FBS.
[0067] 3. The cells in 24 well tissue culture plates were loaded with DAF FM-DA (1 μM) for 30 min, washed twice with serum free medium.
[0068] 4. Subsequently, cells were stimulated with different concentration of EGCG for 30 mins and washed twice with serum free medium.
[0069] 5. The stimulated cells were trypsinized with 0.25% Trypsin-EDTA and fixed with 2% PFA for 15 min.
[0070] 6. The suspension of cells were acquired using flow-cytometry. A population of 10,000 cells were gated and segregated based on their relative fluorescence intensities using FACS Calibur (BD; SanDiego). The mean yield of two distinct populations was measured and compared with the respective population in untreated cells.
[0071] The data on the Nitric Oxide activity is summarized in Table-1 for the various compositions which may be gallated catechins (EGCG) alone at various concentrations or folic acid alone or EGCG in combination with folic acid. Compositions exhibiting an NO activity value higher than 3.0 preferably higher than 3.8 are taken as those expected to provide the enhanced microcirculation benefits of the present invention.
[0000]
TABLE 1
Ratio of
Example
Concentration of
Concentration of
EGCG:Folic
NO
Number
EGCG, μg
Folic acid, μg
acid
activity
1
0
0
—
1.00
2
2.29
0
—
2.87
3
4.58
0
—
2.98
4
11.45
0
—
3.75
5
22.91
0
—
3.58
6
33.07
0
—
2.32
7
44.1
0
—
1.64
8
110.25
0
—
0.63
9
0
4.41
0
1.00
10
2.29
4.41
0.52
2.73
11
4.58
4.41
1.04
3.27
12
11.45
4.41
2.60
4.37
13
22.91
4.41
5.20
5.59
14
33.07
4.41
7.50
3.96
15
44.1
4.41
10.0
3.50
16
110.25
4.41
25.0
3.09
17
220.5
4.41
50.0
2.29
18
0
1.00
—
1.08
19
0
5.00
—
1.02
20
0
10.00
—
1.03
21
0
25.00
—
1.03
[0072] The data in Table-1 indicates that increasing folic acid concentration alone does not improve the NO activity. Increasing the EGCG concentration alone increases NO activity till an EGCG concentration of about 11 μg and thereafter the NO activity decreases. Further, it is to be noted that an NO activity of 1.0 is indicative of no increase over untreated sample (and is in fact an indication of nil activity over control). Further, the mechanisms by which folic acid and gallated catechins are believed to interact are different (as described hereinabove) and therefore synergy is not to be interpreted by comparing the NO activity of the compositions with respect to the arithmetic sum of the individual contributions. The data in the table above indicate that the compositions indeed demonstrate synergy since the NO activity achievable by the combination between about a weight ratio of 1:1 to about 10:1, preferably 2.5:1 to 7.5:1 is not achievable at any concentration of the individual ingredients. The data in Table-1 above indicates that there is optimum activity between the gallated catechin (EGCG) and folic acid when the weight ratio is between 1:1 to 10:1 preferably between 2.5:1 to 7.5:1. | The invention relates to a topical composition that provides enhanced skin health by way of providing anti-aging benefits that are evident from visibly reduced wrinkles and under-eye dark circles. This is achieved through use of a synergistic combination of folic acid and gallated catechin in a specific weight ratio range. | 0 |
[0001] Priority is claimed under 35 U.S.C. § 119(e) to provisional application U.S. 60/564,926, filed Apr. 23, 2004.
FIELD OF THE INVENTION
[0002] The present invention relates to a method of determining the efficacy of an extraction step in a process for the working up of a biological sample containing a nucleic acid. The present invention also relates to a packaged array for extracting a nucleic acid from a biological sample.
DESCRIPTION OF RELATED ART
[0003] Extracting a nucleic acid from a sample is an important operation in processes in clinical diagnosis, cloning, purification and isolation and other processes in biotechnology. For instance, gene recombinant technology requires the isolation of both a vector DNA and the cloned and/or expressed DNA. In order to diagnose a genetic disease or detect a cancer gene, it is necessary to extract the desired nucleic acid from the tissue, the cells, and the various other biological materials in a sample.
[0004] A nucleic acid does not occur free in nature. It is found in bacteria, cells, or virus particles, surrounded by a cell membrane and/or cell wall composed of proteins, lipids and sugars. A nucleic acid generally forms complexes with histone and/or other proteins in its natural environment. To extract a nucleic acid, the surrounding cell membranes and cell walls must be disrupted. In the case of isolating a nucleic acid, the nucleic acid-protein complex needs to be denatured or degraded to free the desired nucleic acid from the complex so that it can be solubilized and extracted. Methods of extracting nucleic acids are described, for example, in U.S. Pat. No. 6,043,032, incorporated herein in its entirety.
[0005] Internal standards have been applied in nucleic acid analysis. These include constitutively expressed mRNAs to control for the effectiveness of the workup. Further, external controls have been applied in the extraction step in nucleic acid amplification-based analysis. However, the detection and/or quantification of the control has required amplification, so it is not possible to distinguish whether a problem in the process has arisen from the amplification step or in the extraction step. For example, in U.S. Pat. No. 6,387,652 B1, addition of G. candidum sequences as a reference to assays for fungal target sequences was employed as a control. However, it was necessary to assume an amplification efficiency of one (col. 19, lines 45-61).
[0006] Up to the present there has been no method of verifying the extraction process alone for a nucleic acid, independent of the downstream application, such as an amplification step.
SUMMARY OF THE INVENTION
[0007] The present invention relates to a method of determining the effectiveness of an extraction step in the workup of a sample of a target nucleic acid. The present invention further relates to a packaged array for extracting a target nucleic acid from a biological sample. In a further embodiment, the method and packaged array of the present invention can be incorporated in a robotic assembly for the automated analysis for the presence of a disease organism in a biological sample.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a flowchart for one embodiment of an extraction protocol using an automated system for the extraction of DNA from urine and vaginal specimens on the BD Viper™ Sample Processor.
[0009] FIG. 2 is a graph of the results presented for Example 1.
[0010] FIGS. 3 a and 3 b show the results of recovery of the extraction control (EC) from urine and vaginal specimens when used in conjunction with the BD ProbeTec™ ET Amplified CT ( Chlamydia trachomatis ) Assay in the absence of target DNA.
[0011] FIGS. 4 a and 4 b show the results of recovery of the extraction control (EC) from urine and vaginal specimens when used in conjunction with the BD ProbeTec™ ET Amplified GC ( Neisseria gonorrhoeae ) Assay in the absence of target DNA.
[0012] FIG. 5 shows the results of the recovery of the extraction control (EC) from two different biological matrices when used in either CT or GC assays.
[0013] FIGS. 6 a and 6 b are graphs of the effects of different levels of the extraction control (EC) on amplification and detection of an internal amplification control (IAC) used in strand displacement amplification (SDA) assays for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). The results show that the extraction control does not interfere with subsesquent analysis of the extracted nucleic acid by amplification and fluorescence-based detection.
[0014] FIG. 7 shows the effect of an extraction control (EC) on the downstream detection of internal amplification controls (IACs) that are employed in SDA-based assays for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). The efficiency of amplification of the IAC is monitored using a passes-after-threshold (PAT) algorithm.
DETAILED DESCRIPTION
[0015] The present invention relates to a method of ensuring or verifying the extraction of a target nucleic acid from a biological sample.
[0016] The target is a nucleic acid such as single or double-stranded DNA and RNA. Examples of nucleic acid that can be extracted by the method include not only genomic DNA or RNA from animals, plants, bacteria, viruses, fungi and parasitic organisms, but also the DNA or RNA of mitochondria or chloroplasts. Examples of other classes of nucleic acid that can be extracted by the method include not only mRNA, but also tRNA, rRNA, and tmRNA (transfer-messenger RNA) as well as plasmid DNA. DNA and RNA extracted by the method of the invention may also be either wholly or partially single-stranded or possess other tertiary or quaternary structure. A sample containing nucleic acids is exemplified by viable samples such as leukocyte cells, the culture of host cells containing vectors or the like that are typically prepared by gene recombinant technology, cells infected with viruses or phages, viruses in blood, and the culture of a sample microorganism. The culture may contain microorganisms but its supernatant alone is sufficient. Not only an artificial culture but also a naturally occurring culture is applicable. In case of a sample containing lumps of microorganism, homogenization or sonication may be performed as required to achieve good efficiency of extraction.
[0017] Alternative sample types include but are not limited to biological specimens for the diagnosis of infectious or non-infectious diseases, environmental specimens, or samples of food or water. The target nucleic acid may be a particular sequence or it may be a class of nucleic acid. A class of nucleic acid is, for a particular assay method, those molecules of nucleic acid whose chemical, physical or biological properties are such that they can be expected to be extracted effectively in methods used for nucleic acid extraction. Typically, but not necessarily, the nucleic acids of a class are all DNA or DNA analogs or all RNA or RNA analogs.
[0018] Targeted organisms can include but are not limited to Chlamydia trachomatis, Neisseria gonorrhoeae, Human Immunodeficiency Virus 1/2, Hepatitis C Virus, Hepatitis B Virus, Severe Acute Respiratory Syndrome Virus, Influenza A/B, Herpes Simplex Viruses 1-6, Enteroviruses, West Nile Virus, Parainfluenza viruses, Adenoviruses, Respiratory Syncytial Virus A/B, Mycobacterium paratuberculosis, Mycobacterium avium-intracellulare complex, Mycobacterium tuberculosis complex, Cytomegalovirus, Group B Streptococcus, Bordetella pertussis, and Bordetella parapertussis.
[0019] In one aspect of the invention, the target nucleic acid is a particular RNA or cDNA from one ore more of the following sources: bacterial pathogens, bacterial non-pathogens, viral pathogens, viral non-pathogens, fungal pathogens, fungal non-pathogens, yeast pathogens, yeast non-pathogens, parasitic pathogens, parasitic non-pathogens, plants, animal products, food, total RNA or cDNA within the sample matrix, total prokaryotic RNA or cDNA, total eukaryotic RNA or cDNA, or total viral RNA or cDNA.
[0020] In another aspect of the invention, the target nucleic acid sought is DNA from one or more of the following sources: bacterial pathogens, bacterial non-pathogens, viral pathogens, viral non-pathogens, fungal pathogens, fungal non-pathogens, yeast pathogens, yeast non-pathogens, parasitic pathogens, parasitic non-pathogens, plants, animal products, food, total DNA within the sample matrix, total genomic prokaryotic DNA, total genomic eukaryotic DNA, or total viral DNA.
[0021] According to the method of the present invention, an extraction control is added to the biological sample before the extraction step. The extraction control is a nucleic acid sequence with a distinguishable label. By distinguishable label is meant a label or marker that can be identified and quantified by a radiometric, spectrometric, fluorogenic or colorimetric method in the presence of unlabeled nucleic acid and other components of the sample matrix. The use of an extraction control for the extraction process is understood as the use of a reference or standard to allow for verification that the extraction occurred as desired. Calibration and quantification of the extraction control are also possible. The extraction control is designed to be detected without amplification of its nucleotide sequence, and further designed so as not to interfere with amplification of the target nucleic acid.
[0022] Nucleic acid labels are known in the art. These include, but are not limited to, donor quencher dye pairs such as fluorescein isothiocyanate (FITC)/tetramethylrhodamine isothiocyanate (TRITC), FITC/Texas Red™ (Molecular Probes), FITC/N-hydroxysuccinimidyl 1-pyrenebutyrate (PYB), FITC/eosin isothiocyanate (EITC), N-hydroxysuccinimidyl 1-pyrenesulfonate (PYS)/FITC, FITC/Rhodamine X, FITC/tetramethylrhodamine (TAMRA), and others. The selection of a particular donor/quencher pair is not critical. For energy transfer quenching mechanisms it is only necessary that the emission wavelengths of the donor fluorophore overlap the excitation wavelengths of the quencher, i.e., there must be sufficient spectral overlap between the two dyes to allow efficient energy transfer, charge transfer or fluorescence quenching. P-(dimethyl aminophenylazo) benzoic acid (DABCYL) is a non-fluorescent quencher dye which effectively quenches fluorescence from an adjacent fluorophore, e.g., fluorescein or 5-(2′-aminoethyl) aminonaphthalene (EDANS). Any dye pair which produces fluorescence quenching can be used in the methods of the invention, regardless of the mechanism by which quenching occurs.
[0023] Preferred labels for extraction control include fluorophores such as fluorescein and rhodamine, radioactive labels such as 32 P or 35 S, enzymes such as horseradish peroxidase, alkaline phosphatase, glucose oxidase, β-galactosidase, soybean peroxidase or luciferase. Methods for linking the detectable moieties with the nucleic acid in a form that is stable to most methods of handling nucleic acid are known in the art. For example, methods for making covalent linkages are provided commercially by companies such as Integrated DNA Technologies (see IDT technical bulletins, available via the internet at the Integrated DNA Technologies website). Other labeling methods include having the detectable moiety attached to one member of a highly stable binding pair, and the other member of the binding pair attached to the nucleic acid. Such a binding pair can be, for example, avidin (or streptavidin) and biotin. Avidin-biotin labeling techniques are described for example in Advances in Biomagnetic Separation (M. Uhlen, E. Hornse, and O. Olsvik) (Eds.), Eaton Publishing 1994).
[0024] The nucleotide sequence of the extraction control must be sufficiently long to have the general physical and chemical properties of nucleic acid. In one embodiment, the extraction control consists essentially of a nucleotide sequence between 21 and 61 bases in length and a label. In another embodiment, the nucleotide sequence, labeled with for example rhodamine, must be sufficiently long to reversibly bind to an iron oxide particle under extraction conditions such as described in U.S. Pat. No. 6,433,160, where free rhodamine does not bind to an iron oxide particle.
[0025] The extraction control can be added to a biological sample before or after lysis/disruption of the cell membrane or cell wall. In certain circumstances, such as with an RNA-based extraction control that is susceptible to degradation by RNAses, the extraction control should not be added until the point immediately before extraction. For procedures involving binding of nucleic acid to a solid support, the extraction control generally may be added at any point prior to the binding, and thereby control for all subsequent phases of the process.
[0026] Following addition of an extraction control, the step of extracting nucleic acid is performed. The phrase “extracting nucleic acid” refers to purifying nucleic acid sufficiently away from protein or other material within the sample matrix so that it has purity reasonably sufficient for assays to identify or quantify segments of nucleic acid. The term “protein” is used to include chains of amino acids or amino acid derivatives comprising peptides, polypeptides or full-length proteins. Methods of extracting nucleic acids are known in the art. For example, U.S. Pat. No. 6,043,032 describes several methods of extracting nucleic acid, including liquid phase extraction methods, incorporated herein in its entirety.
[0027] The extraction procedure can include a step in which the nucleic acid is bound to a solid support. The solid support is typically washed to remove undesired material. In many instances, the nucleic acid is released from the solid support and processed further. In other instances, the nucleic acid bound to the solid support is processed further. Those of skill will recognize when it is appropriate to assess extraction as opposed to assessing a subsequent procedure. Often, the assessment is made after release from the solid support. Or, if no such release is required, the assessment can be made of the nucleic acid bound to the support. Appropriate supports for non-specific capture of nucleic acids include, but are not limited to, crushed glass powders (e.g., available from Bio101 as GeneClean®) and glass fiber filters (e.g., available from Roche as the High Pure™ system, Celite (e.g., available from BioRad Laboratories as Prep-A-Gene™), and iron-containing paramagnetic particles (e.g., as described in U.S. Pat. No. 6,433,160, which discloses nucleic acid binding under acidic conditions). For target-specific capture, paramagnetic particles with modified surfaces may be used (e.g., such as described in European Specification EP 0 446 260 B1 and U.S. Pat. No. 5,512,439, with each particle carrying a plurality of molecules of an oligonucleotide). The captured oligonucleotides may be conjugated directly to the particle surface or coupled via an intermediary linker such as a streptavidin-biotin or other receptor-ligand interaction, as is known in the art.
[0028] Following extraction to yield an extract containing the extraction control and the target nucleic acid, the presence of the extraction control in the extract is verified by detection of the label, also known as a detectable marker. The extraction control label can be further analyzed by the detection method to allow for quantification of the amount of extraction control in the extract. Suitable methods for detection of the label include radiometric, spectrometric, fluorogenic or colorimetric methods.
[0029] The extraction control can have a detectable marker whose detection characteristics (e.g., emission or absorption wavelengths) overlap the detection characteristics that will be utilized in a post-extraction procedure, such as an assay for a specific molecule. For example, the chromophores or fluorophors used for the extraction control and in the second post-extraction procedure can be the same. In such case, the detection of the extraction control and the detection in the subsequent procedure are designed so that a positive extraction yields an amount of detectable marker that will, in the subsequent procedure, contribute only an amount of signal to the result as can be reliably compensated for in a controlled-for background signal.
[0030] The data from detection of the labeled extraction control is optionally normalized. The step of normalizing data can comprise interpolating from the control data how much any experimental data point should be normalized or can comprise discarding data points that the control data indicates is unreliable or which may be considered as background signal. The detection and normalization of data can be combined in a single step for purposes of automation.
[0031] In one embodiment, the nucleic acid sequence of the extraction control is substantially based on the structure of the target nucleic acid. Thus, for example, the method can seek to extract a given structural gene, open reading frame (ORF), intron, exon, mRNA, cDNA, and the nucleic acid of the extraction control can be designed to contain 1% or more, 10% or more, or 50% or more of the primary structure of the same. Thus, in one embodiment, if RNA is sought to be extracted, the extraction control will be RNA (or an RNA analog), and if DNA is sought to be extracted the extraction control will be DNA (or a DNA analog). In other embodiments, if RNA is to extracted, the extraction control may be DNA (or a DNA analog) and if DNA is to be extracted, the extraction control may be RNA (or an RNA analog).
[0032] A structural gene is defined by the nucleic acid segment (and if relevant its complement) that codes for a transcribed RNA (whether such RNA is later edited to remove introns or the like) or that codes for the minimum contiguous segment that codes for an expressed protein. Given the existence of splice variants, and the typical existence of RNA at the 5′ and 3′ ends of mRNA that is not translated into protein, a given gene may define one, two or several structural genes. In all cases, the presence of a modification with a label of a residue or nucleotide, which would otherwise comprise shared sequence, does not diminish the shared percentage. For recitations of percent identical structure, if the percentage required exists for at least one of the structural genes, then the recitation is satisfied.
[0033] In another embodiment, if two or more target nucleic acids with different characteristics are to be extracted, two or more extraction controls may be added before the extraction step.
[0034] If the target nucleic acid to be extracted has features that are associated with difficulties in extraction, these features may be modeled in the substances selected as the extraction controls. For example, if a particular nucleic acid segment is sought, and that segment includes a high G/C content segment, or a high degree of secondary or tertiary structure that contributes to the difficulty of extracting the desired segment, then such sub-segment or a homolog thereof may be included in the sequence of the extraction control. The design of the extraction control also includes the limitation that the extraction control should not interfere with post-extraction amplification of the target sequence.
[0035] In many contexts for extracting nucleic acid, a hybridization reaction will be used in a post-extraction procedure. For many such post-extraction procedures, the use of nucleic acids for the extraction control with a sequence based on an intron sequence will minimize undesired competing hybridizations. Internal hairpin structures can also minimize undesired competing hybridizations. Where polymerase-based methods are used in post-extraction procedures, the 3′ end of the extraction control can be modified to prevent extension of the extraction control. For example, the detectable marker can be attached to the 3′ end to block extension or the 3′ end of the extraction control may be capped using a dideoxynucleotide, inverted base or other non-extendable terminal moiety as is known in the art. Other methods of inhibiting undesired amplification are known in the art, for example in U.S. Pat. No. 5,972,610 and U.S. Pat. No. 5,849,497. Determining whether or not an extraction control will interfere with amplification of the target sequence can be accomplished by running in parallel an amplification of the target sequence with and without the extraction control.
[0036] A distinction is made between nucleic acid amplification and signal amplification. By nucleic acid amplification is meant a technique such as SDA, PCR, TMA, NASBA, etc., whereby additional copies of the nucleic acid are made. In contrast, signal amplification such as that which occurs with a chemiluminescent or calorimetric label is used in the detection of a label, and does not result in additional copies of the label. The use of the general term “amplification” in reference to post-extraction amplification is meant to refer to nucleic acid amplification. An extraction control sequence is defined as not capable of being amplified during post-extraction amplification if, at the conclusion of amplifying the target sequence, the amount of extraction control sequence present in the reaction mixture is less than 1000-fold more than was present prior to amplification. The extraction control of the present invention is designed to not participate in or interfere with a subsequent amplification step of the target nucleic acid, including amplification of sequences added to independently measure or control for the efficiency of the amplification step. Non-participation or non-interference by the extraction control is defined by running parallel amplifications of the target sequence with and without the extraction control. If the amplification of the target sequence in the presence of the extraction control is roughly equivalent to the amplification of the target sequence without the extraction control, then the extraction control is defined as not participating, or not interfering with, the post-extraction amplification of the target sequence.
[0037] In one embodiment of the invention, multiple extraction controls are included in the extraction procedure, each designed specifically to verify the extraction of one or more classes of nucleic acid. In another embodiment of the invention, the extraction control can be dried for long-term storage without impacting its form or function.
[0038] FIG. 1 contains a general flowchart for an extraction protocol using an automated system for the extraction of DNA from urine and vaginal specimens on the BD Viper™ Sample Processor, which is an example of a packaged array. The following examples further illustrate the present invention, but of course, should not be construed as in any way limiting its scope.
EXAMPLE 1
[0039] An experiment was conducted to evaluate the ability of a Rhodamine (ROX) labeled extraction control to detect automated nucleic acid extraction failures. The control was designated BBTEC-26 (SEQUENCE ID NO. 1). The protocol was as follows:
Spike pooled male and female urine with 7500 copies of Chlamydia trachomatis (CT) plasmid per mL. (Each plasmid carried a single copy of the amplification target sequence.) Heat spiked or unspiked (control) urine samples at 114° C. for 30 minutes. Transfer urine to extraction tubes containing 40 mg ferrosoferric oxide (Fe 3 O 4 ). Transfer 111 picomoles of BBTEC-26 Extraction Control (EC) to the desired tubes. Extract on the BD Viper™ (extraction-equipped breadboard instrument) using the following automated protocol:
Add 50 μL binding acid to the extraction tubes and mix. (Binding acid solution facilitates nucleic acid binding to ferrosoferric oxides as is described in U.S. Pat. No. 5,973,138) Omit binding acid from control tubes. The binding acid was 5M phosphoric acid (H 3 PO 4 ). Position magnets next to extraction tubes to lock Fe 3 O 4 and any bound nucleic acid to sides of tubes. Aspirate unbound sample from the extraction tubes and transfer to waste. Transfer 1030 μL wash buffer to each extraction tube and mix. Wash buffer was 1 mM glycine-HCl. Position magnets next to extraction tubes to lock Fe 3 O 4 and bound nucleic acid to sides of tubes. Aspirate unbound solution from the extraction tubes and transfer to waste. Transfer 370 μL elution buffer to each extraction tube and mix. The elution buffer has a basic pH. The elution buffer was 177.8 mM Bicine, 88.3 mM KOH, 11% DMSO, and 12.1% glycerol. Position magnets next to extraction tubes to lock Fe 3 O 4 to sides of tubes. Aspirate eluate from the extraction tubes and transfer to BD ProbeTec™ ET CT Amplified DNA Assay. Collect, normalize and average ROX signals from passes 20-60 of the incubation in the BD ProbeTec™ ET instrument to assess EC extraction adequacy. Collect BD ProbeTec CT assay results (MOTA scores, corresponding to the area under the amplification curve) to assess the adequacy of CT target recovery and amplification.
[0056] The data below are presented in MOTA values for the CT determinations and in machine-normalized ROX values for the EC determinations. Free ROX dye will not bind to ferric oxide under the conditions used for the extraction. The MOTA values represent the sum of individual fluorescence measurements over time using a fluorometer with an established cutoff level for a positive reaction of 2,000 for the BD ProbeTec™ ET CT and GC Amplified DNA Assays. BD ProbeTec™ brand assay kits are available from Becton, Dickinson and Company, and are designed for use with use the BD ProbeTec™ ET System for Strand Displacement Amplification (SDA). The BD Viper™ Sample Processor automates the sample handling associated with high-volume testing using the BD ProbeTec™ ET System.
[0057] Results
EC Score (ROX Assay EC Score (ROX Assay Target MOTA Well/ROX Normalizer) Target MOTA Well/ROX Normalizer) Tube 1 2 1 3 1 2 1 2 +CT +CT +EC No EC +Binding Acid +Binding Acid 1 82765 81900 2.57 2.72 64083 107523 0.95 1.38 2 89858 72722 2.68 2.25 57317 62082 1.19 1.11 3 61719 92915 2.24 2.62 80405 82031 1.18 1.18 4 83622 96592 2.63 3.00 73549 75247 1.31 1.19 5 55736 89618 2.49 2.31 82858 84116 1.15 1.07 6 47094 48845 2.32 2.55 45150 95490 1.07 1.31 No CT +CT +EC +EC +Binding Acid No Binding Acid 1 0 3 2.12 2.31 2367 7876 0.99 0.83 2 0 0 2.11 2.20 63027 4 1.19 1.09 3 0 0 1.89 2.10 35 15 0.97 0.98 4 0 1 2.52 2.54 78262 10846 1.37 1.16 5 0 53 1.90 2.11 69528 20765 1.09 1.01 6 17 0 2.47 1.98 179 65026 1.05 1.21
In all cases in which both EC and binding acid were present, normalized ROX values were ≧1.89. In all cases where binding acid was present, but extraction control was not added, normalized ROX values were ≦1.38. In all cases where extraction control was present, but binding acid was not added, normalized ROX values were ≦1.38. In all cases where the extraction control was added and CT target was successfully extracted, normalized ROX values were ≧1.89. In all cases where CT target was spiked, but not successfully extracted, the normalized ROX values were ≦1.38.
[0063] The results are presented graphically in FIG. 2 . The results demonstrate that the extraction control (EC) was successfully extracted from a sample and that it accurately identified instances where the extraction of specific target nucleic acid failed. Alternately, the above example can be performed with EC-26.3 (SEQUENCE ID NO. 2). Other extraction controls that conform to the design parameters of the present invention can also be used.
EXAMPLE 2
[0064] To determine whether the EC could be extracted from different matrices, 168 pmol of the EC was spiked into pools of clinical urine and matrix from pressed vaginal swabs. Eight assay replicates were analyzed for each sample, including a negative control lacking EC. The results are presented in FIGS. 3, 4 , and 5 for comparison.
EXAMPLE 3
[0065] The effect of the extraction control (EC) on a separate internal amplification control (IAC) was assessed by adding different levels of the EC to a pool containing matrix from pressed vaginal swabs and extracting as described in Example 1. The resulting eluates were tested in strand displacement amplification assays for CT and GC which contained internal amplification controls. The results are presented in FIGS. 6 and 7 , which show that the extraction control does not interfere with the subsequent amplification for the internal amplification controls. The internal amplification control is given a score in a passes-after-threshold (PAT) algorithm. The thresholds for the PAT algorithm are set by performing a Receiver Operator Characteristic curve analysis on the assay results obtained with positive and negative controls. A preliminary threshold is found, and applied to results obtained with spiked samples for verification.
EXAMPLE 4
[0066] A sequence-specific extraction is performed by modification of Example 1. In place of iron oxide particles, streptavidin-coated beads are used. The beads are mixed with two different biotinylated oligonucleotides, one of which is complementary to the target sequence, while the other is complementary to the extraction control sequence. The extraction control is labeled with rhodamine. Appropriate conditions for hybridization as are well known in the art are used in the extraction step. Variation in salt concentration, temperature, cosolvent, and detergent are used to vary the stringency of hybridization specificity. Following hybridization, the beads are washed under appropriate conditions to remove debris and non-hybridized material. The target nucleic acid and the extraction control are eluted under conditions of low salt, elevated temperature, or other method as known in the art. The rhodamine label of the extraction control is detected to verify the extraction process, and the level of recovered rhodamine is quantified to determine the efficiency of capture, washing, and elution. The results are expressed quantitatively or qualitatively.
[0067] Publications and references, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference in their entirety in the entire portion cited as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as being fully set forth. Any patent application to which this application claims priority is also incorporated by reference herein in the manner described above for publications and references.
[0068] While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred devices and methods may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the claims that follow.
[0069] Alternate embodiments may not have been presented for a specific portion of the invention. Some alternate embodiments may result from a different combination of described portions, or other non-described alternate embodiments may be available for a portion. This is not to be considered a disclaimer of those alternate embodiments. It is recognized that many of those non-described embodiments are within the literal scope of the following claims, and others are equivalent. | The present invention relates to a method of ensuring the effectiveness of the extraction workup from a biological sample of nucleic acid. The inventive method is able to distinguish between possible defects in the extraction of nucleic acid from a sample and possible defects in a subsequent amplification step. The present invention also relates to a packaged array for extracting nucleic acid from a biological sample. | 2 |
RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 09/819,590 filed Mar. 27, 2001 now U.S. Pat. No. 6,419,298, entitled “WINDOW PROTECTOR ASSEMBLY” which was a continuation-in-part of U.S. patent application Ser. No. 09/397,748, filed Sep. 16, 1999, entitled “WINDOW PROTECTOR ASSEMBLY” now U.S. Pat. No. 6,206,453, issued Mar. 27, 2001. This application also claims priority from U.S. Patent Application Ser. No. 09/819,590 filed Mar. 27, 2001, and U.S. Provisional Application Serial No. 60/244,402 filed Oct. 30, 2000, and U.S. patent application Ser. No. 09/395,692 filed Sep. 13, 1999, and U.S. patent application Ser. No. 09/186,513 (now U.S. Pat. No. 6,205,723) filed Nov. 4, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to protective devices for protecting windows from damage and, more specifically, concerns a replaceable window protector assembly adapted to both protect glazing used in windows in public transportation vehicles and also allow for the replacement of the same.
2. Description of the Related Art
Vandalism of windows in public transportation vehicles has been an on-going problem for decades. Vandals cause damage by writing or painting on the glazing of the window with marking pens or spray paint. Further, vandals often damage the exposed glazing of the window by scratching the glazing with sharp instruments.
Oftentimes, the vandal is a passenger that damages the interior surface of the glazing. However, the exterior surface of the glazing on public transportation vehicles are increasingly being defaced or vandalized. It will be appreciated that the vandalism usually takes the form of crude or otherwise disagreeable expressions being permanently marked onto the windows. Hence, there is an on-going problem of vandalism and defacement of public transportation vehicles and, in particular, damage or defacement of both the interior and exterior surfaces of the glazing of these windows.
Likewise, unintentional breaking or fracturing of the glazing on public transportation vehicles has been an on-going problem as well. Oftentimes, road debris, interior debris, or passengers may accidentally strike the glazing with enough force to break or fracture it. Broken glazing presents an unacceptable hazard to passengers because the broken glazing can cut them. Also, fractured windows are unattractive and might cause a carrier to lose respect and business. Also, broken and fractured windows diminish the climate control capabilities of public transportation vehicles. Simply put, broken and fractured glazing must be replaced as soon as possible, but removal of the glazing is difficult and expensive. Hence, there is an on-going problem with the difficulty of replacing the glazing on public transportation vehicles.
To address these problems, various devices have been developed. For example, U.S. Pat. No. 5,242,207, which is owned by the assignee of this application, discloses one type of window protector which protects the interior surface of the glazing of the window from damage as a result of vandalism or defacement. In particular, U.S. Pat. No. 5,242,207. discloses a window protector which includes a protective sheet positioned against the interior surface of the glazing of the window and is held in place by a plurality of brackets which is attached to the frame of the window. This protective sheet acts as a sacrificial surface that protects the glazing of the window from damage as a result of vandalism or defacement. Whenever necessary, the protective sheet can be replaced with a new protective sheet by removing the brackets and positioning the new protective sheet adjacent the inner surface of the glazing of the window.
While the window protector disclosed in U.S. Pat. No. 5,242,207 has been effective in protecting the interior surface of the glazing of the window, this window protector does not provide protection against damage to the outer surface of the glazing of the window. Also, removing the interior protective sheet from the window protector disclosed in U.S. Pat. No. 5,242,207 requires of the retention brackets, and this process can increase the cost of maintenance and repair.
Moreover, the window protector disclosed in U.S. Pat. No. 5,242,207 is designed to be used in conjunction with the existing window frames of the transportation vehicle. These frames are not designed for quick glazing installation and are rigidly attached to the vehicle. Thus, when the glazing breaks, the broken pieces must be gathered from within the rigid frame, the entire frame must be removed from the vehicle and disassembled, new glazing must be inserted into the frame, the frame must be reassembled, and the entire assembly must be reinstalled into the vehicle. This tedious process can increase the cost of maintaining and repairing the public transportation vehicle windows.
From the foregoing, it will be appreciated that there is a need for an improved window protector that is capable of protecting both the interior surface and the exterior surface of the glazing of the window from damage as a result of vandalism or accident. It will also be appreciated that there is a need for an improved window protector that allows its owner to quickly replace both protective layers and the glazing in response to damage caused by vandalism or accident. To this end, there is a need for a window protector that provides protection to the window glazing on both the interior and exterior surfaces of the glazing and also allows for easy and quick access to the protective layers and the glazing itself.
SUMMARY OF THE INVENTION
The aforementioned needs are satisfied by one aspect of the invention which in one aspect relates to a window assembly mounted in a wall of a vehicle having an interior and an exterior surface. The assembly comprises a molded frame that is adapted to be positioned within the wall of the vehicle. The frame includes a transverse surface that extends through an opening in the wall and defines a window opening and an external perpendicular surface that is positioned adjacent the external surface of the wall of the vehicle when the frame is positioned within the wall. The frame further includes a seating member that extends inward from the transverse surface of the frame into the window opening such that the transverse surface of the frame and the seating member define a glazing mounting location. The frame further includes a flange that is offset from the seating member towards the interior surface of the vehicle and extends inward from the transverse surface of the frame into the window opening such that the flange is substantially parallel to the seating member. The seating member, the transverse surface, and the flange define a recess that extends substantially about at least two opposed sides of the window opening adjacent the interior surface of the vehicle. The assembly further comprises a piece of glazing positioned at the glazing mounting location within the frame of the vehicle so as to occupy the window opening. The seating member inhibits the piece of glazing from moving inwards towards the interior surface of the wall of the vehicle but permits the piece of glazing to be removed from the frame adjacent the exterior surface of the wall of the vehicle when the frame is positioned within the wall of the vehicle. The assembly further comprises a protective sheet positioned adjacent the piece of glazing such that at least two opposing edges of the protective sheet are positioned within the recess at the at least two opposed sides of the window.
In one embodiment, the recess is sized and positioned about the window opening and the protective sheet is sized such that when the protective sheet is positioned within the recess, the protective sheet can be moved in a first direction with respect to the recess such that a first edge of the protective sheet can be exposed from the recess to thereby permit removal of the protective sheet. The assembly further comprises a retainer that extends into the recess so as to inhibit movement of the protective sheet in the first direction so as to prevent the first edge of the protective sheet from being exposed from the recess so that the retainer inhibits removal of the protective sheet without previous removal of the retainer. The protective sheet preferably comprises a sheet of acrylic material.
In one embodiment, the assembly further comprises at least one retaining member pivotally attached to the frame so as to pivot outward from the exterior surface of the vehicle when the frame is positioned within the wall of the vehicle. The at least one retaining member is movable between an open position and a closed position such that the at least one retaining member in the open position allows the piece of glazing to be removed from the window opening of the frame adjacent the exterior surface of the wall of the vehicle and such that the at least one retaining member in the closed position retains the piece of glazing in the glazing mounting location in the closed position. The at least one retaining member is comprised of a first and a second U-shaped retaining members that are pivotally attached to the frame so as to extend substantially around the first perimeter of the frame when in the closed position. The first and second U-shaped retainers have first and second arms with beveled ends, wherein the beveled ends of the first and second arms of the first U-shaped retainer are positioned underneath the beveled ends of the first and second arms of the second U-shaped retainer when the first and second U-shaped retainers are in the closed position. At least one securing device is attached to the first U-shaped retainer so as to retain the first U-shaped retainer in the closed position. The fist U-shaped retainer has at least one opening and wherein the securing device comprises a securing member mounted within the at least one opening in the first U-shaped retainer so as to be rotatable therein. The securing member further includes a lateral member that rotates between a first position when the lateral member engages with the frame to retain the first U-shaped retainer in the closed position and a second position. The lateral member disengages with the frame to permit the first and second U-shaped members to be moved into the opened position. The securing member has a first exposed face that has an opening adapted to receive a tool having a first configuration so that positioning the tool having the first configuration into the opening permits manipulation of the securing member between the first and second positions.
In one embodiment, the assembly further comprises a protective sheet mounted between the glazing and the retaining member so as to be interposed between the exterior surface and the piece of glazing to thereby inhibit damage or defacement to the piece of glazing by persons or debris adjacent the exterior surface of the vehicle. Preferably, the protective sheet comprises a sheet of acrylic material.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an elevational view illustrating a public transportation vehicle incorporating windows having an embodiment of a window protector assembly of the present invention;
FIG. 2 is an inside elevational view illustrating the window protector assembly of FIG. 1;
FIGS. 3A and 3B are cross-sectional views of the window protector assembly of FIG. 2 taken along the lines of 3 — 3 ;
FIG. 4 is a cross-sectional view of the window protector assembly of FIG. 2 taken along the lines 4 — 4 ;
FIGS. 5A and 5B are perspective views of the window protector assembly of FIG. 2, illustrating the assembly in both a closed and an opened configuration;
FIGS. 6A and 6B are cross-sectional views of another embodiment of the window protector assembly of FIG. 2 illustrating another interconnection between retaining members of the window protector assembly and the frame of the window protector assembly;
FIG. 7 is a side cross-sectional view of a securing mechanism of the assembly of FIG. 2;
FIG. 8 is a top view of the securing mechanism of FIG. 2;
FIG. 9 is an elevational view of another embodiment of a public transportation vehicle incorporating windows having another embodiment of a window protector assembly of the present invention;
FIG. 10 is an outside elevational view illustrating the window protector of FIG. 9;
FIGS. 11A and 11B are cross-sectional views of the window protector assembly of FIG. 10 taken along the lines of 11 — 11 ;
FIG. 12 is a cross-sectional view of the window protector assembly of FIG. 10 taken along the lines of 12 — 12 ;
FIGS. 13A and 13B are perspective views of the window protector assembly of FIG. 10, illustrating the assembly in both a closed and an opened configuration;
FIG. 14 is a side cross-sectional view of a securing mechanism of the assembly of FIG. 10; and
FIG. 15 is a top view of the securing mechanism of FIG. 10 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Reference will now be made to the drawings wherein like numerals refer to like parts throughout. FIG. 1 illustrates an exemplary public transportation vehicle 100 that incorporates windows 102 having window frames 114 mounted within openings 106 in the side wall 110 of the vehicle 100 . It will be appreciated from the following discussion that, while the window protector assembly of this embodiment is described in connection with a bus, that the window protector assembly 112 can be used in a number of different applications including other types of public transportation vehicles and also in windows that are positioned in fixed environments, such as buildings, where the window is likely to be damaged or defaced due to vandalism or accident. As will be also apparent from the following discussion, the window protector assembly of the preferred embodiment is designed to both protect the glazing of the window and also to facilitate rapid change and replacement of protective sheets and the glazing of the window protector assembly.
Referring to FIG. 2, one embodiment of a window protector assembly 112 is illustrated. In this embodiment, the window protector assembly 112 incorporates a frame 114 that is adapted to mount within the opening 106 in the side wall 110 of the vehicle 100 in a well-known manner. The frame 114 defines an opening 116 into which one or more pieces of glazing 120 are to be positioned. As will be understood, the term “glazing” refers to either glass windows or windows formed of any other generally transparent or translucent material.
In this embodiment, a first retaining member 122 and a second retaining member 124 are pivotally mounted to the frame 114 so as to be positioned about the outer perimeter of the opening 116 in the frame 114 . As is shown in FIG. 2, the first retaining member 122 is generally U-shaped having two arms 123 a , 123 b that extend along the side walls of the frame 114 and pivoting section 127 . Similarly, the second retaining member 124 is also generally U-shaped having a pivoting section 128 and two arms 125 a , 125 b that also extend along the side walls of the frame 114 so as to engage with the two arms 123 a , 123 b of the first retaining member 122 . The engagement between the arms 123 a , 123 b of the first retaining member 122 and the arms 125 a , 125 b of the second retaining member 124 secures the glazing and protective layers within the opening 116 of the frame 114 in a manner that will be described in greater detail below.
As will also be described in greater detail below in reference to FIGS. 5A and 5B, the pivoting section 127 of the first retaining member 122 and the pivoting section 128 of the second retaining member 124 are pivotally attached to the frame 114 so as to be pivotable between a closed position, as shown in FIG. 2, and an opened position whereby the outer perimeter of the glazing 120 and any protective layer is exposed. As is shown in FIG. 2, the arms and pivoting sections of the first retaining member 122 and the second retaining member 124 are selected to have a width sufficient so as to fully cover the outer edge of the glazing 120 and any protective layers positioned within the opening 116 of the frame 114 .
FIGS. 3A and 3B illustrate the interconnection between the first retaining member 122 and the second retaining member 124 and corresponding sections of the frame 114 . In particular, as illustrated in FIGS. 3A and 3B, the frame 114 includes an upper frame section 130 a and a lower frame section 130 b . The upper and lower frame sections 130 a , 130 b have an L-shaped section 132 that is suitable for mounting in the opening 106 of the side wall 110 of the vehicle 100 . In particular, the L-shaped section 132 has an exterior lip 134 that is adapted to mount flush against the outer surface of the side wall 110 of the vehicle adjacent the window openings 106 . The L-shaped section 132 further includes a laterally extending member 136 that is adapted to be positioned adjacent the inner walls of the openings 106 in the side walls 110 of the vehicle so as to extend substantially through the opening 106 .
A pivoting member 140 is formed on an inner wall 142 of the laterally extending member 136 so as to extend perpendicularly outward therefrom into the opening 116 defined by the frame 114 . As will be described in greater detail below, the pivoting member 140 extends the full length of the upper frame section 130 a and the lower frame section 130 b , and provides a surface to which the pivoting section 127 of the first retaining member 122 and the pivoting section 128 of the second retaining member 124 can be respectively attached to the frame 114 of the window protector assembly 112 .
The L-shaped section 132 also defines a seating member 144 that extends inward into the opening 116 defined by the window frame 114 . The seating member 144 is adapted to receive a seal 146 that is retained in the seating member 144 as a result of a deformable section 150 of the seal 146 being positioned within an opening 152 formed in the seating member 144 of the upper and lower frame members 130 a , 130 b . Hence, the seal 146 is press-fit within the seating member 144 of the upper frame section 130 a and lower frame section 130 b . It will be appreciated that while the upper and lower frame sections 130 a , 130 b have been described as being comprised of a plurality of discrete components, in the illustrated embodiment, the upper frame section 130 a and the lower frame section 130 b are comprised of a single uniform component preferably formed of extruded or molded aluminum.
The pivoting members 140 are positioned on the inner surface 142 of the L-shaped section 132 so that the pivoting member 140 is positioned within the opening 116 of the window frame 114 . The pivoting sections 127 and 128 of the retaining members 122 and 124 define an opening 141 that receives the pivoting member 140 to permit the pivoting movement of the retaining members 122 and 124 . More particularly, the pivoting member 140 defines a ball 143 at its distal end that extends outwardly towards the outer surface of the window frame 114 . Since the pivoting member 140 is positioned on the inside surface of the L-shaped section 132 of the frame 114 , access to the interconnection between the retaining members 122 and 124 and the pivoting members is inhibited. Moreover, an end portion 145 of each of the retaining members 122 , 124 is adapted to be flushly positioned within a recess 147 (FIGS. 3A and 3B) when the retaining members 122 , 124 are in the closed position so that access to the interconnection between the retaining members 122 , 124 is further inhibited. In this way, the likelihood of a person prying the retaining members 122 , 124 free from the pivoting members 140 and thereby dismantling or damaging the window protector assembly 112 is inhibited.
As is illustrated in FIGS. 3A and 3B, the first retaining member 122 and the second retaining member 124 can be pivoted about the pivoting members 140 so as to extend outward from the opening 116 . This allows a protective sacrificial sheet 156 to be positioned within the opening 116 on the seal 146 . Subsequently, one or more pieces of glazing 120 can be positioned on an inner surface 160 of the protective sheet 156 in the manner shown in FIGS. 3A and 3B. Subsequently, an inner sacrificial protective sheet 162 can be positioned on an inner surface 164 of the glazing 120 . The first and second retaining members 122 , 124 can then be pivoted into the closed position as shown in FIG. 3 B. The first and second retaining members 122 , 124 further include an inner seal 166 which extends entirely around the perimeter of the opening 116 so that the inner seal 166 makes contact with the inner sacrificial protective sheet 162 in the manner shown in FIG. 3 B.
FIG. 4 is a cross-sectional view which illustrates the side frame sections 170 a , 170 b of the frame 114 . The side frame sections 170 a , 170 b are integrally connected to the upper and lower frame sections 130 a , 130 b so that the entire frame 114 is a single integral piece. The side frame sections 170 a , 170 b are also configured to have an L-shaped section 172 that has a side wall member 174 that is adapted to be flushly positioned against the outer side wall 110 of the vehicle 100 adjacent the window opening 106 . The L-shaped section 172 also has a laterally extending section 176 that extends inward through the opening 116 of the frame 114 in the same manner as the laterally extending section 136 of the upper and lower frame sections 130 a , 130 b as described above. A bracing member 180 extends inwardly into the opening 116 of the frame 114 so as to provide a bracing contact so that the first and second retaining members 122 , 124 will be positioned adjacent the bracing member 180 when the retaining members 122 , 124 are in the closed position. As is also illustrated in FIG. 4, the side frame sections 170 a , 170 b include a seating member 184 that extends inward into the opening 116 from the inner surface 182 of the laterally extending section 176 . The seating member 184 is adapted to receive one or more seals 186 that extend laterally around the perimeter of the window.
As illustrated in FIGS. 3A and 4, the protective sacrificial sheet 156 is positioned adjacent a seal 186 which is retained in the side frame members 170 a , 170 b in substantially the same manner as discussed above in connection with the seal 146 and the upper and lower frame members 130 a , 130 b . The glazing 120 is then positioned adjacent the outer sacrificial layer 156 and the inner protective sheet 162 is then positioned adjacent the inner surface 164 of the glazing 120 in the same manner as described above in connection with FIGS. 3A and 3B. As illustrated in FIG. 4, when the first and second pivoting retaining members 122 , 124 are in the closed position, the one or more seals 166 , are positioned adjacent the inner sacrificial protective sheet 162 . In one embodiment, the window 110 is square in which case the seals are comprised of a plurality of pieces. In another embodiment, the window 110 is curved and the seals comprise a single seal.
As is shown in FIGS. 2, 5 A and 5 B, the frame 114 is comprised of a single uniform piece that is comprised of the upper and lower sections 130 a , 130 b and the side sections 170 a , 170 b . The retaining members 122 , 124 are pivotally attached and define retaining surfaces that extend about the outer perimeter of the opening 116 defined by the frame 114 so as to overlap the outer perimeter of the glazing 120 and the protective sheets 156 , 162 . The seating member 144 of the upper and lower frame sections 130 a , 130 b and the seating member 184 of the side frame sections 170 a , 170 b also extend into the opening 116 defined by the frame 114 so that the protective sheets 156 , 162 and the glazing 120 can be securely retained in the opening 116 of the frame 114 by the retaining members 122 , 124 pressing the protective sheets 156 , 162 and the glazing 120 against the seating members 144 , 184 about substantially the entire perimeter of the glazing 120 and the protective sheets 156 , 162 .
FIGS. 5A and 5B further illustrate the configuration and operation of the window protector assembly 112 . In particular, as illustrated in FIG. 5A, the first and second retaining members 122 , 124 are pivotable with respect to the upper and lower frame sections 130 a and 130 b thereby removing the first and second retaining members 122 , 124 from the outer perimeter of the outer sacrificial layer 156 , the glazing 120 , and the inner sacrificial layer 162 . This allows each of these layers to be lifted out of the opening 116 defined by the frame 114 .
As shown in FIG. 5B, when the first and second retaining members 122 , 124 are closed, they are positioned about the outer perimeter of the outer protective layer 156 , the glazing 120 and the inner protective layer 162 thereby capturing these three layers adjacent the seal positioned on the inner sections of the frame 114 . As the outer perimeter of the sacrificial protective layers 156 , 162 and the glazing 120 is covered by the pivoting retaining members 122 , 124 , these layers cannot be removed without moving the first and second retaining members 122 , 124 into the open position illustrated in FIGS. 3A and 5A. In this embodiment, the sacrificial protective layers 156 and 162 are comprised of an acrylic material that is adapted to be positioned adjacent the exposed surfaces of the glazing 120 such that the exposed surfaces of the glazing 120 on both the inside and the outside of the window is covered by the protective layers 156 , 162 . In this way, damage to the more expensive glazing 120 as a result of vandalism or defacement is inhibited as the protective acrylic layers provide protection against such damage.
FIGS. 6A and 6B illustrate an alternate embodiment of the retaining members and their attachment to the frame of the window frame assembly. In particular, FIGS. 6A and 6B illustrate an alternate embodiment of the portions 127 , 128 of the retaining members 122 , 124 that pivotally attach the retaining members to the window frame. Specifically, in this embodiment, a retaining member 214 has a ball 216 formed on a first end that is adapted to be positioned within a recess 218 formed on an L-shaped section 232 of the frame. The embodiment of FIGS. 6A and 6B is substantially similar to the embodiment of FIGS. 3A and 3B except that the retaining members in this embodiment have the rotatable ball formed thereon and the recess is formed in the L-shaped section 232 of the frame as opposed to the other way around as described above in connection with FIGS. 3A and 3B.
As is also illustrated in FIGS. 6A and 6B, the retaining member has a seal portion 220 that receives a seal 222 . The ball portion 216 is rotatable within the recess 218 between an open and a closed position. In the closed position, the radius of the ball 216 prevents removal of the retaining member 214 from the recess 218 . However, the ball 218 has a flat surface 223 that decreases the radius of the ball 216 with respect to the opening of the recess 218 when the retaining member 214 has been moved to the open position as shown in FIG. 6 A. Hence, the retaining member can be fully removed from engagement with the frame thereby permitting easy removal and installation of the retaining members.
When the retaining members are in the closed position, a securing mechanism, such as the mechanism illustrated in FIGS. 7 and 8 hereinafter can be used to secure the retaining members in the closed position. In the closed position, the seal 222 engages with the inner protective sheet 156 so as to secure the protective sheets and glazing within the window frame in substantially the same manner as described above.
FIG. 7 illustrates a securing mechanism 191 that is adapted to secure the first and second retaining members 122 , 124 in a locked and closed position. In particular, as illustrated in FIGS. 3A and 3B, the outer edge of the arms 123 a , 123 b of the first retaining member 122 and outer edge of the arms 125 a , 125 b of the second retaining member 124 are beveled so that the outer tip 183 of the arms 125 a , 125 b of the second retaining member 124 is positioned over the outer tip 185 of the arms 123 a , 123 b of the first retaining member 122 when the first and second retaining members are positioned in the closed position in the manner shown in FIGS. 3B and 5B. A securing member 190 is positioned within an opening 192 in both the arms 125 a , 125 b of the second retaining member 124 . Preferably, the securing member 190 is pivotable within the opening 192 such that a laterally extending arm 194 of the securing member 190 can be positioned within an opening 196 formed in a side wall of the frame 114 .
In this embodiment, the opening 196 is preferably formed in the bracing member 180 and has a curved opening to permit the extending arm 194 to be rotated into the opening 196 in response to the user turning the securing member 190 . As illustrated in FIG. 8, the securing member 190 is preferably pivotable between an opened position and a closed position wherein the laterally extending member 194 is positioned within the opening 196 and the frame 114 in the closed position and is retracted from the opening 196 in the opened position.
As is also illustrated in FIG. 8, the outer face 200 of the securing member 190 includes a tool recess 202 that is adapted to receive only a specially configured tool (not shown) such that manipulation of the securing member 190 between the opened and closed positions can preferably only be accomplished by an authorized person possessing a specially configured tool. As is illustrated in FIG. 2, there are preferably two securing members 190 positioned in both of the outer ends of the arms 125 a , 125 b of the second retaining member 124 to secure the second retaining member 124 in the closed position adjacent the frame 114 . As discussed above, because the outer end 183 of the second retaining member 124 overlaps the outer end 185 of the first retaining member 122 , securing the second retaining member 124 in the closed position against the frame 114 in the manner shown in connection with FIGS. 7 and 8 results in the first retaining member 122 similarly being secured in the closed position.
Advantageously, it is simple to remove and replace the inner sacrificial layer 162 and the outer sacrificial layer 156 and the glazing 120 by simply manipulating the retaining members 122 , 124 into the open position and extracting each of the layers positioned within the opening 116 of the frame 114 . Hence, the window protector assembly 112 of the illustrated embodiment allows for simpler and easier replacement of the protective layers 156 , 162 and the glazing 120 as compared to similar protective devices of the prior art. As a result of permitting such easy access and replacement, it is now possible to have a protective layer positioned on the outer surface of the glazing 120 in addition to a protective surface on the inner surface of the glazing 120 . However, it will also be appreciated that the window frame and protector 112 of the present invention can be used with only an inner protective layer 162 without departing from the spirit of the present invention.
Hence, the window protector 112 of the present invention allows for easier replacement of protective sheets as compared to window protective devices of the prior art. This easier access facilitates the use of a protective layer on the outside surface of the glazing as replacement of this sheet is now simplified due to the ease of access provided by the window protector assembly of the preferred embodiment.
FIG. 9 illustrates another embodiment of an exemplary public transportation vehicle 300 that incorporates windows 302 having window frames 314 mounted within openings 306 in the side wall 310 of the vehicle 300 . It will be appreciated from the following discussion that, while the window protector assembly of this embodiment is described in connection with a bus, that the window protector assembly 312 can be used in a number of different applications. These applications include other types of public transportation vehicles and also windows that are positioned in fixed environments, such as buildings, where the window is likely to be accidentally or intentionally damaged or defaced. As will also be apparent from the following discussion, the window protector assembly of the preferred embodiment is designed to both protect the glazing of the window and also to facilitate rapid change and replacement of protective sheets and the glazing of the window protector assembly.
FIG. 10 illustrates one embodiment of a window protector assembly 312 . In this embodiment, the window protector assembly 312 incorporates a frame 314 that is adapted to mount within the opening 306 in the side wall 310 of the vehicle 300 in a well-known manner. The frame 314 defines an opening 316 into which one or more pieces of glazing 320 are to be positioned.
In this embodiment, a first retaining member 322 and a second retaining member 324 are pivotally mounted to the frame 314 so as to be positioned about the outer perimeter of the opening 316 in the frame 314 . As is shown in FIG. 10, the first retaining member 322 is generally U-shaped having two arms 323 a , 323 b that extend along the side walls of the frame 314 and pivoting section 327 . Similarly, the second retaining member 324 is also generally U-shaped having a pivoting section 328 and two arms 325 a , 325 b that also extend along the side walls of the frame 314 so as to engage with the two arms 323 a , 323 b of the first retaining member 322 . The engagement between the arms 323 a , 323 b of the first retaining member 322 and the arms 325 a , 325 b of the second retaining member 324 secures the glazing and protective layers within the opening 316 of the frame 314 in a manner that will be described in greater detail below.
As will also be described in greater detail below in reference to FIGS. 13A and 13B, the pivoting section 327 of the first retaining member 322 and the pivoting section 328 of the second retaining member 324 are pivotally attached to the frame 314 so as to be pivotable between a closed position, as shown in FIGS. 10 and 12, and an opened position, as shown in FIG. 11 A.
As is illustrated in FIGS. 10 and 11B, the retaining members 322 , 324 open outward of the window so as to secure the glazing in the window frame. When the glazing is to be replaced, the retaining members 322 , 324 are opened and the glazing is then removed towards the outside of the vehicle in the manner that will be described in greater detail hereinbelow, thereby greatly simplifying the replacement of damaged or defaced glazing.
As is shown in FIG. 10, when the retaining members 322 , 324 are in a closed position, the retaining members 322 , 324 cover the outer perimeter of the glazing 320 and any outer protective member. This is because the arms and pivoting sections of the retaining members 322 , 324 are selected to have a width sufficient so as to fully cover the outer edge of the glazing 320 and any outer protective layers positioned within the opening 316 of the frame 314 . As is shown in FIG. 12, when the retaining members 322 , 324 are in an open position, the outer perimeter of the glazing 320 and any outer protective layer is exposed. With the outer perimeter of the glazing 320 exposed, the glazing 320 can be removed from the frame via the exterior surface of the vehicle in a known manner.
FIGS. 11A and 11B illustrate the interconnection between the first retaining member 322 and the second retaining member 324 and corresponding sections of the frame 314 . In particular, as illustrated in FIGS. 11A and 11B, the frame 314 includes an upper frame section 330 a and a lower frame section 330 b . The upper and lower frame sections 330 a , 330 b have an L-shaped section 332 that is suitable for mounting in the opening 306 of the side wall 310 of the vehicle 300 . In particular, the L-shaped section 332 has an exterior lip 334 that is adapted to mount flush against the outer surface of the side wall 310 of the vehicle adjacent the window openings 306 . The L-shaped section 332 further includes a laterally extending member 336 that is adapted to be positioned adjacent the inner walls of the openings 306 in the side walls 310 of the vehicle so as to extend substantially through the opening 306 .
A pivoting member 340 is formed on an inner wall 342 of the laterally extending member 336 so as to extend perpendicularly outward therefrom into the opening 316 defined by the frame 314 . As will be described in greater detail below, the pivoting member 340 extends the full length of the upper frame section 330 a and the lower frame section 330 b , and provides a surface to which the pivoting section 327 of the first retaining member 322 and the pivoting section 328 of the second retaining member 324 can be respectively attached to the frame 314 of the window protector assembly 312 .
The L-shaped section 332 also defines a seating member 344 that extends inward into the opening 316 defined by the window frame 314 . The seating member 344 is adapted to receive a seal 346 that is retained in the seating member 344 as a result of a deformable section 350 of the seal 346 being positioned within an opening 352 formed in the seating member 344 of the upper and lower frame members 330 a , 330 b . Hence, the seal 346 is press-fit within the seating member 344 of the upper frame section 330 a and the lower frame section 330 b . The glazing 320 is preferably positioned within frame 314 so as to be positioned adjacent the seal 346 . When the retainers 322 , 324 are closed, the glazing 320 is compressed against the seal 346 such that the glazing seals the window so as to inhibit the entry of moisture or air from the outside environment into the interior of the vehicle. It will be appreciated that while the upper and lower frame sections 330 a , 330 b have been described as being comprised of a plurality of discrete components, in the illustrated embodiment, the upper frame section 330 a and the lower frame section 330 b are comprised of a single uniform component preferably formed of extruded or molded aluminum.
The pivoting members 340 are positioned on the inner surface 342 of the L-shaped section 332 so that the pivoting member 340 is positioned within the opening 316 of the window frame 314 . The pivoting sections 327 and 328 of the retaining members 322 and 324 define an opening 341 that receives the pivoting member 340 to permit the pivoting movement of the retaining members 322 and 324 . More particularly, the pivoting member 340 defines a ball 343 at its distal end that extends outwardly toward the center of the window 302 . Since the pivoting member 340 is positioned on the inside surface of the L-shaped section 332 of the frame 314 , access to the interconnection between the retaining members 322 and 324 and the pivoting member 340 is inhibited. Moreover, an end portion 345 of each of the retaining members 322 , 324 is adapted to be flushly positioned within a recess 347 (FIGS. 11A and 11B) when the retaining members 322 , 324 are in the closed position so that access to the interconnection between the retaining members 322 , 324 is further inhibited. In this way, the likelihood of a person prying the retaining members 322 , 324 free from the pivoting member 340 and thereby dismantling or damaging the window protector assembly 312 is inhibited.
As is illustrated in FIGS. 11A and 11B, the first retaining member 322 and the second retaining member 324 can be pivoted about the pivoting members 340 so as to extend outward from the opening 316 . This allows one or more pieces of glazing 320 to be positioned within the opening 316 on the seal 346 . Subsequently, an outer sacrificial protective sheet 362 can be positioned on an outer surface 364 of the glazing 320 . The first and second retaining members 322 , 324 can then be pivoted into the closed position as shown in FIG. 11 B. The first and second retaining members 322 , 324 further include an inner seal 366 which extends entirely around the perimeter of the opening 316 so that the inner seal 366 makes contact with the outer sacrificial protective sheet 362 . Once contact is made between the seal 366 and the outer sacrificial protective sheet 362 , the outer sacrificial protective sheet 362 in turn contacts the glazing 320 which contacts the seal 346 which is rigidly attached to the rest of the frame 314 . Thus, by closing the retaining members 322 , 324 , the outer sacrificial protective sheet 362 and the glazing 320 are held rigidly inside the frame 314 . However, it will be appreciated that both the outer sacrificial protective sheet 362 and the glazing are easily removable once the retaining members 322 , 324 are opened.
Advantageously, because the retaining members 322 , 324 open only to the outside of the vehicle, passengers would be unable to open the retaining members 322 , 324 . This significantly reduces the abilities of a vandal to dismantle or damage the window protector assembly 312 from the inside of the vehicle, where vandalism is most likely to occur. Furthermore, passengers would be unable to open the retaining members 322 , 324 to gain access to the fragile and expensive glazing 320 . Hence, because the retaining members 322 , 324 open only to the outside, the cost of repairing the effects of vandalism is decreased while the safety of the other passengers is increased.
Furthermore, as illustrated in FIGS. 11A and 11B, the upper and lower frame sections 330 a , 330 b include an upper and lower flange 355 a , 355 b that extends toward the center of the opening 316 defined by the window frame 314 . The upper and lower flanges 355 a , 355 b are positioned on the interior surface of the window frame 314 , lying parallel to the seating member 344 and to the plane of the glazing 320 . The upper and lower flanges 355 a , 355 b are separated from the seating member 344 by a distance 360 so as to define an upper and lower recess 359 a , 359 b.
In the preferred embodiment of the window protector assembly 312 , an inner sacrificial protective sheet 356 resides in the upper and lower recesses 359 a , 359 b . To install the inner sacrificial sheet 356 , the inner sacrificial protective sheet 356 should be flexible enough such that the edges of the inner sacrificial protective sheet 356 can be bent over the upper and lower flanges 355 a , 355 b and into the upper and lower recesses 359 a , 359 b without breaking.
In one embodiment, a gasket 351 is positioned on the bottom surface 357 inside the lower recess 359 b . Preferably, the gasket 351 is of such a thickness that it centers the inner sacrificial protective sheet 356 inside the window protector assembly 312 . Also in this embodiment, one or more retainer fasteners 353 are drilled perpendicularly through the upper flange 355 a , at a location above the upper edge 349 a of the inner sacrificial protective sheet 356 . Preferably, the retainer fasteners 353 lie close enough to the upper edge 349 a such that the retainer bolts 353 prevent the inner sacrificial protective sheet 356 from shifting inside the recess 359 . Also in the preferred embodiment, the fasteners 353 are removable only with a special tool such that a passenger would not be able to remove the fasteners 353 easily.
Preferably, the distance measured between a lower edge 349 b of the inner sacrificial protective sheet 356 to the top of the lower flange 355 b is less than the distance measured between an upper edge 349 a of the inner sacrificial protective sheet 356 to the base of the upper flange 355 a . Thus, after the retainer fasteners 353 are removed, the inner sacrificial protective sheet 356 can be shifted upwards until the lower edge 349 b of the inner sacrificial protective sheet 356 is exposed. Then, in order to remove the inner sacrificial protective sheet 356 from the window protection assembly 312 , the lower edge 349 b could be grasped in order to bend the inner sacrificial protective sheet 356 out of the upper and lower recesses 359 a , 359 b . Advantageously, this embodiment of the widow protector assembly 312 allows for quick installation and removal of the inner sacrificial protective sheet 356 , yet the addition of the fasteners 353 prevents a passenger from shifting and removing the protective sheet 356 .
FIG. 12 is a cross-sectional view illustrating the side frame sections 370 a , 370 b of the frame 314 . The side frame sections 370 a , 370 b are integrally connected to the upper and lower frame sections 330 a , 330 b so that the entire frame 314 is a single integral piece. The side frame sections 370 a , 370 b are configured to have an L-shaped section 372 that has a side wall member 374 that is adapted to be flushly positioned against the outer side wall 310 of the vehicle 300 adjacent the window opening 306 . The L-shaped section 372 also has a laterally extending section 376 that extends inward through the opening 316 of the frame 314 in the same manner as the laterally extending section 336 of the upper and lower frame sections 330 a , 330 b as described above. As is also illustrated in FIG. 12, the side frame sections 370 a , 370 b include a seating member 384 that extends inward into the opening 316 from the inner surface 382 of the laterally extending section 376 . The seating member 384 is adapted to receive one or more seals 386 that extend laterally around the perimeter of the window. Finally, as illustrated in FIG. 12, the side frame sections 370 a , 370 b include a flange 378 that extends inward into the opening 316 from the inner surface 382 of the laterally extending section 376 . The flange 378 extends parallel to the seating member 384 , and the flange 378 and the seating member 384 are separated at a distance 379 to define a recess 375 .
As illustrated in FIGS. 11A and 12, the glazing 320 is positioned adjacent a seal 386 which is retained in the side frame members 370 a , 370 b in substantially the same manner as discussed above in connection with the seal 346 and the upper and lower frame members 330 a , 330 b . The outer sacrificial layer 362 is then positioned adjacent the glazing 320 in the same manner as described above in connection with FIGS. 11A and 11B. As illustrated in FIG. 12, when the first and second pivoting retaining members 322 , 324 are in the closed position, the one or more seals 366 , are positioned adjacent the outer sacrificial protective sheet 362 . In one embodiment, the window 310 is square in which case the seals are comprised of a plurality of pieces. In another embodiment, the window 310 is curved and the seals comprise a single seal.
Also as illustrated in FIGS. 11A and 12, the inner sacrificial protective sheet 356 is positioned inside the recess 375 in the same manner as described above in connection with the upper and lower recesses 359 a , 359 b . In addition, a gasket 377 resides inside the recess 375 in order to center the inner sacrificial protective sheet 356 in the window protector assembly 312 .
As is shown in FIGS. 10, 13 A and 13 B, the frame 314 is comprised of a single uniform piece that is comprised of the upper and lower sections 330 a , 330 b and the side sections 370 a , 370 b . The retaining members 322 , 324 are pivotally attached and define retaining surfaces that extend about the outer perimeter of the opening 316 defined by the frame 314 so as to overlap the outer perimeter of the glazing 320 and the outer protective sheet 362 . The seating member 344 of the upper and lower frame sections 330 a , 330 b and the seating member 384 of the side frame sections 370 a , 370 b also extend into the opening 316 defined by the frame 314 so that the outer protective sheet 362 and the glazing 320 can be securely retained in the opening 316 of the frame 314 by the retaining members 322 , 324 pressing the outer protective sheet 362 and the glazing 320 against the seating members 344 , 384 about substantially the entire perimeter of the glazing 320 and the protective sheet 362 .
FIGS. 13A and 13B further illustrate the configuration and operation of the window protector assembly 312 . In particular, as illustrated in FIG. 13A, the first and second retaining members 322 , 324 are pivotable with respect to the upper and lower frame sections 330 a and 330 b thereby removing the first and second retaining members 322 , 324 from the outer perimeter of the outer sacrificial layer 362 and the glazing 320 . This allows each of these layers to be lifted out of the opening 316 defined by the frame 314 .
As shown in FIG. 13B, when the first and second retaining members 322 , 324 are closed, they are positioned about the outer perimeter of the outer protective layer 362 and the glazing 320 thereby capturing these two layers adjacent the seal positioned on the inner sections of the frame 314 . As the outer perimeter of the sacrificial protective layer 362 and the glazing 320 is covered by the pivoting retaining members 322 , 324 , these layers cannot be removed without moving the first and second retaining members 322 , 324 into the open position illustrated in FIGS. 11A and 13.
In this embodiment, the sacrificial protective layers 356 and 362 are comprised of an acrylic material that is adapted to be positioned adjacent the exposed surfaces of the glazing 320 such that the exposed surfaces of the glazing 320 on both the inside and the outside of the window is covered by the protective layers 356 , 362 . In this way, damage to the more expensive glazing 320 as a result of vandalism or accident is inhibited as the protective acrylic layers provide protection against such damage.
It should be noted that the alternate embodiment of the retaining members and their attachment to the frame described supra and illustrated in FIGS. 6A and 6B can be fully incorporated into this alternate embodiment of the window protector assembly 312 .
FIG. 14 illustrates a securing mechanism 391 that is adapted to secure the first and second retaining members 322 , 324 in a locked and closed position. In particular, as illustrated in FIGS. 11A and 11B, the outer edge of the arms 323 a , 323 b of the first retaining member 322 and outer edge of the arms 325 a , 325 b of the second retaining member 324 are beveled so that the outer tip 383 of the arms 325 a , 325 b of the second retaining member 324 is positioned over the outer tip 385 of the arms 323 a , 323 b of the first retaining member 322 when the first and second retaining members are positioned in the closed position in the manner shown in FIGS. 11 and 13. A securing member 390 is positioned within an opening 392 in both the arms 325 a , 325 b of the second retaining member 324 . Preferably, the securing member 390 is pivotable within the opening 392 such that a laterally extending arm 394 of the securing member 390 can be positioned within an opening 396 formed in a side wall of the frame 314 .
In this embodiment, the opening 396 is preferably formed in the bracing member 380 and has a curved opening to permit the extending arm 394 to be rotated into the opening 396 in response to the user turning the securing member 390 . As illustrated in FIG. 15, the securing member 390 is preferably pivotable between an opened position and a closed position wherein the laterally extending member 394 is positioned within the opening 396 and the frame 314 in the closed position and is retracted from the opening 396 in the opened position.
As is also illustrated in FIG. 15, the outer face 400 of the securing member 390 includes a tool recess 402 that is adapted to receive only a specially configured tool (not shown) such that manipulation of the securing member 390 between the opened and closed positions can preferably only be accomplished by an authorized person possessing a specially configured tool. As is illustrated in FIG. 10, there are preferably two securing members 390 positioned in both of the outer ends of the arms 325 a , 325 b of the second retaining member 324 to secure the second retaining member 324 in the closed position adjacent the frame 314 . As discussed above, because the outer end 383 of the second retaining member 324 overlaps the outer end 385 of the first retaining member 322 , securing the second retaining member 324 in the closed position against the frame 314 in the manner shown in connection with FIGS. 14 and 15 results in the first retaining member 322 similarly being secured in the closed position.
Advantageously, it is simple to remove and replace the outer sacrificial layer 362 and the glazing 320 by simply manipulating the retaining members 322 , 324 into the open position and extracting each of the layers positioned within the opening 316 of the frame 314 . Likewise, it is simple to remove and replace the inner sacrificial layer 356 by shifting the sacrificial layer 356 until its edge 349 b is exposed and then grasping the edge 349 b and pulling on it until the sacrificial layer 356 bends out of the recesses 359 a , 359 b , 375 . Hence, the window protector assembly 312 of the illustrated embodiment allows for simpler and easier replacement of the protective layers 356 , 362 and the glazing 320 as compared to similar protective devices of the prior art. As a result of permitting such easy access and replacement, it is now possible to have a protective layer positioned on the outer surface of the glazing 320 in addition to a protective surface on the inner surface of the glazing 320 . However, it will also be appreciated that the window frame and protector 312 of the present invention can be used with only an inner protective layer 356 without departing from the spirit of the present invention.
Hence, the window protector 312 of the present invention allows for easier replacement of protective sheets as compared to window protective devices of the prior art. This easier access facilitates the use of a protective layer on the outside surface of the glazing as replacement of this sheet is now simplified due to the ease of access provided by the window protector assembly of the preferred embodiment.
Although the illustrated embodiments of the present invention have shown, described and pointed out the fundamental novel features of the invention, as applied to these embodiments, it will be understood that various omissions, substitutions and changes in the form of the detail of the device illustrated may be made by those skilled in the art without departing from the spirit of the present invention. Consequently, the scope of the invention should not be limited to the foregoing description, but should be defined by the appended claims. | A window protector assembly that protects both the inside and outside of standard panes of glazing from vandalism or other damage. The assembly comprises a pane of glazing, a sheet of protective material on the inside and outside of the glazing, and a frame. The frame pivots on the outer side of the glazing for quick loading and unloading of the glazing and the protective sheet on the outside of the glazing, and the frame also pivots closed to seal the glazing and protective sheets securely within the window protector assembly. The frame also comprises a recess wherein the protective sheet on the inside of the glazing is positioned. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to a cup holder for use with beverage containers such as those containing hot or cold liquids. The cup holder includes unique structural features which enables a beverage consumer to more effectively grasp and safely hold the combined holder and container when consuming a beverage from the container. The cup holder more effectively stabilizes the beverage container when supported on a supporting surface, provides insulation between the exterior of the beverage container and the hand of a beverage consumer and enables containers of recyclable material to be used for hot liquids. The cup holder is constructed as a planar blank of recyclable material which simplifies manufacture of the cup holder and eliminates the use of glue and the step of applying glue when making or assembling the cup holder. The cup holder can be quickly and easily assembled onto the beverage container and removed therefrom without requiring skilled manual dexterity.
2. Description of the Prior Art
Disposable beverage containers of tapered cylindrical configuration for hot and cold beverages have become universally used by carryout or fast food restaurants and similar establishments. Hot beverages are usually dispensed into a polystyrene cup which protects the hand of a beverage consumer when holding the cup. Cold beverages are usually dispensed in a paper cup which may be coated to render the cup less prone to leakage. Presently available beverage cups or containers are tapered from a larger upper end to a smaller lower end for nesting purposes which renders the containers somewhat unstable when placed on a supporting surface due to the small diameter of the lower end of the cup. The smaller lower end of the cup provides an unstable support especially when the cup is substantially full inasmuch as only a slight tilting of the beverage cup or container will cause spillage of the beverage from the cup or container.
Various efforts have been made to improve the handling of beverage containers by beverage consumers including the provision of handle tabs which can be folded out from the peripheral side wall of a beverage container and insulating tubes mounted on the exterior of the beverage container and tapering in the same manner as the tapered configuration of the beverage container. While such known devices alleviate somewhat the problem of discomfort caused by a beverage consumer grasping a very hot beverage cup or container, such devices do not improve the stability of the beverage cup when placed on a supporting surface and are not readily assembled with the beverage container at the point of use.
The following U.S. patents disclose tapered sleeve-type insulating holders or attachments to beverage cups or containers.
U.S. Pat. No. 5,205,473
U.S. Pat. No. 5,425,497
U.S. Pat. No. 5,425,497 discloses a cup holder which can be stored flat and assembled by a user to fit around the cup which increases the gripability and insulation value of the cup. However, to assemble the cuts 32 and 38 when assembling the holder onto the beverage cup requires considerable manual dexterity in aligning the cuts and does not alter the stability of the cup when placed on a supporting surface.
U.S. Pat. No. 5,205,473 discloses a corrugated cup construction for insulation purposes with the preferred holder being a corrugated tubular sleeve on a cup which can be folded flat for storage. The structure in this patent also fails to enhance the stability of the cup.
The prior art does not disclose a cup holder for a beverage cup or container which provides insulation characteristics, more effective gripping and safe holding of the beverage cup or container and increases the stability of the beverage cup or container when it is placed on a supporting surface. The prior art also fails to disclose a cup holder formed from a planar blank which can be die cut in a single operation and which does not employ glue or glueing operation during manufacture thereby simplifying the manufacture of the cup holder thus reducing the cost and enhancing the recyclable characteristics of the cup holder.
SUMMARY OF THE INVENTION
The cup holder of this invention includes a longitudinally extending sleeve having an opening in the top which enables a beverage cup or container to be inserted with the bottom end of the cup entering the opening in the top of the cup holder. The cup then descends into the cup holder until the flange or lip at the upper end of the beverage cup or container engages the top edges of the cup holder or the taper of the cup limits insertion into the holder. The vertical height of the cup holder is greater than the vertical height of the beverage cup or container or engages the cup so that the lower end of the cup is spaced above the lower edges of the cup holder when the lower edges of the cup holder engage a support surface laterally outwardly of the periphery of the bottom of the beverage cup or container thereby stabilizing the beverage cup or container when supported on a supporting surface.
The cup holder is constructed from a planar blank of cardboard, corrugated board or the like provided with a transverse slit at a central portion thereof. A fold line extends outwardly from each end of the slit to enable the planar blank to be folded into overlying halves along a transverse center line. Longitudinal fold lines at the ends of the slit enable the opposite side edges of the folded blank to be moved inwardly to open the folded blank by moving the slit edges outwardly to form a sleeve. Either or both side edges of the folded blank is provided with structure to facilitate the opposed side edges being moved inwardly. Such structures include laterally extending arms at the upper edge of the folded blank which contain the fold lines or a lateral extension either notched or straight at the upper edge of the folded blank which contain the fold lines to enable the folded blank to be moved to form a sleeve. Fold lines may be provided longitudinally of the folded blank at the center thereof to define fold lines extending longitudinally at the central portion of the outwardly deflected portions of the blank when forming the sleeve for receiving the beverage cup or container. The cup holder is formed and assembled onto a cup without using glue which simplifies manufacture and reduces cost of the cup holder and without requiring a high degree of manual dexterity.
Accordingly, it is an object of the present invention to provide a cup holder for a beverage cup or container which will protect the hand when gripping the cup to consume the beverage and stabilize the cup when the cup is inserted into the cup holder and placed on a supporting surface such a tabletop surface, or a movable supporting surface such as a food supporting tray in an airplane, automobile, railroad car or the like.
Another object of the invention is to provide a cup holder having a lateral outward projection or projections to engage upper surface areas of a hand holding the cup which prevents the cup from slipping out of the hand when holding the cup or consuming beverage from the cup.
A further object of the invention is to provide a cup holder in the form of a flat one-piece blank having a transverse central slit and a transverse fold line extending to the side edges of the blank at each end of the slit by which the blank can be folded into overlying halves. The side edges of the folded blank are then moved toward each other to open the slit to form a sleeve to enable a cup to be inserted bottom first into the upper end of the cup holder.
A still further object of the invention is to provide a cup holder having a length that enables the bottom edges to project beyond the bottom of the cup and engage a supporting surface in laterally spaced relation to the periphery of the bottom of the cup thereby, in effect, increasing the size of the supporting surface engaged by the cup holder thereby stabilizing the cup that is supported in the cup holder. The weight of the cup and the beverage in the cup exerts a downward force on the cup holder with the lower ends of the cup holder engaging a support surface being biased outwardly to cause the upper edges of the slit opening to move inwardly about the fold line to provide a gripping engagement of the slit edges at peripherally spaced areas on the beverage cup.
Still another object of the invention is to provide a cup holder constructed of corrugated paper or cardboard material, pressed cardboard or other cardboard material, heavy paper or the like without the use of glue and without a glue applying step when making the cup holder which renders the cup holder inexpensive for disposability and also recyclable with the cup holder enabling beverage cups or containers of recyclable material to be more effectively used under more circumstances since it no longer will be necessary to provide polystyrene cups for hot beverages.
Yet a further object of the invention is to provide a cup holder in accordance with the preceding objects in which the lower edge of the cup holder may be provided with diametrically opposed tabs or projections, defined by right angle slits, which project beyond the periphery of the bottom edge of the cup holder when the cup holder is formed into a sleeve by moving the side edges of the cup holder toward each other.
Yet another important object of the invention is to provide a cup holder in accordance with the preceding objects which is easy to assemble onto a beverage cup or container and does not require a high degree of manual dexterity and can be constructed so that a user can save the cup holder for subsequent use with another beverage cup or container.
These together with other objects and advantages which will become subsequently apparent reside in the details of construction and operation as more fully hereinafter described and claimed, reference being had to the accompanying drawings forming apart hereof, wherein like numerals refer to like parts throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of a planar blank forming one embodiment of the cup holder of the present invention.
FIG. 2 is a plan view of the blank folded along a center line into two identical halves.
FIG. 3 is a side elevational view of the cup holder in which the cup has been inserted illustrating the side edges of the folded blank moved toward each other to open the slit at the upper end of the cup holder with the cup being inserted bottom first.
FIG. 4 is a bottom plan view of the cup holder and cup illustrating the relationship of the lower edge of the cup holder and the bottom periphery of the cup.
FIG. 5 is a plan view of a planar blank illustrating another embodiment of the cup holder.
FIG. 6 is a plan view of the blank of FIG. 5 folded along a center line.
FIG. 7 is a side elevational view of the cup assembled in the cup holder.
FIG. 8 is an end elevational view of the cup and cup holder of FIG. 7 illustrating the relationship between the cup and cup holder.
FIG. 9 is a bottom plan view of the cup and cup holder of FIG. 7 illustrating the relationship between the bottom of the cup and the cup holder.
FIG. 10 is a plan view of another embodiment of the cup holder illustrating a tab to facilitate opening the transverse slit and material weakening openings defining the fold line outwardly of the ends of the slit.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Although only preferred embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the preferred embodiments, specific terminology will be resorted to for the sake of clarity. It is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
Referring to FIGS. 1-4 of the drawings, the cup holder 10 and its association with a cup 12 is illustrated in FIGS. 3 and 4. FIGS. 1 and 2 illustrate the blank 14 from which the cup holder 10 is formed.
The blank 14 is a generally rectangular, planar panel 16 constructed of cardboard, corrugated cardboard or similar material. A centrally disposed transverse slit or cut line 18 is formed in the center of the panel 16 between the end edges 20 and 22. The slit 18 forms the top edges of the cup holder 10. The slit 18 terminates at longitudinal fold lines 24 and 26 oriented inwardly from the side edges 28 and 30. The slit 18 defines the top edges of the cup holder and each side edge portion of the panel 14 includes a transverse fold line 32 and 34 forming an extension of the ends of the slit 18. A central fold line 36 parallel to the fold lines 24 and 26 extend from the center of the slit 18 to the edges 20 and 22 of the blank as illustrated in FIG. 1. The side edge 30 of the panel 16 is straight whereas the side edge 28 is provided with a pair of notches or recesses 38 which are identical in shape and size on each side of the fold line 32. Also, the notches or recesses 38 include an outer end portion 40 which has less width than the portion adjacent the fold line 32. Also, the panel 16 is provided with a tab 42 on opposite sides of the fold line 36 at the edges 20 and 22 of the blank. The tabs 42 are formed by a right angular cut line 44 associated with the fold lines 36 so that the tabs will project outwardly from the cup holder when folded in a manner to receive the cup 12.
As illustrated in FIG. 2, the blank 14 has been folded along fold lines 32 and 34 with the two halves of the blank being oriented in overlying matching relationship. The opposite side edges 30 and 28 of the folded blank illustrated in FIG. 2 are grasped between the thumb and one finger and the side edges are moved inwardly at the same time that the portions of the panel 16 between the fold lines 36 and 36 angulate about fold lines 24 and 26 as illustrated in FIGS. 3 and 4 thus forming a sleeve for receiving the tapered peripheral wall 46 of the cup 12 which includes a top lip 48 and a bottom end 50 of less diameter than the top lip 48. The thumb and opposing finger can be engaged with the notches 38 in the side edge 28 and the outer edge of the side edge 30 and these edges of the folded blank are moved toward each other to open the slit 18 to form an opening through which the cup 12 can be inserted bottom first. When the folded blank is opened by moving the side edges 30 and 28 toward each other and the panel 16 defines a sleeve with generally straight side wall sections, the tabs 42 will project from the side walls to which they remain connected to increase the lateral dimension of the bottom edges 20 and 22.
The dimensional characteristics of the blank, the length of the slit, the length of the fold lines and the configuration of the side edges can vary to receive different size beverage cups or containers and facilitate gripping engagement of the cup holder and cup when consuming beverages from the beverage cup 12. Both side edges of the cup holder may be provided with recesses or both side edges may be straight. The bottom edges 20 and 22 of the blank increase the dimensional area that engages a supporting surface thereby enhancing the stability of the cup inasmuch as the surface area contacted by the cup support is substantially greater than the surface area that would be engaged by the bottom end of the cup which is spaced upwardly from the support surface a short distance depending upon the size characteristics of the cup holder and the cup with which it is associated.
It is pointed out that the side edges and fold lines 24 and 26 diverge downwardly inasmuch as the bottom edges of the side edge portions outwardly of the fold lines 24 and 26 are not connected while the upper ends of the side edge portions outwardly of fold lines 24 and 26 are connected by the fold lines 32 and 34 thus enabling the side edges outwardly of fold lines 24 and 26 of the cup holder to diverge downwardly to increase the surface area engaged by the cup holder when placed on a supporting surface. Also, the dimensional characteristics of the cup holder determine how far the edges of the slit 18 of the cup holder is spaced from the upper lip or rim 48 of the cup 12 and how far the bottom end 50 of the cup is spaced above the lower edge of the cup holder.
FIGS. 5-9 illustrate another embodiment of the cup holder generally designated by reference numeral 60 associated with a cup 62 having a top lip or rim 64 and a bottom rim or edge 66. This embodiment of the cup holder 60 is also formed from a planar blank 68 in which both side edges are the same with the material forming the blank being corrugated board, cardboard or other material that has insulating characteristics and includes substantial rigidity but is still flexible and constructed of recyclable material.
The blank 68 includes a panel 70 having end edges 72 and 74 and side edges 76 and 78. A central slit 80 extends transversely at the center of the blank 70 with the ends of the slit terminating in short fold lines 82 and 84 which extend from the ends of the slit 80 to the side edges 76 and 78 as illustrated in FIG. 5. The end edges 72 and 74 which form the bottom edges of the cup holder 60 are shorter than the distance between the side edges 76 and 78. Each side edge 76 and 78 includes a recess 86 defined by an inclined edge portion 88 extending inwardly in diverging relation to the fold line 84 and the other end of the edge 88 is spaced from the fold line 84. This structure is the same on both side edges of the blank. The recess 86 is connected to the adjacent end edge by an inclined edge 90. The blank 68 is symmetrical on both sides of the slit 80 and fold lines 82 and 84 so that when the blank 68 is folded to the position illustrated in FIG. 6, the two halves of the blank 68 are exact duplicates and overlie each other.
When the folded blank 68 as illustrated in FIG. 6 is opened to form a sleeve, the thumb and an opposed finger engage the recesses 86 and move the side edges of the folded blank toward each other so that the central portions of the slit 80 move apart to enable insertion of the container 62 by inserting the bottom 66 downwardly through the opening defined by the slit 80 in a manner illustrated in FIGS. 7-9.
In this construction, the blank may be constructed of corrugated material with the facing sheet either inwardly and/or outwardly oriented with the facing sheet or sheets and/or corrugations being provided with shallow fold lines to enable symmetrical opening of the folded blank to receive the cup 62. Since the only connection between the two halves of the cup holder is along the fold lines 82 and 84, the bottom edges 72 and 74 of the cup holder are spaced outwardly from the periphery of the bottom edge 66 of cup 62 when the cup 62 and cup holder 60 are supported on a surface as illustrated in FIG. 8 to stabilize the cup and cup holder. The bottom edges 72 and 74 are also spaced below the bottom edge 66 of the cup 62 to further enhance stability. The weight of the cup 62 and its contents tend to cause the bottom edges of the cup holder to spread apart to move the slit edges against the periphery of the cup. The rim 64 of the cup may engage the edges of the slit 80 as long as the bottom edge 66 is spaced above the bottom edges 72 and 74 of the cup holder. This increased lateral dimensions of the edges 72 and 74 stabilizes the cup when placed on a supporting surface. However, the pivotal connection between the halves of the cup holder along the fold lines 82 and 84 enable opposed side surfaces of the cup holder between the free diverging edges 90 to be easily grasped and squeezed into firm surface-to-surface contact with the periphery of the cup 62. Upon release of the cup holder, the bottom edges 72 and 74 will normally spread apart to a position laterally spaced from the bottom end 66 of the cup 62 as shown in FIGS. 8 and 9.
FIG. 10 is a plan view of a slightly modified embodiment of the cup holder illustrated in FIGS. 5-9 as designated by reference 60'. In this construction, the cut line 80' is provided with a tab 81 of generally semi-circular construction at the center of the cut line or slit 80' to facilitate opening of the slit 80'. Also, an opening or a plurality of openings 83 and 85 to help define the fold lines 82' and 84'. The remainder of the cup holder 60' illustrated in FIG. 10 remains the same as that in FIGS. 5-9 and includes the same reference numerals which have been primed.
When corrugated cardboard is used, either single faced or double faced with the single face on either the inner surface or the outer surface, the corrugations extend lengthwise of the blank such as between the edges 72 and 74 so that when the cup holder receives the cup, the corrugations extend from the top of the cup toward the bottom. This facilitates the cup holder curving or bending at shallow fold lines to conform generally with the configuration of the peripheral wall of the cup. The blank, the central slit in the blank and the fold lines as well as the slits 44 which form the tabs 42 are formed in a conventional manner well known in the art. Glue is not used when making or using the cup holder which simplifies and reduces the cost of manufacture. Also, the absence of glue eliminates failure of glued surfaces during insertion of the cup into the holder and during use of the holder. The blanks are transported, stored and handled while in a flat condition and can be easily assembled with respect to the beverage cup or container by the beverage consumer or by an individual who sells the beverage or supplies the beverage to the consumer without requiring a high degree of manual dexterity thus enabling the cup or container as well as the cup holder to be completely recyclable.
The foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and, accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. | A cup holder for use with beverage containers which enables the beverage consumer to more effectively grasp and hold the combined holder and container when consuming a beverage from the container, more effectively stabilize the beverage container when supported on a supporting surface and provide insulation between the exterior of the beverage container and the hand of the beverage consumer. The cup holder is constructed in the form of a planar blank of recyclable material which can be quickly and easily formed into a sleeve and set up without the use of glue, easily assembled onto a cup or beverage container without requiring manual dexterity, easily removed from the cup and recycled when combined with the cup or separated therefrom. | 1 |
FIELD OF THE INVENTION
The present invention relates generally to the extermination of vermin or pests, such as household insects. In particular, the present invention is concerned with an analysis system for minimizing the use of chemical pesticides used in the control of vermin infestation.
BACKGROUND OF THE INVENTION
Extermination of vermin or pests from environments, such as restaurants, warehouses, and grocery stores, is important because of the harm they create. Pests are known carriers of infectious diseases such as salmonella, dysentery, Bubonic plague, leprosy, Lyme disease, and typhoid fever. Additionally, persons who suffer from allergies or asthma are often allergic to certain types of pests.
Removal of vermin or pests from the interior of buildings by periodic chemical pesticide spray treatments has also produced deleterious effects upon humans, plants and beneficials. Humans may become sick or suffer adverse side effects from routine, scheduled, or over spraying of the chemical pesticides. Beneficials, such as a honey bee, butterfly, preying mantis or spider, which are desirable, many times are exterminated along with the pests. The present invention solves this problem by providing a pest management system to eliminate the need for scheduled and routine spraying of pesticides or eliminate the application of chemical pesticides all together.
One prior art device used in pest extermination which eliminates chemical pesticides is the disposable glue trap. Disposable glue traps, however, have not proven adequate in removing a pest population from buildings. For example, in cockroach extermination, only those cockroaches trapped in the glue trap are exterminated. Those cockroaches in the population which avoid the trap continue to multiply. Chemical extermination is more effective in complete extermination of cockroaches because as cockroaches interact the chemical pesticides spread to other cockroaches. The present invention solves the problem of effectively exterminating pests yet minimizing the amount of chemical spray thereby reducing the deleterious effect of chemical spray on humans, plants and beneficials. In addition, the present invention monitors the effectiveness of prior art devices such as the glue trap and would alert the user if more drastic steps were necessary to keep the pest population in check (i.e., if the pest population is stable, decreasing, or increasing). Chemical applications may be necessary only in the rare cases where nonchemical means prove ineffective.
SUMMARY OF THE INVENTION
The present invention is a system and monitoring device used in extermination of pests, such as household insects. The monitoring device is used to determine the location, traffic patterns and density concentrations of pests in a building or other environment so as to more efficiently exterminate the pest population.
The pest management system is initiated with an on-site inspection by a person knowledgeable in the skills of pest identification. The inspection identifies signs of pest access onto the site and locations upon the site of infestation. Common signs of pest access are structural conditions such as interior and exterior cracks, openings, crevices, ledges, etc. Locations of pest infestation are determined by pest residues, smell, etc. These locations are then recorded and stored in a data base.
After the initial inspection, early preventative measures are made for controlling the infestation. For example, modifying portions of the structure so as to prevent pest entry, such as caulking or screening of openings; cleaning of organic and nonorganic waste products which attract pests to the structural site; proper storing of food products or other organic matter; evaluating occupant practices which increase the risk of pest infestation; and determining the most appropriate chemicals for use in extermination of the site. Certain chemical pesticides should be avoided at certain sites due to the type of environment and health risks to certain individuals. Pesticides should only be used in certain on-site locations, such as bedrooms, closets, hallways, stairwells, planting beds, after careful monitoring.
Once early preventative measures are taken, the pest monitoring devices are put in place. Before placement, location and placement time of each pest monitoring device is recorded either manually or preferably electronically into a data storage device or computer. The monitoring devices are left in place for a period of time and then are retrieved. Data is then recorded manually or entered into a computer regarding the elapse of time, the location of the monitoring device, the type of pest, concentration of pests, and traffic patterns. This data provides the information necessary to more efficiently determine ongoing pest control strategies such as determining precise location of infestation for localized chemical pesticide application, appropriate spray amounts, specific pesticides, and spray concentrations. By determining spray amounts and concentrations, the actual chemical spray can be decreased so as to minimize the harm to humans and beneficials.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of the pest monitoring trap of the present invention.
FIG. 2 is a side view of the pest monitoring trap of the present invention.
FIG. 3 is a cutaway view of the pest monitoring trap taken along lines 3--3 of FIG. 2.
FIG. 4 is a bottom view of the pest monitoring trap of the present invention.
FIG. 5 is a perspective view of a pest monitoring trap of the present invention.
FIG. 6 is a pictorial representation of the pest monitoring system locator device.
FIG. 7 is a pictorial representation of data storage device from a pest monitoring device of the present invention.
FIG. 8 is a perspective view of a second embodiment of the pest monitoring device of the present invention.
FIG. 9 is a perspective view of a third embodiment of the pest monitoring device of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 1 and 2 show a top and side view and FIG. 5 illustrates a perspective view of an insect monitoring device 10 of the present invention. On one side 25 of the monitoring device 10 a data input label or bar code 40 is attached. The bar code 40 may be attached by any conventional adhesion, such as glue, tape, etc. For identification of the particular monitoring device 10, the bar code 40 is read into a data storage device or computer 115 through an optical scanner 110 (FIG. 7). Other than a bar code, other types of computer identification strips may be used for purposes of identification of the location and time of placement of each insect monitoring device 10. In the case of manual monitoring, an alphabetic or numeric identifier may be used.
As shown in FIGS. 1, 2 and 5, the insect monitoring device 10 includes a pick-up strip 50 for ease of placement and removal. The pick-up strip 50 contains a plurality of holes 57 for attachment of a suspension device 55 such as a string or wire. The suspension device 55 allows the user to suspend the monitoring device 10 during scanning.
Below the pick-up strip 50 is an electronic locator beeper 52. The locator beeper 52 may be attached by adhesives to the outside of the monitoring device 10 or may placed in a containment structure 54. As shown in FIG. 6, the locator beeper 52 is activated by a signal generating device 102, such as a hand held transmitter. The locator beeper 52 may also be activated by a noise such as a hand clap. Such locator beepers 52 are similar to those used with vehicles for setting alarms; unlocking doors; or finding keys on a key chain.
FIG. 3 illustrates a cutaway side view taken through lines 3--3 of FIG. 2. Sidewalls 20, 25 and base surface 15 adjoin to form a triangular-shaped monitoring device 10. At the apex of the triangle is the locator beeper containment structure 54, which is shown in FIGS. 3-9 as an elongate compartment. Other cross-sectional shapes are also contemplated such as square, rectangular or other combination of polygonal and/or curvilinear shapes. A triangular-shape is chosen for ease of manufacture and cost savings in materials.
As shown in FIGS. 3, 4 and 5 a transparent adhesive trap or vermin density analysis surface 30 including a top surface 30a and a bottom surface 30b positioned along the base surface 15 of the monitoring device 10. The trap 30 may be integrally formed on the base surface 15 or it may be removable and replaceable for off-site density analysis. The top surface 30a of the trap 30 contains both an adhesive and an attractor. The attractor may be a pheromone or bait adapted to the particular target insect population.
FIG. 8 illustrates a second embodiment of the present invention. The monitoring device 112 can be either three monitoring devices 10 connected together to form an isosceles triangle or it can be integrally formed. The device 112 includes base surfaces 115, 120, 125 having transparent adhesive traps or vermin density analysis surfaces 130, 131, 132 and side surfaces 160, 161, 162. Centrally located is a locator beeper containment structure 150. An advantage of the device 112 is that three separate readings may be taken from the same device without the need for replacing the grid trap surfaces 130, 131, 132 or inputing the location data from a replacement monitoring device.
The third embodiment shown in FIG. 9 has a similar advantage to the second embodiment shown in FIG. 8. Instead of three monitoring devices being connected or having three sides integrally formed, the monitoring device 210 includes four monitoring devices removably or integrally joined. The device 210 includes base surfaces 220, 222, 226, 228 having transparent adhesive traps or vermin density analysis surfaces 231, 232, 233, 234 with side surfaces extending therefrom. Centrally located is locator beeper containment structures 250, 251, 252, 253.
In operation each monitoring device's data input label or bar code 40, 140, 240 is manually recorded or scanned into a data input device or computer 115 to record location and time of placement. After the monitoring device 10 has been left at the monitoring site over a period of time and captured pests are allowed to accumulate in the trap 30, the monitoring device 10 is then retrieved. Capture data is then manually recorded or scanned into the computer by optical scanner 110 across the bar code label 40 and the grid lines 32 on the pest density analysis surface 30. The scanner 110 records where the monitoring device 10 was located and the computer 115 accounts for the time elapsed for that particular monitoring device. The grid lines 32 act as a distance reference frame to assist in recording density and traffic flow data into a data storage device or computer 115. Computer software then filters out overlapped pests and identifies the type of pest by shape and size. The computer software used in the system herewith has not been disclosed, but may be readily obtained through routine experimentation by an artisan of ordinary skill in the art. The density and location of the pests on the grid are recorded manually or scanned into the computer due to the absence of light passage through the transparent trap or density analysis surface 30.
In order to obtain optimal scanning results, the inner surfaces of the sidewalls 20, 25 are formed from a material having a color which differentiates from the target pests. In the case of manual recording or when the density analysis surface 30 is removable for off-site data input, the color of the side walls 20, 25 is not as important.
After all the data has been assimilated, the exterminator uses charts, graphs, tables, records or the like, or the computer software to suggest possible recommendations for elimination of the pest population by methods such as structural modifications, cleaning, etc. If the pest population cannot be efficiently eliminated by non-chemical methods, the appropriate chemical pesticides including spray amounts and concentrations are recommended.
After the system has been implemented, it is continued on a periodic basis to eliminate the infestation. If the infestation has been eliminated, the system is used as a preventative maintenance tool to prevent future infestations.
The embodiments disclosed herein have been discussed for the purpose of familiarizing the reader with the novel aspects of the invention. Although preferred embodiments of the invention have been shown, many changes, modifications and substitutions may be made by one having ordinary skill in the art without necessarily departing from the spirit and scope of the invention as described in the following claims. | A system and monitoring device is disclosed for use in extermination of pests, such as household insects. The monitoring device is used to determine the location, traffic patterns and density concentrations of pests in a building or other environment so as to more efficiently exterminate the pest population by reducing the amount of chemical spray. The monitoring device also includes a remotely activated locator device. The monitoring device may be used singly or ganged in groups of three or more. | 0 |
[0001] This is a nonprovisional application which claims the filing date of the same applicant's provisional application Ser. No. 60/764,026 filed in the United States Patent and Trademark Office on Feb. 2, 2006.
[0002] This invention relates to systems for repairing and reconstructing injured anterior cruciate ligaments. More particularly it relates to a novel method and related family of methods of orthopaedic surgery for repairing and reconstructing an injured anterior cruciate ligament. It also relates to new and improved instruments and implants used in practicing the new method and family of methods.
[0003] Except for the provisional application referred to above, there are no patent applications related to this one. Neither this application nor the provisional application upon which it relies is subject to any federally sponsored research or development or to any joint research agreement.
BACKGROUND OF THE INVENTION
[0004] Orthopaedic surgeons perform reconstructive surgery of the anterior cruciate ligament (ACL) on patients who have traumatically injured this ligament. ACL reconstructive surgery restores the function of the ACL in the human knee and provides stability for the knee allowing patients to return to athletic activities. Without ACL reconstructive surgery, patients typically experience instability, “giving way,” of the knee and incur further injury to other important anatomic structures of the knee, including meniscal and articular cartilage.
BRIEF SUMMARY OF THE INVENTION
[0005] While there are different surgical methods, instruments and implants used to reconstruct an ACL depending upon the patient and the ACL graft selected for the reconstructive procedure, the present invention describes a novel universal system of methods, instruments and implants to repair and reconstruct an ACL irrespective of the type of patient or ACL graft selected. This invention also includes a means to perform single or multiple bundle ACL reconstruction, primary ACL repair, and physeal (growth plate)-sparing ACL reconstruction, in the skeletal immature patient.
[0006] This invention includes a novel guide for “inside-out” creation of a femoral tunnel independent of the tibial tunnel, and it also includes a series of implant options providing a complete set for tibial and femoral fixation of any bone-soft-tissue composite or soft-tissue-only ACL graft.
[0007] Other benefits include more reliable methods for anatomic positioning of femoral tunnels, a technically facile method of creating femoral and tibial tunnels independent of each other, and a universal method for tunnel creation irrespective of patient or ACL graft selection.
[0008] The present invention especially allows a surgeon to become familiar with a single universal system of methods, instruments and implants which allows him or her to treat all patients with any graft and achieve the most reliable and reproducible technical and clinical results.
[0009] Accordingly, one object of this invention is to provide a universal system for a single surgeon to use in repairing and reconstructing an ACL in any patient using any graft.
[0010] Another object of this invention is to provide a novel guide for simply and easily creating an anatomic femoral tunnel independently of a tibial tunnel by directing a guide pin from a separate portal directly through the anatomic footprint of the ACL.
[0011] Another object of this invention is to provide a guide which allows for the passage of a guide wire from multiple directions, through the tibial tunnel and other arthroscopic portals, and also allows for the creation of multiple femoral tunnels, the creation of an epiphyseal (physeal sparing) femoral tunnel, and the repair of the torn stump of the ACL, all using a consistent simple method.
[0012] Another object of this invention is to provide a novel cannulated scalpel for improved accuracy in creating a limited passageway through skin and soft-tissue over a guide wire.
[0013] Another object of this invention is to provide a method of drilling bone tunnels over a guide wire from any direction.
[0014] Another object of this invention is to provide a novel surgical ring fixation tool which includes a ring and a ring capture button for fixing a loop end of a soft-tissue graft in a bone tunnel.
[0015] Another object of this invention is to provide a novel surgical ring fixation tool which can be used in conjunction with a tunnel in any bone according to a simple consistent method.
[0016] Another object of this invention is to provide a novel suspension pin for fixing a loop end of a soft-tissue graft in a tunnel of any bone.
[0017] Another object of this invention is to provide a novel hybrid suspension pin for fixing a loop end of a soft-tissue graft in a bone tunnel.
[0018] Another object of this invention is to provide a surgical pin guide capable of being placed in any bone tunnel from any direction for accurately inserting a pin in the bone across the bone tunnel and facilitating both the placement of a graft and the fixation of the graft with the pin.
[0019] Another object of this invention is to provide a suspension pin insertion tool having a tip with inverse geometry to the rear end of a suspension pin for inserting the pin into any bone.
[0020] Another object of this invention is to provide a wire cutting tool capable of being placed through small percutaneous skin incisions and operable to cut and remove the wire ends of a surgical pin guide wire element.
[0021] Another object of this invention is to provide a guide pin having a sharp leading tip, cannulations at its ends, and a body having an enlarged diameter portion with an outwardly facing cutting surface intermediate the cannulations for cutting a passageway in a bone larger that the rest of the guide pin's body.
[0022] Another object of this invention is to provide a wire passing tool for performing a novel method of passing a flexible wire from one bone tunnel to another.
[0023] Another object of this invention is to provide a method of loading a soft-tissue graft onto a central loop of flexible wire and thereafter straightening the wire to draw the soft-tissue graft into a desired position in a bone tunnel.
[0024] Another object of this invention is to provide a modular and non-modular interference screw-ligament washer for fixing the free end of a graft in a bone tunnel at two sites, namely, at the tunnel inner wall and at the outer cortical surface of the tunnel.
[0025] Another object of this invention is to provide an insertion tensioner tool and its associated components.
[0026] Another object of this invention is to provide a method of performing ACL repair.
[0027] Another object of this invention is to provide a method of performing ACL reconstruction on a skeletally immature patient with open physes (growth plates).
[0028] Other objects and features of this invention will be apparent to orthopaedic surgeons and other persons who are skilled in the art of ACL repair and reconstruction and who design solutions thereto, particularly after reviewing the following description of the preferred embodiments of the present invention and the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is a perspective view of a novel femoral guide in accordance with the present invention.
[0030] FIG. 2 is a top plan view of the guide in FIG. 1 .
[0031] FIG. 3 is a perspective view of an alternative embodiment of the novel femoral guide of FIG. 1 with a semi-circular flexible guide loop.
[0032] FIG. 4 is a schematic view of the disposition of a guide pin in the femur of a knee utilizing the femoral guide of claim 1 in accordance with the present invention.
[0033] FIG. 5 is a schematic view of an alternative manner of disposing a guide pin in the femur of a knee utilizing the femoral guide of claim 1 in accordance with the present invention.
[0034] FIG. 6 is an exploded view of the disposition of a guide pin in the femur of a knee utilizing the femoral guide of claim 1 in accordance with the present invention.
[0035] FIG. 7 is a perspective view of a cannulated scalpel in accordance with the present invention.
[0036] FIG. 8 is a schematic view of a manner of incising the skin and soft-tissue over a guide wire utilizing the cannulated scalpel of FIG. 7 in accordance with the present invention.
[0037] FIG. 9 is a schematic view of a manner of creating a tunnel in a bone over a guide wire utilizing a cannulated reamer or drill in accordance with the present invention.
[0038] FIG. 10 is a schematic view of an alternative manner of creating a tunnel in a bone over a guide wire utilizing a cannulated reamer or drill in accordance with the present invention.
[0039] FIG. 11 is a schematic view of a second alternative manner of creating a tunnel in a bone over a guide wire utilizing a cannulated reamer or drill in accordance with the present invention.
[0040] FIG. 12 is a perspective view of a surgical ring fixation tool with its ring engaged in its ring capture button in accordance with the present invention.
[0041] FIG. 13 is a perspective view of the ring of FIG. 12 .
[0042] FIG. 14 is a perspective view of a ring capture button in the surgical ring fixation tool of FIG. 12 .
[0043] FIG. 15 is a side elevational view of the ring capture button of FIG. 14 .
[0044] FIG. 16 is a schematic view of a manner of passing the ring of FIG. 13 along with a looped end of soft-tissue graft in accordance with the present invention.
[0045] FIG, 17 is a schematic view of a manner of assembling the ring of FIG. 13 and the ring capture button of FIG. 14 in accordance with the present invention.
[0046] FIG. 18 is a schematic view of a manner of femoral placement of the surgical ring fixation tool of FIG. 12 in a knee in accordance with the present invention.
[0047] FIG. 19 is a schematic view of a manner of tibial placement of the surgical ring fixation tool of FIG. 12 in a knee in accordance with the present invention.
[0048] FIG. 20A is a perspective view of a suspension pin in accordance with the present invention.
[0049] FIG. 20B is a perspective view of an alternative embodiment of a suspension pin in accordance with the present invention.
[0050] FIG. 20C is a perspective view of a suspension pin insertion tool in accordance with the present invention.
[0051] FIG. 20D is a perspective view of a guide wire cutting tool for removing the wire ends of a surgical pin guide wire element in accordance with the present invention.
[0052] FIG. 21 is a perspective view of a surgical pin guide in accordance with the present invention.
[0053] FIG. 22 is a perspective view of a surgical guide pin in accordance with the present invention.
[0054] FIG. 23A is a schematic view of a manner of inserting the surgical guide pin shown in FIG. 22 across a bone tunnel in accordance with the present invention.
[0055] FIG. 23B is a schematic view of a manner of inserting the surgical guide pin shown in FIG. 22 across a bone tunnel in accordance with the present invention.
[0056] FIG. 24A is a schematic view of an alternative manner of inserting the surgical guide pin shown in FIG. 22 across a bone tunnel in accordance with the present invention.
[0057] FIG. 24B is a schematic view of a flexible wire attached to the surgical guide pin of FIG. 22 traversing a bone tunnel in accordance with the present invention.
[0058] FIG. 24C is a schematic view of a manner of exchanging the surgical guide pin shown in FIG. 22 with the flexible wire of the suspension pin of the present invention.
[0059] FIG. 24D is a schematic view of an alternative manner of attaching a flexible wire of the suspension pin to the surgical guide pin traversing a bone tunnel in accordance with the present invention.
[0060] FIG. 24E is a schematic view of an alternative manner of exchanging the surgical guide pin of this invention with the flexible wire of the suspension pin of this invention.
[0061] FIG. 25A is a perspective view of a wire passing tool in accordance with the present invention.
[0062] FIG. 25B is an exploded view of the wire passing tool shown in FIG. 25A opening its functional tip.
[0063] FIG. 25C is a schematic view of a manner of utilizing the wire passing tool shown in FIG. 25A to pass a central loop of flexible wire from a tunnel in a bone out through a tunnel in another bone in accordance with the present invention.
[0064] FIG. 26 is a sectional view of FIG. 25C showing the wire passing tool of FIG. 25A passing the central loop of flexible wire in the manner illustrated in FIG. 25C .
[0065] FIG. 27 is a schematic view of a manner of loading a free soft-tissue graft into a central loop of a flexible wire in accordance with the present invention.
[0066] FIG. 28 is a schematic view of a manner of straightening and advancing a flexible wire to draw the loop end of a free soft-tissue graft through a tunnel in a bone into a tunnel of another bone in accordance with the present invention.
[0067] FIG. 29 is a schematic view of a manner of making an additional pass of a central loop of flexible wire from a tunnel in a bone out through an additional tunnel in another bone in accordance with the present invention.
[0068] FIG. 30 is a schematic view of a manner of loading a free soft-tissue graft into a central loop in a flexible wire in accordance with the present invention.
[0069] FIG. 31 is a schematic view of a manner of straightening and advancing a flexible wire to draw a loop end of a second free soft-tissue graft through a second tunnel in a bone into a tunnel of another bone in accordance with the present invention.
[0070] FIG. 32A is a schematic view of a manner of inserting the suspension pin shown in FIGS. 20A and 20B using the suspension pin insertion tool shown in FIG. 20C in accordance with the present invention.
[0071] FIG. 32B is a schematic view of a manner of cutting a flexible wire from the end of a suspension pin of this invention utilizing the wire cutting tool shown in FIG. 20D in accordance with the present invention.
[0072] FIG. 32C is a schematic view of a manner of inserting the suspension pin shown in FIGS. 20A and 20B to secure a loop end of a free soft-tissue graft in a bone tunnel in accordance with the present invention.
[0073] FIG. 33 is a schematic view of an alternative manner of passing a central loop of flexible wire from a tunnel in a bone out through a tunnel in another bone in accordance with the present invention.
[0074] FIG. 34 is a sectional view of FIG. 33 showing the passage of the central loop of flexible wire illustrated in FIG. 33 .
[0075] FIG. 35 is a schematic view of a manner of loading a free soft-tissue graft into a central loop of flexible wire in accordance with the present invention.
[0076] FIG. 36 is a schematic view of a manner of straightening and advancing a flexible wire to draw the loop end of a free soft-tissue graft through a tunnel in a bone into a tunnel of another bone in accordance with the present invention.
[0077] FIG. 37A is a schematic view of a manner of inserting the suspension pin shown in FIGS. 20A and 20B utilizing the suspension pin insertion tool shown in FIG. 20C to secure a loop end of a free soft-tissue graft in a bone tunnel in accordance with the present invention.
[0078] FIG. 37B is a schematic view of a manner of cutting a flexible wire from a suspension pin of this invention utilizing the wire cutting tool shown in FIG. 20D in accordance with the present invention.
[0079] FIG. 38 is a perspective view of a modular interference screw-ligament washer in accordance with the present invention.
[0080] FIG. 39 is a perspective view of a cannulated interference screw component of the modular interference screw-ligament washer shown in FIG. 38 .
[0081] FIG. 40 is a perspective view of a separate cannulated screw component and mobile ligament washer component of the interference screw-ligament washer shown in FIG. 38 .
[0082] FIG. 41 is a perspective view of a non-modular interference screw-ligament washer in accordance with the present invention.
[0083] FIG. 42 is a perspective view of an insertion-tensioner tool in accordance with the present invention.
[0084] FIG. 43 is a top plan view of the insertion-tensioner tool shown in FIG. 42 .
[0085] FIG. 44 is a perspective view of a trocar component of the insertion-tensioner tool shown in FIG. 42 .
[0086] FIG. 45 is a perspective view of a graft loader component of the insertion-tensioner shown in FIG. 42 .
[0087] FIG. 46 is a perspective view of a cannulated screw driver component of the insertion-tensioner tool shown in FIG. 42 .
[0088] FIG. 47 is a perspective view of a cutter component of the insertion-tensioner shown in FIG. 42 .
[0089] FIG. 48 is a schematic view of a manner of loading the free end of a soft-tissue graft into the insertion-tensioner shown in FIG. 42 utilizing the graft loader component shown in FIG. 45 in accordance with the present invention.
[0090] FIG. 49 is a schematic view of a manner of positioning the insertion-tensioner shown in FIG. 42 loaded with a soft-tissue graft over an opening of a bone tunnel utilizing the trocar component shown in FIG. 44 and a guide wire in accordance with the present invention.
[0091] FIG. 50 is a schematic view of a manner of inserting the interference screw component of the modular interference screw-ligament washer shown in FIG. 38 utilizing the insertion-tensioner shown in FIG. 42 and the cannulated screwdriver component shown in FIG. 46 in accordance with the present invention.
[0092] FIG. 51 is a schematic view of a manner of inserting the interference screw component of the modular interference screw-ligament washer shown in FIG. 38 utilizing the insertion-tensioner shown in FIG. 42 and the cannulated screwdriver component shown in FIG. 46 in accordance with the present invention.
[0093] FIG. 52 is a schematic view of a manner of inserting the separate cannulated screw and mobile ligament washer components of the modular interference screw-ligament washer shown in FIG. 40 utilizing the insertion-tensioner tool shown in FIG. 42 and the cannulated screw driver shown in FIG. 46 in accordance with the present invention.
[0094] FIG. 53 is a schematic view of a manner of cutting free ends of soft-tissue graft utilizing the cutter component shown in FIG. 47 of the insertion-tensioner tool shown in FIG. 42 after the graft has been secured by the modular or non-modular interference screw-ligament washer shown in FIGS. 38 and 41 in accordance with the present invention.
[0095] FIG. 54 is a schematic view of a manner of inserting the non-modular interference screw-ligament washer shown in FIG. 41 utilizing the insertion-tensioner tool shown in FIG. 42 and the cannulated screw driver shown in FIG. 46 in accordance with the present invention.
[0096] FIG. 55 is a schematic view of a manner of repairing an ACL tear utilizing the femoral guide tool shown in FIG. 1 , the surgical guide pin shown in FIG. 22 , and the cannulated scalpel shown in FIG. 7 in accordance with the present invention.
[0097] FIG. 56 is an enlarged schematic view of a portion of FIG. 55 illustrating a manner of positioning the surgical guide pin shown in FIG. 22 to pass a suture placed in the torn end of the ACL in accordance with the present invention.
[0098] FIG. 57 is an enlarged schematic view of a portion of FIG. 55 illustrating a manner of positioning the surgical guide pin shown in FIG. 22 to pass an additional suture placed in the torn end of the ACL in accordance with the present invention.
[0099] FIG. 58 is a schematic view of a manner of securing the sutures used to repair the ACL tear after using the femoral guide tool shown in FIG. 1 , the surgical guide pin shown in FIG. 22 and the cannulated scalpel shown in FIG. 7 in accordance with the present invention.
[0100] FIG. 59 is a schematic view of a manner of securing an ACL graft in a femoral and tibial epiphysis of a skeletally immature knee without crossing either the femoral or tibial physis utilizing the femoral interference screw-ligament washer shown in FIGS. 38 and 41 and the suspension pin shown in FIGS. 20A and 20B in accordance with the present invention.
[0101] FIG. 60 is a perspective view of a protective sleeve in accordance with the present invention.
[0102] FIG. 61 is a top plan view of the protective sleeve shown in FIG. 60 .
[0103] FIG. 62 is a perspective view of a bullet guide in accordance with the present invention.
[0104] FIG. 63 is a perspective view of a cannulated drill bit in accordance with the present invention.
[0105] FIG. 64 is a schematic view of a manner of placing a guide pin into the ACL footprint of the tibial epiphysis of a skeletally immature knee without crossing the tibial physis utilizing the protective sleeve of FIG. 60 , the bullet guide of FIG. 62 and a guide pin in accordance with the present invention.
[0106] FIG. 65 is a schematic view of a manner of drilling a bone tunnel into the ACL footprint of the tibial epiphysis of a skeletally immature knee without crossing the tibial physis utilizing the protective sleeve of FIG. 60 , a guide pin, and the cannulated drill bit of FIG. 63 in accordance with the present invention.
[0107] FIG. 66 is a schematic view of a manner of inserting a surgical guide pin of FIG. 22 across a bone tunnel in the tibial epiphysis of a skeletally immature knee without crossing the tibial physis utilizing the surgical pin guide of FIG. 21 in accordance with the present invention.
[0108] FIG. 67 is a schematic view of a manner of passing a central loop of flexible wire from an epiphyseal tibial bone tunnel out through a femoral tunnel in accordance with the present invention.
[0109] FIG. 68 is a schematic view of a manner of loading a free soft-tissue graft into a central loop of flexible wire in accordance with the present invention.
[0110] FIG. 69 is a schematic view of a manner of securing an ACL graft in the femoral and tibial epiphysis of a skeletally immature knee without crossing either the femoral or tibial physis utilizing a femoral interference screw-ligament washer of FIG. 38 and 41 and a tibial suspension pin of FIG. 20A and 20B in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0111] The present invention relates to a family of methods, instruments and implants for performing ACL reparative and reconstructive surgery to the knee 1 , including femur 2 and tibia 3 . The present invention utilizes novel techniques and incorporates a novel femoral guide 12 , a cannulated scalpel 40 , novel graft fixation devices 60 , 80 , 81 , 130 , 140 , a novel surgical pin guide 90 and associated instruments 82 , 83 , 110 , 120 , a novel insertional-tensioner tool 151 and associated instruments 165 , 168 , 180 , 175 , 190 , a special protective sleeve 225 , a bullet guide 235 , and a cannulated drill bit 230 .
[0112] Initially, conventional techniques of arthroscopic assisted ACL surgery are performed. After one or more tibial tunnels 6 are created, creation of a femoral tunnel is undertaken by either a traditional two-incision outside-in femoral guide or the novel femoral guide 12 of the present invention (see FIGS. 1 and 2 ).
[0113] The femoral guide 12 can be used to create a single or multiple femoral tunnels 55 (see FIGS. 4 , 5 , and 6 ). The single femoral tunnel technique is performed as follows. With the arthroscope 10 viewing from either the traditional medial infrapatellar arthroscopic portal 4 or the tibial tunnel 6 , a sharp-tipped guide pin 30 is inserted into the knee 1 from another portal, either the previously created tibial tunnel 6 or an accessory medial infrapatellar arthroscopic portal 7 (or similar separate medial percutaneous insertion). The femoral guide 12 is placed through the lateral infrapatellar arthroscopic portal 5 to grasp and direct the guide pin 30 .
[0114] The femoral guide 12 is a handheld instrument with functional end 13 , shaft 14 and scissor-action handle 15 . In one version of this femoral guide 12 , the functional end 13 has an adjustable calibrated reference tip 16 and a guide ring 17 with a mobile opening and closing arm 18 . The adjustable calibrated reference tip 16 can shorten or lengthen to adjust the offset distance 19 between the tip 16 and the center of the guide ring 17 . The offset distance 19 has a range from 2 to 20 mm, preferably 4 to 8 mm. The reference tip 16 may also swivel to allow it to point in different directions relative to the handle 15 and allow proper positioning of the guide 12 for left and right knees 1 with varying anatomy. The reference tip 16 may also extend and retract to allow variable offset distances 19 . A single adjustable femoral guide 12 (as described), or several guides which are non-adjustable with respect to swivel directions or offset distances, can provide all of the necessary options.
[0115] A modified form 12 A of the guide 12 is shown in FIG. 3 . In the guide 12 A, there is a semi-circular guide loop 20 attached to the functional end 13 on the opposite side from which the mobile arm 18 opens and closes. The radius distance 21 from the guide loop 20 to a point spaced apart from the center of the guide ring 17 is equal in all directions and has an adjustable range from 2 to 20 mm, preferably 4 to 8 mm. This version of the femoral guide may or may not have a reference tip 16 . If there is no reference tip 16 , the distal end of the guide loop 20 attaches to the end of the tool. If there is a reference tip, the distal end of the guide loop 20 attaches 1 to 2 mm short of the reference tip 16 such that the radius distance 21 is 1 to 2 mm smaller than the offset distance 19 .
[0116] For both femoral guides 12 and 12 A, the mobile arm 18 is controlled by the scissor-action handle 15 . As the loops of the handle 15 are separated, the mobile arm 18 opens the guide ring 17 . The handle 15 moves in the same plane as the mobile arm 18 and may lie on the opposite side, as shown in FIG. 3 , or on the same side from the mobile arm 18 . The shaft 14 of the femoral guide 12 , or of the guide 12 A, may range from 1 to 50 cm, preferably 10 to 20 cm. The guide ring 17 directs the spinning guide pin 30 into the femoral bone 2 . The guide ring 17 and/or its bearing surfaces may consist of materials designed to resist surface wear, fatigue and fracture.
[0117] After femoral guide 12 is inserted into the knee 1 from the lateral infrapatellar portal 5 , the handle 15 is opened manually to open the mobile arm 18 . Once open, the femoral guide 12 is maneuvered to catch the sharp tip of the guide pin 30 in the guide ring 17 . The handle 15 is then closed to close the mobile arm 18 and capture the guide pin 30 within the guide ring 17 . With the captured guide pin 30 , the femoral guide 12 is positioned with either the reference tip 16 over the back of the lateral femoral condyle 2 or the guide loop 20 overlying the anatomic position of the femoral attachment site of the ACL. The inner diameter of the guide ring 17 corresponds to the outer diameter of the guide pin 30 to allow it to direct the pin 30 , yet allow it to spin freely. With the tip of guide pin 30 anatomically placed in the femoral attachment site of the ACL, the guide pin 30 is advanced with power drill 11 through the femoral guide 12 and femur 2 to exit the skin on the lateral thigh 35 of the patient. The handle 15 is opened manually to open the mobile arm 18 of the femoral guide 12 in order to release guide pin 30 and allow removal of femoral guide 12 from the knee 1 . Alternatively, the guide pin 30 may be inserted just into the femoral bone 2 to create a blind-ended femoral tunnel 55 .
[0118] A cannulated disposable scalpel 40 is passed over the guide pin 30 exposed from the skin on the lateral thigh 35 to create a passage through the skin and soft-tissue to the lateral cortex of the femur 2 (see FIGS. 7 , 8 ). The cannulated scalpel 40 consists of a leading sharp blade 41 and flat handle 42 with a central cannulation 43 to fit over the guide pin 30 .
[0119] A flexible reamer 50 can be passed through the tibial tunnel 6 or accessory medial infrapatellar portal 7 in retrograde fashion over the guide pin 30 to create a femoral tunnel 55 through the bony lateral femoral condoyle 2 , or a rigid reamer 50 can be passed through the proximal lateral incision in antegrade fashion over the guide pin 30 to create the femoral tunnel 55 , through the bony lateral femoral condyle 2 (see FIGS. 9 , 10 and 11 ).
[0120] For the double or multiple femoral tunnel techniques, a conventional outside-in guide or femoral guide 12 can be used as described above to create two or more separate femoral tunnels 55 . Guide pins 30 can be passed through either the accessory anteromedial arthroscopic portal 7 or the tibial bone tunnel 6 or both, and the remaining steps described above can be repeated, to create multiple separate tunnels 55 . After the creation of the first femoral tunnel 55 , the femoral guide 12 can be positioned to reference off previous tunnels to create additional femoral tunnels like tunnel 55 .
[0121] For a bone-patellar tendon-bone graft or other bone-tendon composite grafts, the graft may be passed either retrograde or antegrade into the tunnels 6 and 55 using conventional techniques, and the bone end grafts may be fixed in their femoral tunnels 55 or tibial tunnels 6 with conventional cannulated interference screws,
[0122] For the hamstring graft or other soft-tissue grafts that can be folded to create a looped end, the novel surgical ring fixation tool 60 may be used to fix a graft in a bone tunnel (see FIGS. 12 , 13 , 14 and 15 ). The surgical ring fixation tool 60 consists of a ring 61 and a ring capture button 62 . The ring 61 and the ring capture button 62 are made of durable materials which are either non-absorbable, bio-absorbable, or capable of bio-integration. The ring has width dimensions 65 ranging from 2 to 20 mm, preferable 4 to 12 mm, and length dimensions 66 ranging from 5 to 100 mm. The ring capture button 62 has a base member 72 which has an outer diameter 64 ranging from 5 to 25 mm, preferably 5 to 15 mm and an inner diameter 67 ranging from 2 to 20 mm, preferably 4 to 12 mm. The base member 72 of the ring capture button 62 has two separate surfaces, deep 68 and superficial 69 . The ring capture button 62 also has a central capture bar 63 which allows capture of the ring 61 . The deep surface 68 may possess bone adhesive properties or geometry. The deep surface 68 may also maintain a protruding shape to interface with either the tibial or femoral tunnel 6 or 55 openings. The superficial surface 69 is smooth to prevent overlying soft-tissue adhesion. The central capture bar 63 of the ring capture button 62 moves on a hinge and allows the capture bar 63 to freely swing open and closed on the superficial surface 69 side. The capture bar 63 stops at the base member 72 of the ring capture button 62 and cannot open towards the deep surface 68 . The capture bar 63 stopping mechanism results from limitations on the hinge, mismatch between the capture bar length 70 and the member 72 inner diameter 67 or other stopping or locking mechanism. The geometry or other design features maintain the ring 61 centered in the opening of the base member 72 of the ring capture button 62 .
[0123] For tibial 6 or femoral 55 tunnel graft fixation, the surgical ring fixation tool 60 can be used in accordance with the methods illustrated in FIGS. 16 , 17 , 18 and 19 . The free ends of the soft-tissue grafts 75 are passed through the ring 61 so that equal lengths of soft-tissue grafts 75 protrude from each side of the ring 61 . The ring 61 , with the looped ends of the soft-tissue grafts 75 , is passed either antegrade through the femur 2 and out the tibia 3 , or retrograde through the tibia 3 and out through femur 2 . After ring 61 and the looped ends of the soft-tissue grafts 75 are passed, the ring 61 is assembled with the ring capture button 62 . Once assembled, the free ends of the soft-tissue grafts 75 are tensioned, thus drawing the surgical ring fixation tool 60 into position with its deep surface 68 up against either the tibial 3 or femoral 2 cortical bone surfaces. The outer diameter 64 of the base member 72 of the ring capture button 62 is larger than the tibial or femoral tunnels 6 and 55 , respectively, restricting further advancement of the graft 75 and the surgical ring fixation tool 60 into knee 1 .
[0124] For a hamstring graft or other soft-tissue grafts which can be folded to create a looped end, the suspension pin 80 (or alternatively, the suspension pin 81 ) may be utilized to fix a graft in a bone tunnel (see FIGS. 20A and 20B ). Such fixation is accomplished in the following manner. After creating the tibial tunnel 6 and the femoral tunnel 55 , the surgical pin guide 90 is used to prepare for insertion of the suspension pin 80 ( or, alternatively, of pin 81 ). The surgical pin guide 90 may be used on both the femur 2 and the tibia 3 .
[0125] The guide 90 consists of three components, a target arm 91 , a curved guide arm 100 and a bullet 105 . The diameter of the target arm 91 may vary from 2 mm to 25 mm, preferably from 5 to 15 mm. Targeting tips 92 may be of various sizes. The tip 92 has an open target slot 94 at the target end ranging in depth from 0 to 100 mm, preferably 40 mm. Targeting tip 92 of the target arm 91 optionally has a small hook 93 protruding from its end. The small hook 93 protrudes up to 5 mm, but preferably about 2 mm. The small hook 93 may incorporate a mechanism to make the hook retractable.
[0126] The targeting tip 92 of target arm 91 may also include a groove 95 which allows for attachment of an elastic ring or open horseshoe-shaped ring 96 which can be attached at the site of the groove 95 to close the open end of target slot 94 .
[0127] Target arm 91 may possess a mechanism to open or close the open end of the target slot 94 , and it may also be calibrated to reference either direction along the target arm 91 from target point 97 in the target slot 94 . Target point 97 is a consistent point in space along the target slot 94 to which a surgical guide pin 110 will be directed by the completely assembled surgical pin guide 90 . Target point 97 is located a short distance from the end of the target tip 92 of the target arm 91 in the target slot 94 . That distance may range from 0 to 100 mm, preferably 10 to 25 mm.
[0128] There is a target marker 98 on the surface of target tip 92 , marking the level of the target point 97 . The marker 98 may be radiographic, such as linear radio-opaque mark or a radiolucent hole, notch, or defect, which can be identified with conventional intraoperative radiographic techniques.
[0129] The surgical pin guide 90 also includes a curved guide arm 100 and aiming bullet 105 . The curved guide arm 100 incorporates an aiming end 104 which allows for the attachment of an aiming bullet 105 and a separate mobile target arm attachment site 101 . The mobile arm attachment site 101 moves freely along the curved arm guide 100 and its position can be secured by a locking mechanism 102 . The curved arm guide 100 is calibrated with degrees to measure the angle between the aiming end 104 and the mobile target arm attachment site 101 . With the target arm 91 attached to the mobile target arm attachment site 101 of the curved guide arm 100 and the aiming bullet 105 attached to the aiming end 104 of the curved guide arm 100 , the surgical pin guide 90 is assembled. Thereafter, a surgical guide pin 110 may be passed through cannulation 106 in the aiming bullet 105 , and the tip of the surgical guide pin 110 directed to the target point 97 located in the target slot 94 of the target guide 91 .
[0130] After creating the tibial and femoral tunnels 6 and 55 , the target arm 91 of the assembled surgical pin guide 90 is placed into a bone tunnel, preferably either the tibial tunnel 6 or the femoral tunnel 55 . The target arm 91 can be placed in the bone tunnel in either an antegrade fashion (inside-out on the tibia 3 , outside-in on the femur 2 ) or a retrograde fashion (outside-in on the tibia 3 , inside-out on the femur 2 ). If the tunnels are co-linear, the target arm may traverse either the tibial tunnel 6 or the femoral tunnel 55 to be placed in the opposite tunnel, either 6 or 55 . Conventional intraoperative radiographic techniques can assist with proper placement of the target arm 91 in the tunnels 6 and 55 by identifying the radiographic marker 98 overlying the target point 97 . The mobile target arm attachment site 101 allows movement and proper positioning of the aiming end 104 of the curved guide arm 100 relative to either femur 2 or tibia 3 to provide a safe trajectory for the surgical guide pin 110 . Once in proper position, a small incision is made in the skin and soft tissue in-line with the cannulation 106 of the aiming bullet 105 . The aiming bullet 105 within its connection 104 to the curved guide arm 100 is advanced down the bony surface of either femur 2 or tibia 3 .
[0131] Using power drill 11 , the surgical guide pin 110 is advanced through the cannulation 106 in the aiming bullet 105 through the skin 35 , soft tissue, and bone of the femur 2 or tibia 3 until both ends of the surgical guide pin 110 extend outside the knee 1 and its bone, soft-tissue, and skin (see FIGS. 23A , 23 B, 24 A, and 66 ). The surgical guide pin 110 possesses cannulations or slots 111 , preferably two or more, and a sharp leading tip (see FIG. 22 ). The slots 111 preferably are positioned near the opposite ends of the surgical guide pin 110 .
[0132] The surgical guide pin 110 may possess a region of slightly increased diameter with a cutting surface 113 , preferably near its leading tip 112 but situated between the cannulations or slots, 111 . As this region 113 is passed completely through the bone, it cuts a slightly larger diameter than the diameter of the other portions of the surgical guide pin 110 to assist with the passage of flexible wire 120 to be described later. Cannulated drills, reamers and/or taps may be passed over either end of the surgical guide pin 110 and used to prepare either the femoral 2 or tibial 3 bone for later passage of the novel suspension pin 80 or 81 . These drills, reamers, and/or taps may be calibrated to assist in determining the size of the suspension pin 80 or 81 to be used. The surgical guide pin 110 may also be calibrated to assist in determining the size of the suspension pin, referencing from the aiming bullet 105 against the femoral or tibial bones 2 and 3 . Surgical pin guide 90 can be removed from knee 1 .
[0133] Flexible guide wire 120 is exchanged, using surgical guide pin 110 , by connecting an end of the wire to one of the exposed ends of the guide pin 110 and withdrawing guide pin 110 by its other exposed end to pull flexible wire 120 into position (see FIGS. 24B , 24 C, 24 D and 24 E). The guide pin 110 has cannulations or slots 111 running perpendicular to the long axis of the pin near either of both of its ends. One method of making the flexible wire exchange using the guide pin 110 is to pass the guide pin 110 as previously described and advance a few centimeters of the flexible wire 120 through either of the exposed slots 111 . The guide pin 110 is then withdrawn by its opposite end, pulling flexible wire 120 into its previous position.
[0134] Using wire passing tool 125 , a central loop of the flexible guide wire 120 can be drawn outside of knee 1 through either of the femoral or tibial tunnels 55 or 6 which is opposite to the tunnel which wire 120 initially traversed as shown in FIGS. 25A , 25 B, 25 C, 26 , 29 , 33 , 34 and 67 . The wire passing tool 125 consists of a long thin shaft 128 and a handle with a scissor-like mechanism 127 which controls the opening and closing of the claw-like wire-grasping tip 126 . Alternatively, an elastic ring or open horseshoe-shaped ring 96 can be attached to close the open end of the target slot 94 of surgical pin guide 90 . Using the closed end, the exchanged flexible wire 120 is drawn out of the tunnel with the target arm 91 of the surgical pin guide 90 to help facilitate the passage of the flexible wire 120 . Free ends of soft-tissue grafts 75 are passed through the exposed central loop of flexible wire 120 so that equal lengths of soft tissue grafts 75 protrude from each side of the loop, as illustrated in FIGS. 27 , 30 , 35 and 68 . Then, the free ends of flexible wire 120 outside of knee 1 are pulled to straighten flexible wire 120 and reduce the central loop of the soft-tissue grafts 75 through one of the tunnels 6 or 55 and into the opposite tunnel 6 or 55 , as illustrated in FIGS. 28 , 31 and 36 .
[0135] If there are two or more tunnels on the opposite side of the knee from the tunnel traversed by the flexible wire 120 , the steps described above can be repeated by individually passing the same central loop of wire 120 out of the remaining empty tunnel, loading another graft 75 A, and re-straightening wire 120 to reduce the additional loop of soft-tissue graft through the additional tunnel into the initial tunnel traversed by the flexible wire 120 , as illustrated in FIGS. 29 , 30 and 31 .
[0136] With flexible wire 120 straight and the soft-tissue graft 75 in position within both the femoral tunnel 55 and the tibial tunnel 6 , novel suspension pin 80 , or alternatively, novel suspension pin 81 , is inserted, using the suspension pin insertion tool 83 , into either femur 2 or tibia 3 , replacing the position of the flexible wire 120 , traversing either the femoral tunnel 55 or the tibial tunnel 6 , and securing the loop end of soft-tissue graft 75 , as illustrated in FIGS. 20A , 20 B, 31 , 32 A, 36 , 37 A, 69 .
[0137] There are two versions, 80 and 81 , of the novel suspension pin which are shown in FIGS. 20A and 20B , respectively. The pin 80 is a cannulated pin not yet assembled on the flexible guide wire 120 , and the pin 81 is already assembled as a unit on wire 120 . The cannulated suspension pin 80 has a central longitudinal cannulation 79 which allows the pin to be engaged on the wire, and, thus mounted, inserted within either the femur 2 or the tibia 3 and across either the femoral tunnel 55 or the tibial tunnel 6 to secure the looped end of the soft-tissue graft 75 in position. Pin 81 is already assembled with the flexible wire 120 component, either freely moving over it by a cannulation 79 or fixed in place upon the wire 120 at a site or assembled with two separate flexible wire 120 components, one attached each end of the pin's body component.
[0138] Pin 80 and pin 81 's body component are longitudinal pins of mostly uniform diameter corresponding to that of the widest diameter of the surgical guide pin 110 . Alternatively, the diameter of the pins may vary and the outer surfaces may possess different geometry and bone adhesive properties (such as threads of a screw) to assist with fixation in the bone. The length of pin 80 , and of the body component of pin 81 , may vary, ranging up to 200 mm, but preferably from 40 mm to 100 mm. The pins are made of durable materials which are either non-absorbable, bio-absorbable, or capable of bio-integration. Pin 80 and pin 81 's body component each possess a pointed end 89 and a rear end 87 . The rear end 87 has specialized geometry which interfaces with inverse geometry on tip 86 of the suspension pin insertion tool 83 .
[0139] Insertion tool 83 includes a handle 85 , a shaft 84 ; and an insertion tip 86 which incorporate a cannulation 77 , as shown in FIG. 20C . The cannulation 77 allows the tool 83 to be placed on the flexible wire 120 to guide the insertion of a suspension pin such as pin 80 or its alternate, pin 81 . The handle 85 allows a surgeon to provide manual insertion forces with his hands or with an instrument such as a mallet. The tip 86 includes specialized geometry which interfaces with an inversely geometrical surface on the rear end 87 of suspension pin 80 or its alternate, pin 81 to prevent tip 86 from disengaging from rear end 87 during the pin insertion process.
[0140] Flexible wire 120 and the flexible wire 120 components of pin 81 preferably are made of durable materials which are non-absorbable, bio-absorbable, or capable of bio-integration, but they may also be made of materials which are similar to other commercially available surgical wires or sutures.
[0141] After the suspension pin 80 (or its alternate, pin 81 ) is secured in either femur 2 or tibia 3 , the flexible wire 120 is removed from the cannulation 79 . When a wire 120 component is fixed to a suspension pin 81 , a wire cutter 82 with cannulation 78 is placed on the flexible wire 120 and inserted through skin 35 and soft-tissue to the bone surface of either femur 2 or tibia 3 , as illustrated in FIGS. 20D , 32 B, 32 C and 37 B. Handle 15 of the cutter 82 is closed, causing the sharp jaw 88 of the cutter to close completely and sever the wire 120 flush with the bone surface.
[0142] The free ends of soft-tissue grafts 75 and 75 A are fixed in a bone tunnel using a novel interference screw-ligament washer which may be a modular form 130 or a non-modular form 140 . The modular form is shown in FIGS. 38 , 39 and 40 , while the non-modular form is shown in FIG. 41 . The interference screw-ligament washer is made of durable materials which are non-absorbable, bio-absorbable, or capable of bio-integration.
[0143] The modular interference screw-ligament washer 130 includes a cannulated interference screw component 131 , a separate cannulated screw component 135 , and a mobile ligament washer component 138 , shown in FIGS. 38 , 39 and 40 . The sizes of the cannulated interference screw component 131 may vary, with length ranging up to 100 mm, but preferably 20 mm to 30 mm, and having an outer diameter up to 25 mm, preferably 4 mm to 15 mm. The component 131 also incorporates a central longitudinal cannulation 144 to allow it to be inserted over a guide wire 190 . The outer surface 132 of the cannulated interference screw component 131 is threaded for purchase in both the walls of the bone tunnel and in the adjacent soft-tissue graft. The rear end 134 of the cannulated interference screw component 131 may be flat, tapered or oblique. In addition to its cannulation 144 for guide wire 190 , the cannulated interference screw component 131 additionally includes a longitudinal female socket 133 having a hexagonal, star, diamond or other complementary cross sectional geometry to accept a male connector on the tip 181 of a cannulated screw driver 180 ( FIG. 46 ).
[0144] The separate cannulated screw component 135 includes a partially threaded end 136 and a head 137 , as shown in FIGS. 38 and 40 . The screw component 135 has a central longitudinal cannulation 141 to allow it to be inserted over guide wire 190 . The partially threaded end 136 has a diameter and length which corresponds to that of the female socket 133 of the interference screw component 131 in order to allow the separate cannulated screw component 135 to seat all the way to the depth of its head 137 and gain purchase. The head 137 is low-profile with the female socket 129 , and the size and geometry of head 137 is sufficiently different from cannulation 145 in mobile ligament washer component 138 to allow head 137 to capture washer component 138 .
[0145] The mobile ligament washer component 138 can be of variable geometry but is relatively flat in one dimension in order to allow it to be low profile when seated, as shown in FIGS. 38 , 40 and 41 . This washer's width, or diameter, ranges up to 25 mm, and is preferably between 5 mm and 15 mm. Other cannulations 146 may be formed in mobile ligament washer 138 which provide additional means for fixing an ACL graft with sutures passed through these cannulations and secured or tied.
[0146] The central cannulation 145 in the mobile ligament washer component 138 possesses sufficient size and geometry to allow it to tilt up to 90 degrees relative to the long axis of the cannulated screw component 136 , preferably between zero and 60 degrees. The undersurface 139 of the ligament washer component 138 is an irregular surface, formed with spikes or other soft-tissue adhesive features, and it may possess other protruding surface geometry to assist in centering the washer 138 over the entrance to either of the femoral tunnels 55 or the tibial tunnels 6 . The central cannulation 75 in the washer component 138 may be surrounded by a recessed portion in the washer 138 which accepts the head 137 of the separate cannulated screw component 135 .
[0147] After a soft-tissue graft 75 is positioned in a bone tunnel, preferably with its free ends extending beyond the outside end of the tunnel, the modular form 130 of the interference screw-ligament washer is inserted. First, the cannulated interference screw component 131 is advanced over a guide wire 190 to a position adjacent to the soft-tissue graft 75 in the bone tunnel using a proper screw driver 180 , as in FIGS. 50 and 51 . Once the rear end 134 of the interference screw component 131 is advanced to the level of the opening of the bone tunnel or just below it, another cannulated screw driver is used to advance the separate cannulated screw component 135 with the mobile ligament washer component 138 into female socket 133 of the interference screw component 131 until the irregular undersurface 139 of the ligament washer component 138 firmly compresses the protruding ends of the soft-tissue graft 75 up against the cortical surface of the bone surrounding the tunnel opening (see FIGS. 52 , 53 , 59 and 69 ). Sutures 200 are placed in the protruding ends of the soft-tissue grafts 75 to provide manual tension while the interference screw-ligament washer device 130 is inserted.
[0148] The non-modular form of the interference screw-ligament washer is a single unit made of a single or composite material (see FIG. 41 ). The features of the non-modular form are identical to the modular form 130 , including a threaded outer surface on the interference screw portion 132 , a flat, tapered or oblique rear-end 134 , a mobile ligament washer component 138 , and a head 142 with sufficient size and geometry to capture the ligament washer component 138 . The non-modular form of the interference screw-ligament washer 140 is a single preassembled or manufactured unit which can be inserted into a bone tunnel in a single step until the irregular undersurface 139 of the ligament washer component 138 firmly compresses the protruding ends of the soft-tissue graft 75 up against the cortical surface of the bone surrounding the tunnel opening, as illustrated in FIGS. 54 , 59 and 69 . Non-modular form 140 also maintains a longitudinal female socket 143 of specified cross-sectional geometry (hexagonal, star, diamond, or the like) to accept a male connection on the tip 181 of cannulated screw driver 180 . The female socket 143 extends just into head 142 , although it may extend all of the way through the head into the interference screw portion 132 of the non-modular form 140 of interference screw-ligament washer. Also, there is a longitudinal cannulation 144 in the non-modular form 140 which allows the non-modular form to be inserted over guide wire 190 .
[0149] If the free ends of soft-tissue graft 75 are not long enough to exit the bone tunnel, sutures 200 placed in the ends of graft 75 may be passed through small cannulations 146 in the ligament washer component 138 before insertion and then tied after either the modular form 130 or the non-modular form 140 of the interference screw-ligament washer is inserted into the tunnel adjacent to graft 75 .
[0150] The modular and non-modular forms 130 and 140 of the interference screw-ligament washer may also be used on a bony free end of a graft 75 . The sutures 200 attached to the bone plug may be passed through small cannulations 146 in the ligament washer component 138 before insertion and tied after either the modular form 130 or the non-modular form 140 of the interference screw-ligament washer is inserted in the bone tunnel adjacent to the bone end of the graft.
[0151] The interference screw component 131 of modular interference screw-ligament washer 130 may also be used alone to fix either a bony or a soft-tissue end of graft 75 .
[0152] Either of the modular or non-modular forms of the interference screw-ligament washer, 130 or 140 , may be inserted using an insertion-tensioner tool 151 and the components 165 , 168 , 175 , 180 shown in FIGS. 48 , 49 , 50 , 51 , 52 , 53 and 54 . The insertion-tensioner 151 assists with graft tensioning and with the insertion of fixation devices to secure free ends of graft 75 in a bone tunnel (see FIGS. 42 and 43 ). These devices include a trocar component 168 , a graft loader component 165 , a cutter component 175 and a cannulated screw driver 180 (see FIGS. 44 , 45 , 46 and 47 ).
[0153] The insertion-tensioner 151 includes two hollow tubes 157 and 159 which have coordinating inner and outer diameters to allow tube 159 to telescope into tube 157 , as shown in FIGS. 42 and 43 . The inner diameter of tube 159 may be up to 50 mm, but preferably 15 mm to 25 mm. There is a unidirectional stopping mechanism which prevents tube 159 from exiting tube 157 whenever tube 159 is moved through tube 157 toward tube 159 's end 152 . There is a separate locking mechanism 156 which may be engaged or released by a lever 160 attached to tube 157 , including teeth or other surface-engaging geometry 161 on the lever which interface with opposing surface 162 on tube 159 . The tubes 157 and 159 move freely when lever 160 is not engaged, but when it is engaged, the tubes may be moved freely in one direction and prevented from moving in the opposite direction. Preferably, that restriction prevents tube 157 from moving along tube 159 towards the end 152 of tube 159 . A spring (not shown) may be used to keep lever 160 in place when it is not manipulated by a surgeon.
[0154] Handles 154 and 155 may be used by a surgeon to grasp and manipulate tubes 157 and 159 relative to each other. Tube 159 may include indicia to help calibrate movement between the tubes. Tube end 152 may be beveled or flat. There are multiple cannulations 153 in tube 159 , preferably four, through which the ends of soft-tissue graft 75 may pass. At the end of tube 157 , an arrangement of cleats 158 , or similar graft engaging elements, allow the temporary fixation of sutures 200 attached to grafts 75 . Handle 155 may be attached firmly to tube 157 , or it may be spring-biased by attaching it in series to tube 157 and the cleat arrangement 158 by means of a calibrated spring mechanism 163 in order to measure the tension of the tube engagement.
[0155] The trocar 168 (see FIG. 44 ) preferably is a long rod with an outer diameter sufficiently corresponding to the inner diameter of tube 159 to allow trocar 168 to just fit within the tube. However, the trocar may be formed as a tube, or have a central longitudinal cannulation 171 . The length of trocar 168 , excluding its stop end 170 and its leading tapered end 169 is equal to the combined length of tubes 157 and 159 when they are telescoped at their shortest starting position. The stop end 170 of the trocar 168 has a diameter greater than the diameter of tube 157 , thus limiting the depth to which trocar 168 may be inserted into the insertion-tensioner. 151 . When trocar 168 is inserted to its full depth, its tapered end 169 protrudes from end 152 of tube 159 to facilitate penetration of the insertion-tensioner down through the skin and soft-tissue of knee 1 to femur 2 or tibia 3 . Slots 173 are formed in the tapered end 169 of trocar 168 which extend beyond the inclination of the taper, allowing free ends of the soft-tissue graft 75 to run freely along the slots 173 and into the end 152 of tube 159 and on out through cannulations 153 in tube 159 .
[0156] The cutter 175 (see FIG. 47 ) is a hollow tube with a stop end 177 and a sharp cutting end 176 . Cutter 175 has an outer diameter corresponding to the inner diameter of tube 159 . The length of cutter 175 , excluding its stop end 177 , is such that when the cutter 175 is inserted into the insertion-tensioner 151 to the full depth with the telescoping tubes 157 and 159 extended to their longest finishing tensioned position, the sharp cutting end 176 extends just beyond cannulations 153 in the end 152 of tube 159 . Sharp cutting end 176 is inwardly beveled. The outer edge of the cutting end 176 is straight in order to maintain a constant outer diameter. The inner edge is beveled inwardly from the outer edge to the inner surface of the tube to create a sharp-ended cutting tube.
[0157] The graft loader 165 , a long stiff but flexible wire 168 with a loop end 166 and an optional handle 167 , is shown in FIG. 45 . The loop end is flexible and has a loop with sufficient diameter to carry a suture or the free ends of graft 75 .
[0158] The cannulated screw driver 180 includes a tip 181 , a calibrated shaft 182 , and a handle 183 which has an optional stop 184 (see FIG. 46 ). The tip 181 is formed with a specific geometrical cross section, such as a hexagon, star, diamond or the like, to fit with like connections in the interference screw-ligament washers 130 or 140 or other fixation devices. Calibrated shaft 182 , excluding its handle 183 , the stop 184 and the tip 181 , is at least as long as the combined length of telescopically connected tubes 157 and 159 extended to their longest finishing tensioned position.
[0159] The above-described components are used with the insertion-tensioner 151 in the following manner.
[0160] With the free ends of a soft-tissue graft 75 fixed at their opposite ends and protruding from a bony tunnel, each free end is individually placed through the loop end 166 of the graft loader 165 where it was previously positioned, i.e., extending through one of the cannulations 153 and exiting out of end 152 of tube 159 of the insertion-tensioner 151 (see FIG. 48 ). It is preferable that the graft ends have been prepared with sutures 200 prior to loading to help facilitate graft passing and tensioning later.
[0161] With all of the free ends of the soft-tissue graft 75 or their sutures 200 passed into the end 152 and out of their own cannulation 153 of tube 159 , trocar 168 is inserted into the insertion-tensioner 151 while its tubes 157 and 159 are telescoped to their shortest length, as shown in FIG. 49 . While holding the free ends of the graft 75 or their attached sutures 200 under tension in one hand, the surgeon inserts the insertion-tensioner 151 with trocar 168 through the skin and soft-tissues down to the bone at the opening of a bone tunnel, preferably that of femur 2 or tibia 3 . The insertion-tensioner 151 with the cannulated trocar 168 may also be inserted over a guide wire 190 previously placed in bone tunnels 6 or 55 . The longitudinal cannulation 171 in trocar 168 accepts the guide wire 190 to properly direct the insertion-tensioner 151 through the skin and soft-tissue down to the opening of a bone tunnel. Once down to bone, trocar 168 is removed. The free graft ends of graft 75 or their attached sutures 200 are tensioned and secured to the cleats 158 on the insertion-tensioner 151 . With one hand on handle 154 to stabilize tube 159 and hold the tube end 152 on the bone tunnel opening, the surgeon distracts on handle 155 of tube 157 with the other hand to the desired tension and activates lever 160 to engage the locking mechanism 156 , thus holding the graft ends of graft 75 at a desired tension.
[0162] Maintaining the position of the insertion-tensioner 151 with a hand on handle 154 and tube 159 , the surgeon inserts either the modular form 130 or the non-modular form 140 interference screw-ligament washer, as described above, over the guide wire 190 , fixing the graft ends of graft 75 in a bone tunnel, preferably that of femur 2 or of tibia 3 (see FIGS. 50 , 51 , 52 , 53 , 54 , 59 and 69 ).
[0163] The surgeon may also elect to insert another ACL fixation device by another method utilizing the insertion-tensioner 151 .
[0164] After the ACL fixation device is placed and the free graft ends of graft 75 are secured, cutter 175 is inserted into the exposed end of the insertion-tensioner 151 and advanced until the free ends of graft 75 or their attached sutures are cut, as in FIG. 53 .
[0165] Different combinations of fixation devices may be utilized when multiple bone tunnels are formed in either or both of femur 2 and tibia 3 as long as a cross pin device such as a suspension pin 80 or 81 or a surgical ring fixation tool 60 is used on the looped ends of the graft 75 and either the modular form 130 or non-modular form 140 of the interference screw-ligament washer are used on the free soft-tissue or bony ends of graft 75 .
[0166] Primary repair of an ACL stump 215 torn off the femur 2 may also be performed using femoral guide 12 , as seen in FIGS. 55 , 56 , 57 and 58 . After sutures 200 are passed through stump 215 , arthroscope 10 is positioned in a conventional medial infrapatellar arthroscopic portal 4 , and a conventional arthroscopic cannula 210 is positioned in an accessory medial infrapatellar arthroscopic portal 7 . The sutures 200 attached to ACL stump 215 are retrieved out of knee 1 through cannula 210 . Then a surgical guide pin 220 is introduced into knee 1 through the same arthroscopic cannula 210 , and femoral guide 12 is placed through the lateral infrapatellar arthroscopic portal 5 to grasp and direct the leading end of surgical guide pin 220 as it is drilled through femur, skin and soft-tissue with a power drill such as drill 11 . With both ends of the surgical guide pin 220 exposed from knee 1 , one limb of sutures 200 attached to ACL stump 215 is loaded through slot 221 at the back end of a surgical guide pin 220 . A cannulated scalpel, such as scalpel 40 , is then passed over the exposed leading end of guide pin 220 to create a passage through the skin and soft-tissue to the lateral bony cortex of a femur 2 . The guide pin 220 is then advanced out of knee 1 to shuttle a suture limb through the femur and out through the passageway created by the cannulated scalpel 40 . The steps just described are repeated until all of the limbs of suture 200 attached to the ACL stump are passed. The passed sutures 200 are tensioned and secured over either a conventional cannulated button or the natural cortical bony bridges remaining between each of the sutures 200 on the lateral aspect of the femur 2 , as shown in FIG. 58 .
[0167] For skeletally immature patients with open femoral and tibial growth plates such as plate 222 , nominally referred to as physes, the epiphyseal tunnel and graft fixation procedure holds substantial benefit by avoiding injury to the growth plate 222 . Using intraoperative radiographic assistance, all-epiphyseal femoral tunnels, like tunnel 55 , can be created using a conventional outside-in femoral guide or the novel femoral guide 12 , as described above, and transphyseal tibial tunnels, like tibial tunnel 6 , can be created with conventional tibial guides (see FIG. 59 ). For epiphyseal femoral 2 graft fixation, modular form 130 and non-modular form 140 interference screw-ligament washers may be inserted into the femoral epiphysis 2 E using the methods and instruments described above (see FIG. 59 ). For tibial epiphyseal graft fixation in a transphyseal tunnel, the suspension pin 80 or its alternative 81 may be inserted into the tibial epiphysis 3 E using the methods and instruments described above (see FIG. 59 ).
[0168] However, an alternative and novel method of antegrade epiphyseal tunnel creation and graft fixation will now be described. To perform this procedure, the surgeon needs a specially designed protective sleeve 225 , a cannulated bullet guide 235 , and a specially designed cannulated drill bit 230 , as shown in FIGS. 60 , 61 , 62 and 63 .
[0169] The protective sleeve 225 is a hollow tube with a beveled tip 227 and a handle 226 . Preferably, the handle points 90 degrees counterclockwise from the longest side of the beveled tip 227 as viewed looking down the longitudinal axis of the sleeve from the handle side. The inner diameter of the sleeve ranges up to 20 mm, preferably between 4 mm and 12 mm.
[0170] Cannulated bullet guide 235 and cannulated drill bit 230 have outer diameters that correspond to the inner diameter of protective sleeve 225 which permits bullet guide 235 and cannulated drill bit 230 to just fit but move freely within sleeve 225 . Bullet guide 235 has a central longitudinal cannulation 238 , a tapered end 236 and an end with a stop 237 which abuts the handle end of the protective sleeve 225 when inserted. The length of the bullet guide, excluding the tapered end 236 and stop 237 equals the length of the protective sleeve 225 . Cannulated drill bit 230 is partially threaded at its cutting end 232 and smooth, with depth marks 231 which reference off the handle end of sleeve 225 . The cannulated drill bit possesses a longitudinal cannulation 233 which allows the drill bit 230 to be run over a guide pin.
[0171] With the arthroscope in the conventional lateral infrapatellar arthroscopic portal 5 , the alternative method of tunnel creation and graft fixation referred to above is performed by inserting the protective sleeve 225 with the cannulated bullet guide 235 into a high medial infrapatellar portal 240 down onto the ACL footprint on tibial bone 3 (see FIG. 64 ). Using intraoperative fluoroscopic techniques, a guide pin 30 is inserted through the cannulation 238 in the bullet guide 235 and advanced into the tibia 3 to a depth just short of the level of the tibial physis 222 . The depth of the guide pin 30 is measured from the calibrations on pin 30 referenced from the stop end of bullet guide 235 . The bullet guide 235 is removed from the protective sleeve 225 and cannulated drill bit 230 is advanced over the guide pin 30 to a depth just short of the depth of guide pin 30 as shown in FIG. 65 . Cannulated drill bit 230 is calibrated and references off the handle end of protective sleeve 225 . Target arm 91 of surgical pin guide 90 is inserted through the high medial infrapatellar portal 240 to the depth of the blind-ended tibial tunnel 6 (see FIG. 66 ). The radiographic marker 98 on the surface of target tip 92 marking the level of the target point 97 can be identified using intraoperative radiographic assistance in order to confirm proper positioning of the guide 90 . The remaining steps are performed as described above to place a suspension pin, such as pin 80 or pin 81 , in the tibial epiphysis 3 E of tibia 3 and an interference screw-ligament washer, such as washer 130 or washer 140 , in femoral epiphysis 2 E of femur 2 (see FIGS. 67 , 68 and 69 ).
[0172] However, passage of the flexible wire 120 with wire passing tool 125 is done with a slight variation because of the blind-ended tibial tunnel 6 (see FIG. 67 ). First, the wire passing tool 125 is inserted through the high medial infrapatellar portal 240 to grasp the central loop of the flexible wire 120 in the tibial tunnel 6 and pass it to a second wire passing tool 125 A which was inserted through femoral tunnel 55 . The second wire passing tool 125 A withdraws the central loop of flexible wire 120 outside the knee through femoral tunnel 55 .
[0173] From all of the foregoing it will be evident that, although particular forms have been illustrated and described, nevertheless various modifications can be made without departing from the true spirit and scope of the invention. Accordingly, no limitations are intended by the foregoing description and the accompanying drawings, and the true spirit and scope of the invention are intended to be covered by the following claims. | A system is disclosed for repairing and reconstructing an injured anterior cruciate ligament (ACL); This system may be used irrespective of the type of patient or the ACL graft selected. Means for performing single or multiple bundle reconstruction, primary ACL repair and physeal-sparing ACL reconstruction are disclosed. A guide for inside-out creation of a femoral tunnel independent of the tibial tunnel is also disclosed, as well as a series of implant options for tibial and femoral fixation of any bone-soft-tissue composite or soft-tissue-only graft. | 0 |
BACKGROUND OF THE INVENTION
The invention relates to a winding device for safety belts in vehicles, with a high-speed turning device driven by pyrotechnical gases and interacting with an extraction force limiting device, and with a belt rolling device which is equipped with a pawl device which responds with an inertia pendulum and which is connectable to the high-speed turning device by the aid of the propellant gases.
Owing to the limit space available in motor vehicles and aircraft, attempts are made to ensure that the size of pyrotechnically driven winding devices of the kind will be slightly larger, if at all, than automatic mechanical belt rolling devices. A further problem is that of ensuring that the parts exposed to the power gases will be gastight and that the friction which is generated will nevertheless be very slight. This property is required if satisfactory efficiency is to be obtained with a moderate charge of propellant.
From the prior art a winding device for tightening aircraft and motor vehicle passenger safety belts is already known, in which the winding roller for the belt consists of a rotary piston designed as a belt roller and subjected to propellant gases. In this winding device the rotary piston, provided with a vane, can only be rotated by about 310°, which in general does not suffice to render it sufficiently taut.
The purpose of the invention is to provide a compactly constructed winding device for safety belts wherein the drawbacks of known devices will be avoided, and particularly one which will ensure that the winding roller can be turned through a sufficient angle for the required belt tension.
SUMMARY OF THE INVENTION
Briefly, the present invention may be defined as a winding assembly for a vehicle safety belt system which comprises a belt rolling device having a safety belt arranged in winding engagement therewith, a high speed turning device adapted to be driven by pyrotechnical gases, means for generating the pyrotechnical gases to drive the turning device when the vehicle is decelerated at a given rate, and interconnecting means for connecting the high speed turning device with the belt rolling device to effect winding therein of the safety belt when the pyrotechnical gases are generated. More specifically, the invention is directed to the structure of the high speed turning device which comprises a rotatably mounted shaft, means defining a pair of annular chambers about the shaft, a pair of vanes affixed to the shaft, said vanes extending radially from the shaft, one into one of said annular chambers and the other into the other of said annular chambers, a first fixed blade extending into one of the annular chambers and arranged to engage one of the vanes to stop rotation thereof, a second blade extending into the other of the annular chambers and arranged to be engaged by the other of the vanes, said second blade being mounted in operative relationship with the interconnecting means to impart driving rotation of the shaft therethrough, and means for introducing the generated pyrotechnical gases into the annular chambers to effect rotation of the shaft, with the blades and the vanes being arranged to permit rotation of the shaft by the propellant force of the pyrotechnical gases against the vanes and thereby to effect winding of the safety belt until said one vane engages said first fixed blade whereupon the rotating action is stopped.
In the application of the invention, a two-sided pin is provided which is connected with a shaft. On the pin there is rotatably mounted one end of the rear cover of a high-speed turning device and on the other end of the pin a side disc of the belt rolling device is rotatably mounted. The side disc has the form of a ratchet wheel having a number of borings distributed over its periphery.
In a further development of the invention, a bolt which is inserted in the rear annular chamber, preferably in the upper edge of the rear cover, can be actuated by the propellant gases and is insertable into one of the borings of the side disc of the belt rolling device.
The invention also includes a pendulum which responds to inertia and which is connected with a small pawl which, upon deflection of the pendulum, can be raised by means of a rocker, thus engaging within a gap between the teeth of the ratchet wheel, in which process it raises a main pawl and causes it to drop into the gap without undue impact.
The invention enables an automatic mechanical belt rolling device of the usual kind to be combined with a pyrotechnically operated belt tightening device within a minimum of space, with this object being considerably facilitated by the fact that the solid propellant charge is accommodated in the hollow shaft of the high-speed turning device.
Despite the compact construction, the high-speed turning device contains two annular chambers with rotary pistons which, by means of their vanes, subjected to the propellant gases, enable the belt drum to perform almost two complete rotations. This compact construction is further facilitated by the fact that the belt rolling device and the shaft of the high-speed turning device are mounted on one common pin with only a small gap between them. This enables the two assemblies to be rapidly interconnected by means of the bolt subjected to the propellant gases.
The principle is already known of providing winding devices for belts with a pawl which locks the belt drum when the vehicle decelerates, e.g. owing to the application of the brakes. According to the prior art, a device is known wherein a pawl is lifted, by a pendulum responding to inertia, into one of the teeth of the ratchet wheel. This direct insertion of the pawl into the sharp teeth of the ratchet wheel places an excessive strain on both parts. The provision of a small pawl as a preliminary pawl engaging the tooth gap before the main pawl does so, in accordance with the invention, ensures more gentle engagement of the main pawl, thus considerably lengthening the life of the entire pawl system. Furthermore, the main pawl can be constructed with a rounded front edge and also with a rounded part corresponding to the base of the teeth, providing an improved seating and enabling greater forces to be transmitted.
According to a further characteristic of the invention, a first annular gap between the housing and the outer casing contains a toothed rack which can rotate freely in a widened portion, when the high-speed turning device is caused to rotate by the propellant gases, whereas when the high-speed turning device rotates in the reverse direction the rack rolls between the housing and the casing with dissipation of energy.
In order to ensure, after a vehicle has made impact and the belt become taut as a result, that its wearers will be caught up in as comfortable a manner as possible, the kinetic energy acting on the occupants as a result of the forward acceleration is converted in a simple manner into deformation energy by the toothed rack provided between the internal wall of the housing and the cylindrical casing. This force limiting device according to the invention thus provides for the force of a traject limited to approximately two rotations and therefore necessitates hardly any of the additional space required for constructions already known.
In a further development of the invention, a backed-off attachment is provided on the outer periphery of the rear cover of the high-speed turning device, so that the cover forms, between the side disc acting as a ratchet wheel and the housing, a second annular gap into which is inserted a wedge, which latter is provided with an elastic tongue and on a rotation of the high-speed turning device due to the propellant gases, is caused to accompany this movement until it presses against a bearing part of the main pawl, in which process its tongue, which then moves forward and comes to rest against an edge of the second annular gap, blocks its return movement and prevents the main pawl from entering the gap. This system provides a simple means of nullifying the locking of the main pawl in the ratchet wheel, since the belt rolling device must not be locked during the return rotation or extraction of the belt, which occurs when the passenger is restrained.
In a further embodiment of the invention the vanes and the ring disc are sealed off against one another and against the casing by means of plastic parts which are mounted on the latter and become plastic or are deformable as a result of the heating caused by the propellant gases, the plastic parts being wholely or partly constructed as coatings.
It has been found in tests that to ensure satisfactory efficiency for the propellant gases, the vane surfaces in the annular chambers must be efficiently sealed even at high temperatures. By coating the vane surfaces with plates or parts made of foamable polystyrene, for instance, a foam with a relatively tight cell structure is caused to form, under the action of the hot propellant gases, and ensures a fully satisfactory sealing effect.
To ensure the required temperature range for the use of a winding device, i.e., -40° to +90°, and a life of at least 10 years for the apparatus, provided no abrasive substances find their way in between the rotating components during the consumption of the propellant, it is proposed, according to a further characteristic of the invention, that the solid propellant charge should consist of a pyrotechnical composition in a pulverous or granulate form, consisting of 55-75% sodium azide (NaN 3 ) and 25-45% copper (II)-oxide (CuO). The propellant according to the invention offers the advantage of being suitable for use under temperature conditions ranging from -40° to 120° and that Cu forms during combustion and serves, in particular, as a lubricant while the toothed rack is performing its rolling movement, thus preventing it from jamming between the housing and the cylindrical casing.
The propellant charge is preferably ignited by means of a primer capsule which, according to the invention, is provided with a preset puncturing point or a capacitative blocking with undamped or damped transfer resistance. The preset puncturing point already responds at a certain defined voltage which is far below the rupturing voltage between housing and detonation bridge. The capacitative blocking ensures, for example, that an electrostatic charge of up to 500 pF and 5 kV, in the case of an undamped discharge, corresponding to 0 ohms, will not cause the primer capsule to detonate.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its use, reference should be had to the accompanying drawings and descriptive matter in which there are illustrated and described preferred embodiments of the invention.
DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1: a longitudinal section along the lines I--I through the winding device in FIGS. 2 and 3.
FIG. 2: a section along the lines II--II of FIG. 1.
FIG. 2a: a section in accordance with FIG. 2, with the vane positions occurring when the belt is tightened.
FIG. 3: a section along the lines III--III of FIG. 1.
FIG. 3a: a section in accordance with FIG. 3, with vane positions corresponding to FIG. 2a.
FIG. 3b: a section according to FIG. 3, when the winding device is rotated in the reverse direction.
FIG. 4: a section according to the lines IV--IV of FIG. 1.
FIG. 5: a section according to the lines V--V of FIG. 4.
FIG. 6: a section according to the lines VI--VI of FIG. 1.
FIG. 7: a section according to the lines VII--VII of FIG. 1.
FIG. 8: a view, in perspective, of the central part of a high-speed turning device.
FIG. 9: a section according to FIG. 2, with a sealing bag.
FIG. 10: a primer capsule with a preset puncturing point.
FIG. 11: a primer capsule with a capacitative blocking.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The main assemblies of a winding device according to FIG. 1 consist of a high speed turning device 1 and a belt rolling device 2, installed together in a housing 3. The high speed turning device 1 consists of a shaft 4 with an annular disc 5, a front cover 6, a rear cover 7 and rotating vanes 8 to 11. The shaft 4 is rotatably mounted on the front and rear cover and has a boring 12 accommodating pins 13 and 14 each of which are provided with a collar with the rear pin 14 being of the two-sided type, acting as a trunnion and having a fixed end 14a. The rear cover 7 is provided, with a casing 15 which extends in a dish-shaped configuration as far as the front cover 6 and is mounted thereon. This provides, between the shaft 4 and the casing 15, two annular chambers 16 and 17 separated from each other by the annular disc 5. Each of the annular chambers consists of two rotating vanes, of which the vane 8 and 9 are integral with the shaft 4 and the annular disc 5, while the vane 10 is attached to the front cover 6 (See FIG. 2) and the vane 11 to the rear cover 7 (see FIG. 3). As the front cover 6 is rigidly connected to the housing 3 and the rear cover 7 is rotatably mounted on the shaft 4 and the flanged pin 14, it is only the vane 10 that is non-rotatable in the front annular chamber 16. A small bolt 18 is inserted in the transition between the rear cover 7 and the casing 15. the rear cover also has an attachment 19. From each of the annular chambers a boring half embedded in the vane passes through the cover to the outside, i.e., the boring 20 in the case of the front annular chamber (see FIG. 2) and the boring 21 in the case of the rear annular chamber (see FIG. 3).
The boring 12 of the shaft 4 contains a solid propellant charge 22, consisting of powder or granulate, either filled or cast into the said boring. The propellant charge preferably consists of a mixture of 55 to 75% sodium azide and 25 to 45% copper (II) oxide, which has the properties and advantages already described in the foregoing. The solid propellant charge 22 is ignited by a primer capsule 23 inserted in the front pin 13. The wall of the shaft has a boring 24 for the front annular chamber 16 (see FIG. 2) and a corresponding boring 25 for the rear annular chamber 17 (see FIG. 3).
The belt rolling device 2 consists, in a known manner, of a belt roller 30 onto which can be wound a belt 31, a front and a rear side disc 32 and 33 and a winding spring 34 constructed as a helical spring. The belt roller 30 is rotatably mounted on the pin 14a of the high speed turning device 1 and a pivot pin 35 mounted in the housing 3. The front side disc 32, made in one piece with the belt roller 30, is constructed, on the side facing towards the high speed turning device, in the form of a ratchet wheel with teeth 36 and tooth gaps 37, a number of borings 38 being distributed around its periphery.
According to FIGS. 4 and 5, a housing attachment contains a pawl system 40 which responds to inertia and which interacts with the ratchet wheel 32. The pawl system comprises a pendulum 42 inserted in a boring 43 of a housing insert 41. The pendulum has a conical recess 44 which is engaged by a hemispherical projection 45 of rocker 46. The rocker is also fitted with a crosspiece 47 which is capable of lifting a small pawl 48 which in its turn can lift a main pawl 49. The entire winding device can be mounted by a flange 3b of the housing attachment 3a, with a bolt inserted through a boring 39.
Between the inner wall of the housing 3 and the casing 15, as shown in FIGS. 1 and 3, a toothed gear 52 is inserted in a widened portion 50 of a first annular gap formed between the cover attachment 19 and the housing 3, the gear being prevented, by a lug 53 or support 61, from falling out of the annular gap. The first annular gap 51 is delimited at the other end by a reinforced edge 54.
On the other side of the attachment 19 of the cover 7, as shown in FIG. 6, a wedge 56 can be inserted between the cover, the ratchet wheel 32 and the housing 3. The wedge, preferably consisting of plastic with resilient properties, is inserted in such a way that is is not caused to accompany the movement when only the belt roller 30 is rotating. It is only when the high speed turning device 1 rotates that the wedge is carried along by the cover 7 and pressed against an attachment 57 of the support 58 for the main pawl 49. This process releases a tongue 59 which belongs to the wedge 56 and which can thus come to rest against an edge 60 at the end of the annular gap 55.
FIGS. 8 and 9 show various versions of a sealing system between the rotating parts of the high speed turning device 1. In the view in perspective, provided in FIG. 8, triangular coatings of plastic 65 are provided on the vanes 8 and 9. These coatings, preferably consisting of foamable polystyrene, seal the rotating vanes, when the hot gases flow through borings 66, of which the only one shown is that adjacent to the vane 9, the coatings either becoming pasty of foaming, in either of which cases they seal the outer sealing edges 67 and 68 of the vanes 8 and 9. In accordance with the example shown in FIG. 8, the vanes 10 and 11 connected with the covers may be provided with a quadrangular plastic coating 69, covering the entire surface of the vane. A further version of the sealing system shown in FIG. 9, corresponds to that shown in FIG. 2. In this case a plastic bag 70, open towards the boring 24, is interposed between the vanes 8 and 10. At its bending point 71 the bag 70 is so thin that it tears in this position, on the impact of the hot propellant gases developed by the propellant charge 22, as a result of which the two parts of the bag, on the rotation of the vanes 8 and/or 10, remain with these latter and seal them.
The primer capsule 23, in accordance with FIGS. 10 and 11, is to be prevented from accidentally detonating from a voltage caused by an electrostatic charge. With a primer capsule not so protected, a voltage of this kind can act as an internal breakdown voltage between a bridge 77 formed from the ignition wires 75 and 76 and a housing casing 78 of the primer capsule, in which process an ignition charge and a priming charge are initiated. In FIG. 10 the protection is provided by a preset puncturing point (spark gap) 81, situated between the ignition wire 75 and the housing casing 78. This spark gap responds when a certain defined voltage is reached, which is far below the breakdown voltage inside the primer capsule. According to FIG. 11, a capacitor 83, bridged with a safety resistor 82, is provided between the ignition wire 75 and the housing casing 78, its capacity being far lower than the breakdown voltage between the ignition bridge 77 and the casing 78.
The winding device according to the invention operates as follows:
In normal use the winding device operates in the known manner, in that the helical spring 34 winds the belt 31 onto the belt roller 30 with a suitable force. When the vehicle decelerates, e.g., as a result of a sudden application of the brakes, the pendulum 42 in the pawl device 40 oscillates in the direction shown by an arrow 85, as a result of which the rocker 46, as well as the small pawl 48, via the crosspiece 47, assume the position in which they engage a gap 37 between the teeth of the ratchet wheel 32 (FIG. 4). The small pawl 48, which thus serves as a prelimiary locking device, then lifts the main pawl 49 into the same gap 37, blocks the ratchet wheel 32 and thus prevents the belt 31 from being extracted further. With this graduated locking system, with the small pawl 48 serving as a preliminary locking device, the main pawl 49 and the ratchet wheel 32 are largely protected from wear and damage, and the locking action can be effected more rapidly, owing to the smaller mass of the small pawl 48. The rotationally symmetrical flat supportiing system for the vertical pendulum 42 in the housing insert 41 ensures a stable position of rest for the pendulum in the case of normal vehicle movements and also ensures the response of the locking system to deceleration effects occurring from any direction. On the slackening of the belt load and cessation of the vehicle deceleration, all parts of the pawl device 40 are returned to their position of rest.
If a vehicle collides with any object, a sensor, not shown in the drawing, produces an impulse in the primer capsule 23, which ignites the propellant charge 20 situated in the shaft 4. The propellant gases thus developed flow simultaneously through the borings 24 and 25 into the two annular chambers 16 and 17 between the vanes 8 and 10 (FIG. 2) and 9 and 11 (FIG. 3). In the annular chamber 17 the small bolt 18 is immediately actuated, moves into one of the borings 38 in the ratchet wheel 32 and thus connects the high speed turning device 1 with the belt rolling device 2. In the annular chamber 16 the propellant gases rotate the vane 8 in the direction shown by the arrow 86 (FIG. 2), while in the annular chamber 17 they cause the vane 11 attached to the rear cover 7 to rotate in the direction shown by the arrow 87 (FIG. 3), in which process the vane 9 rigidly connected to the vane 8 via the annular disc 5 is caused to participate in the rotation. In the position shown in FIG. 2a the vane 8, in relation to the vane 10, which is the only one secured against relative rotation, has moved by approximately half a rotation, in the annular chamber 16, in the direction shown by the arrow 86. FIG. 3a shows the corresponding position for the vane 9 in the annular chamber 17. It may be seen that the vane 11 and thus the belt roller 30 have within this same period performed an almost complete rotation, the belt 31 being thereby retracted, in the direction shown by the arrow 88.
The high speed turning device can only tighten the belt to the point at which the blade 8 comes to rest against the fixed blade 10 and the blade 11 against the blade 9, after not quite two rotations. These circumstances are shown by the broken lines in FIGS. 2a and 3a, the blade being shown in the end position with 8a, 9a and 11a. The rotation of the blades in the annular chambers 16 and 17 is damped, over the last portion of the traject, as a result of the fact that the air present in the annular chambers is compressed between the blades before it can escape from the small borings 20 and 21. The damping of the belt tightening device can thus be varied by adjusting the size of these borings. It is improbable that the complete rotation angle of about 620° has to be utilized in order to tighten the belt. If a smaller rotation angle is adequate for the tightening of the belt, the propellant gases will emit their energy with greater force over the shorter rotation traject.
After the belt has pressed the passenger into his seat, during the collision, the kinetic energy which is inherent in his body and which is still present and which interacts with the deformation of the vehicle has to be reduced by the toothed gear 52 serving as a force limiting device, on the return rotation of the belt rolling device, in accordance with the arrows 89 (See FIG. 3b). While the gear, in the course of the belt tightening process, only rotates loosely in the widened portion 53 of the first annular gap 51 (see FIG. 3a), it will be carried along by the casing 15, on the return rotation of the high speed turning device 1, and rolls between the casing 15 and the housing 3 in the first annular gap 51, resulting in the absorption of energy by the imprint of the tooth profile (see FIG. 3b). The dimensions of the toothed gear 52 are preferably made small enough to ensure that while it is rolling in the first annular gap 51 the high speed turning device 1, performs about two full rotations, with equal absorption of energy, before the rack 51 encounters the reinforced edge 54.
During the belt tightening phase of operation of the device, the wedge 56 shown in FIG. 6 is carried along and, by making impact with the attachment 57, prevents the main pawl 49 from engaging a gap 37 in the ratchet wheel 32, the wedge 56 being held in this position by the projection of its tongue 59. This is necessary because during the reverse rotation of the winding device the belt drum 30 must not be blocked, so that the kinetic energy can be dissipated by the force-absorbing toothed rack 52.
While specific embodiments of the invention have been shown and described in detail to illustrate the application of the inventive principles, it will be understood that the invention may be embodied otherwise without departing from such principles. | A winding assembly for a vehicle safety belt system is provided with a belt rolling device and a high speed turning device adapted upon actuation of a propellant charge to wind the safety belt at high speeds as a result of the generation of pyrotechnical gases. The high speed turning device and the belt rolling device are interconnected when a given rate of vehicle deceleration is achieved and the high speed turning device is constructed with a rotatably mounted shaft, a pair of annular chambers extending about the shaft, a pair of vanes affixed to the shaft each extending into one of the annular chambers, a first blade fixed within one of the annular chambers and arranged to be engaged by one of the vanes and a second blade extending into the other of the annular chambers and arranged to be engaged by the other vane with the second blade being mounted in driving relationship through the interconnecting means to impart driving rotation of the shaft to the belt rolling device when the high speed turning device is driven by the pyrotechnical gases. The fixed blade is adapted to engage the first vane in order to stop rotation of the vanes and winding of the safety belt. | 1 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a process for preparing Cefepime and cephalosporin analogues, i.e. Cefpirome and Cefquinome.
[0003] 2. Discussion of the Background Art
[0004] U.S. patent application Ser. No. 10/916,532, filed on Aug. 12, 2004 (which is a continuation of U.S. patent application Ser. No. 10/821,986 filed on Apr. 12, 2004) describes a process for preparing cephalosporins of formula
characterised by a 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain in the 7-position of 7-ACA and its derivatives of formula
in which R 2 can have different meanings including CH 2 OCOCH 3 for 7-ACA, being the cefotaxime nucleus, or
for 7-ACT, being the ceftriaxone nucleus and
for Furaca, being the ceftiofur nucleus.
[0005] In said application, the synthesis takes place in two passages: the first consists of preparing an intermediate of formula
by reacting a compound of formula (I)
suitably silylated, with a compound of formula (V)
in which X is Cl or Br, Y is Cl, or O—CH═N + (CH 3 ) 2 Cl − , isolating a compound of aforegiven formula (IV) in which X is Cl or Br and the carboxyl is salified with benzathine.
[0006] This procedure has however proved inapplicable in the case of compounds of formula (IV) containing a strongly basic substituent R 2 of the following type:
[0007] In this respect the aforesaid basic group R 2 forms an internal salt with the carboxyl group in the 4-position, which is hence present as COO − and does not enable the benzathine to salify the carboxyl.
[0008] This assertion is confirmed, for example, by U.S. patent application 2003/0199712 in which a process is claimed (claim 5) for preparing a compound of formula (II) by passing via a compound similar to that of formula (IV), but in which the carboxyl can be a carboxylate ion, while the substituent in the 3-position can have one of the three aforesaid meanings for R 2 , thus giving rise to an internal salt between the carboxylate ion and the basic group indicated as R 2 .
[0009] It is therefore evident that the presence of the strongly basic group in the 3-position, in the case of the compound of formula (IV), gives rise to an internal salt, at least according to the expectations of one skilled in the art, while the benzathine salt alternative has proved to be impractical.
SUMMARY OF THE INVENTION
[0010] It has now been surprisingly found that a compound of formula
suitably silylated, in which R 2 is one of the three aforesaid substituents, can be reacted with a compound of formula (V)
in which X is Cl or Br, Y is Cl, or O—CH═N + (CH 3 ) 2 Cl − , in order to isolate a compound of formula
in which COOR 4 is not in the form of a carboxylate ion but rather is simply COOH, while the substituent R 3 in the 3-position is of the following type:
i.e. a quaternary ammonium group accompanied by a chloride anion.
[0011] The aforesaid compound of formula (VI) is therefore a quaternary ammonium salt which can be isolated in pure form by separating it from the reaction impurities and subsequently reacted with thiourea to produce a salt of a compound of formula (II) in which COOR 1 is COO − and R 2 is one of the following three substituents,
as reported in the Merck Index XIII Ed. for Cefepime, Cefpirome and Cefquinome. The salt of said compound, again according to the Merck Index XIII Ed., can be a hydrochloride or a sulfate in the case of Cefepime and a sulfate in the case of Cefpirome and Cefquinome.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] The invention relates therefore to a process for preparing a pharmaceutically acceptable salt chosen from the group consisting of a hydrochloride or a sulfate of a compound of formula (II) in which COOR 1 is a carboxylate ion and R 2 is chosen from the group consisting of
and also relates to a compound of formula (VI) in which X is Cl or Br; R 4 is H and R 3 is chosen from the group consisting of
EXAMPLES
Example 1- Preparation of the Compound of Formula VI
[0013] 7-[4-chloro-3-oxo-2-methoxyiminobutanoyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-methyl-(1-methylpyrrolidinium) chloride.
[0014] Two separate solutions are prepared.
[0015] Solution A:
[0016] 4g of (6R,7R)-7-amino-3-(1-methyl-1-pyrrolidinium)methyl-ceph-3-em-4-carboxylate hydrochloride (compound of formula III) (M.W. 333.92) are suspended in 150 ml of acetonitrile and cooled to +10° C. 0.1 ml of methanesulfonic acid are added followed by 8.6 g of N,O-bistrimethyl-silyl-acetamide (M.W. 203.43) allowing the temperature to rise spontaneously and freely. The mixture is stirred for 90 minutes at +33/+35° C. until a solution forms, and then cooled to −40° C.
[0017] Solution B:
[0018] 1.4 ml of N,N-dimethylformamide are added to 30 ml of acetonitrile, the temperature is brought to +25° C., then after allowing it to rise to +36° C. 1.6 ml of phosphorus oxychloride (M.W. 153.33- d=1.675) are added. The mixture is stirred for 15-20 minutes at +36° C., then cooled to 0° C., to which 2.9 g of 4-chloro-3-oxo-2-methoxyimino-butyric acid, commonly known as COMBA (M.W. 179.56), are added without allowing the temperature to exceed +5° C. The mixture is agitated for 1 hour at 0° C./+5° C.
[0019] Solution B is poured into solution A over 15 minutes, while maintaining the temperature at −35/−40° C., it is agitated for 15-20 minutes and the reaction goes to completion. The reaction contents are poured into 50ml of wet isopropanol previously cooled to 0° C./−5° C. The temperature is raised to +25/+30° C. and the acetonitrile is evaporated under reduced pressure The product is taken up 3 times with 20 ml of isopropanol, and finally made up to a total volume of 100 ml with isopropanol. After cooling to 0° C. and stirring at this temperature for 1 hour, the mixture is filtered and the product washed twice with 20 ml of isopropanol. It is dried and 5.8 g (yield 98%) of the compound of formula (VI) are obtained, presenting the following spectrum:
[0020] 1 HNMR (DMSO-d6, 300 MHz): 9.54, (1H, d); 5.90, (1H, dd); 5.29, (1H, d); 4.86, (2H, s); 4.60 and 4.24, (2H, AB system, J AB =13.5 Hz); 4.05, (3H, s); 4.00 and 3.63, (2H, AB system, J AB =17 Hz); 3.60, (3H, m); 3.43, (1H, m); 2.92, (3H, s); 2.11, (4H, m).
Example 2- Preparation of Cefepime Hydrochloride Monohydrate
[0021] 5.8 g of the compound of formula (VI) obtained in Example 1 are suspended in 50 ml of water at +20/+25° C. 1.8 g of thiourea are added, the temperature is maintained at +20/+25° C., 5.9 g of sodium acetate are added and the mixture is stirred at this temperature for 3 hours. On termination of the reaction 240 ml of acetone are added. 35% hydrochloric acid is added at +20/+25° C. until pH 1.5 is attained. A further 360 ml of acetone are added dropwise over 1 hour, then the mixture is stirred for 30 minutes at +20/+25° C., cooled to 0° C. and stirred for 1 hour. The mixture is filtered and the product washed with 250 ml of acetone, then dried at +30° C. under reduced pressure. 6.3 g (93% yield) of Cefepime hydrochloride monohydrate are obtained, presenting the following spectrum:
[0022] 1 HNMR (DMSO-d6, 300 MHz): 9.8, (1H, d); 6.8, (1H, s); 5.85, (1H, dd); 5.36, (1H, d); 4.6 and 4.4, (2H, AB system, J AB =14 Hz); 4.1 and 3.7, (2H, AB system, J AB =17 Hz); 3.9, (3H, s); 3.62, (3H, m); 3.46, (1H, m); 2.96, (3H, s); 2.1, (4H, m).
Example 3- Preparation of Cefepime Sulfate
[0023] 5.8 g of the compound of formula (VI) obtained in Example 1 are suspended in 25 ml of water at +20° C./+25° C. 1.8 g of thiourea are added, the temperature is maintained at +20/+25° C., 5.9 g of sodium acetate are added and the mixture is stirred for 3 hours at +20/+25° C. On termination of the reaction 90 ml of acetone are added.
[0024] The solution is cooled to 0°/+5° C. then brought to pH 1.8 with a solution consisting of 30% H 2 SO 4 and acetone (1:2.5 v:v).
[0025] The solution is then stirred for 1 hour, filtered, washed with 50 ml of acetone and dried under reduced pressure at +30° C. 4.8 g (yield 72%) of Cefepime sulfate are obtained whose 1 HNMR spectrum coincides with that of Cefepime hydrochloride.
[0026] By applying the same method to compounds of formula (III) in which R 2 is chosen from the following group
Cefpirome sulfate is obtained in the first case and Cefquinome sulfate in the second case. | Process for producing Cefepime, Cefpirome and Cefquinome, whereby a cephalosporin containing a quaternary ammonium group is reacted with thiourea to provide the aforesaid cephalosporins. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. §119 to Korean Patent Application No. 10-2013-0014959 filed on Feb. 12, 2013, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a method for preparing a semi-furanic copolyamide containing at least one furanic dicarboxylic acid moiety and at least one aliphatic diamine moiety in the backbone using solid-state polymerization. More particularly, the present invention relates to a method for preparing a semi-furanic copolyamide that uses a biomass-derived furanic dicarboxylic acid as a raw material.
[0004] 2. Description of the Related Art
[0005] With the recent violently fluctuating oil prices and increasing concern about environmental pollution, there has been a growing interest in the development of natural polymers found in nature and bioplastics as synthetic polymers synthesized from biomass-derived monomers due to their potential replacements for existing fossil fuels.
[0006] The world's annual biomass production is estimated to be 10 times the world's total annual energy consumption. The idea to effectively use biomass as a renewable energy source is on the rise. Thus, strategies to use biomass have recently been issued in the field of biotechnology. Biodegradable plastics have been suggested as examples of the strategies. Particularly, bioplastics are recyclable materials that are produced using biomass resources as raw materials by biological or chemical processes, but they have the problem of high production costs and are required to have high performance.
[0007] Much research has been conducted for many years on natural polymers, such as natural rubbers and celluloses. Such natural polymers have already been used in large amounts. The history of research on synthetic polymers derived from biomass is not relatively long. Only a few of the synthetic polymers are commercially successful and are applied to practical use.
[0008] The most well-known synthetic polymers are polylactides, which are currently produced on an industrial scale. Research is underway to improve the physical properties of polylactides in countries around the world. In addition to this research, studies are underway to synthesize polyolefins using monomers converted from bioethanol and to synthesize triglycerides as major ingredients of animal and vegetable oils and fats. Most monomers for polyamides, such as adipic acid and caprolactam, are currently produced by petrochemical processes. Proposals have been made recently on methods for producing the monomers from biomass. However, studies on the synthesis of polyamides based on the proposed methods still remain at the early stages because the methods are disadvantageous in terms of economic efficiency compared to petrochemical processes. Examples of polyamides synthesized using biomass-derived monomers include polyamide 11 produced from castor oil and polyamide 4 produced from glucose.
[0009] Melt polymerization, solution polymerization, and solid-state polymerization are known as processes for producing the polyamides.
[0010] Melt polymerization is advantageous in that a polymer can be produced in a single step. However, when it is intended to produce a polymer having a high melting point by melt polymerization, the polymer is likely to undergo thermal decomposition, gelation, and other troubles, resulting in deterioration of quality. As the polymerization proceeds, the polymer becomes viscous, which makes stirring and temperature control difficult. Further, by-products are not easy to remove. As a result, it is difficult to obtain a high molecular weight of the polymer. For solution polymerization, only a limited number of solvents, such as concentrated sulfuric acid, can be used to dissolve polyamides. That is, the choice of solvents is restrictive in solution polymerization.
[0011] Solid-state polymerization for the production of a polymer is performed at a temperature between the glass transition temperature and melting point of the polymer. This reaction temperature can reduce the possibility of heat-induced side reactions. Solid-state polymerization is performed in the absence of solvents. Accordingly, solid-state polymerization is free from disadvantages associated with the use of solvents, unlike solution polymerization. Solid-state polymerization for the production of a polymer is generally performed by the following procedure. First, a prepolymer having a low molecular weight is produced by melt polymerization. The prepolymer is pulverized into a powder, and then the prepolymer powder is introduced into a suitable reactor, such as a packed bed reactor, a fluidized bed reactor, a fixed bed reactor or a moving bed reactor. The prepolymer is polymerized in a solid state at a temperature between the glass transition temperature and melting point of the polymer while feeding a continuous flow of a sweep fluid for removal of by-products into the reactor. The polymerization increases the molecular weight of the prepolymer.
[0012] The presence of an aromatic monomer in a polyamide increases the crystallinity of the polyamide and ensures superior heat resistance, stiffness and dimensional stability of the polyamide. Due to these advantages, polyamides can be used as engineering plastics in a wide range of applications where high strength and good heat resistance are required, particularly, electronic/electrical materials, such as surface mounting devices (SMTs), LED reflectors and I/O connectors, lightweight interior/exterior materials for automotive vehicles capable of substituting for metals to reduce the weight of automotive vehicles and protect automotive vehicles from corrosion, industrial materials, and aeronautical materials, which are usually produced by injection molding. Examples of such semi-aromatic polyamides include polyamide 4,T produced from terephthalic acid and 1,4-butanediamine, and polyamide 6,T produced from terephthalic acid and hexamethylenediamine.
[0013] Polyamide 4,T and polyamide 6,T have high crystallinity and superior heat resistance but are not suitable for injection molding due to their higher melting temperatures, 430° C. and 370° C., respectively, than those of conventional polyamides. Accordingly, it is difficult to use the polyamides in the above-described applications. Thus, attempts have been made to produce highly heat resistant copolyamides suitable for injection molding by adjusting the melting points of polyamide 4,T and polyamide 6,T within the range of 300 to 330° C. As the copolyamides, copolyamide 4,T/4,6, copolyamide 6,T/4,6, and copolyamide 4,T/6,T/4,6 have been proposed. Copolyamide 4,T/4,6 is obtained by copolymerization of polyamide 4,6 produced from adipic acid and 1,4-butanediamine and polyamide 4,T. Copolyamide 6,T/4,6 is obtained by copolymerization of polyamide 4,6 and polyamide 6,T. Copolyamide 4,T/6,T/4,6 is obtained by copolymerization of polyamide 4,6, copolyamide 4,T and polyamide 6,T.
[0014] Efforts have been made to produce semi-furanic copolyamides as substitutes for semi-aromatic copolyamides by introducing FDCA instead of terephthalic acid. However, the colors of the semi-furanic copolyamides tend to change or the molecular weights of the semi-furanic copolyamides are not sufficiently high. Due to these problems, none of the semi-furanic copolyamides reported hitherto are successful. Under such circumstances, there is a need for a novel semi-furanic copolyamide and a preparation method thereof.
SUMMARY OF THE INVENTION
[0015] The present invention has been made in view of the problems of conventional copolyamides derived from biomass, and it is an object of the present invention to provide a novel semi-furanic copolyamide represented by Formula 1:
[0000]
[0016] wherein X, Y, l, m, n, p and q are as defined below.
[0017] It is another object of the present invention to provide a method for preparing the semi-furanic copolyamide of Formula 1.
[0018] According to an aspect of the present invention, there is provided a semi-furanic copolyamide represented by Formula 1:
[0000]
[0019] wherein X, Y, l, in, n, p and q are as defined below.
[0020] According to another aspect of the present invention, there is provided a method for preparing the semi-furanic copolyamide of Formula 1, the method including:
[0021] (a) preparing a copolyamide prepolymer containing furanic dicarboxylic acid, aliphatic dicarboxylic acid and aliphatic diamine moieties; and
[0022] (b) increasing the molecular weight of the prepolymer prepared in (a) to obtain a furanic copolyamide.
[0023] The method of the present invention enables the preparation of a semi-furanic copolyamide from a biomass-derived furanic dicarboxylic acid. The semi-furanic copolyamide has molecular weight and color levels that are practically required in industrial applications. In addition, the semi-furanic copolyamide can replace fossil fuels due to its good thermal stability and is suitable for use as an environmentally friendly bioplastic.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] These and/or other aspects and advantages of the invention will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
[0025] FIG. 1 is a graph showing changes in the intrinsic viscosity of copolyamides prepared at different solid-state polymerization temperatures in Examples 1 to 3 as a function of reaction time;
[0026] FIG. 2 graphically shows the Tm values and degrees of crystallinity of a copolyamide prepared in Example 2, as measured by differential scanning calorimetry; and
[0027] FIG. 3 is a graph showing the thermal stability of a copolyamide prepared in Example 2, as measured by thermogravimetric analysis.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention will now be described in detail.
[0029] The present invention provides a compound represented by Formula 1:
[0000]
[0030] wherein X and Y are each independently selected from the group consisting of oxygen (O), sulfur (S) and nitrogen (N) atoms,
[0031] l, m and n are each independently an integer from 1 to 30, and
[0032] p and q are each independently an integer from 1 to 10,000.
[0033] Preferably, in Formula 1, X and Y are each independently selected from the group consisting of oxygen (O), sulfur (S) and nitrogen (N) atoms, l, m and n are each independently an integer from 3 to 11, and p and q are each independently an integer from 50 to 1,000.
[0034] The present invention also provides a method for preparing the semi-furanic copolyamide, including:
[0035] (a) adding two different polyamide salts to a stirred reactor, and reacting the polyamide salts in a nitrogen atmosphere to prepare a copolyamide prepolymer containing at least one furanic dicarboxylic acid moiety, at least one aliphatic dicarboxylic acid moiety and at least one aliphatic diamine moiety in the copolyamide backbone; and
[0036] (b) pulverizing the copolyamide prepolymer prepared in (a), and reacting the copolyamide prepolymer in a solid-state polymerization reactor while feeding a mixed fluid of an inert gas and water into the reactor, to increase the molecular weight of the copolyamide prepolymer.
[0037] In step (a), two different polyamide salts are introduced into a stirred reactor where high temperature and high pressure conditions can be maintained, and are allowed to react with increasing reaction temperature and pressure for a predetermined time in the presence of a predetermined amount of water to prepare a prepolymer.
[0038] The copolyamide prepolymer prepared in step (a) may contain a moiety of at least one furanic dicarboxylic acid selected from the group consisting of 1,4-furandicarboxylic acid and its dialkyl ester derivatives, a moiety of at least one aliphatic dicarboxylic acid selected from the group consisting of C 4 -C 12 straight-chain dicarboxylic acids and C 4 -C 12 cyclic dicarboxylic acids, and a moiety of at least one aliphatic diamine selected from the group consisting of C 4 -C 12 straight-chain diamines.
[0039] The polyamide salts used to prepare the copolyamide prepolymer in step (a) are selected from the group consisting of polyamide 4,F, polyamide 4,6, polyamide 4,T and polyamide 6,T salts. As the polyamide salts, polyamide 4,F and polyamide 4,6 salts are preferably used.
[0040] The polyamide salts used to prepare the copolyamide prepolymer in step (a) may be prepared separately. Alternatively, the polyamide salts may be prepared by mixing all constituent monomers at one time.
[0041] In step (a), the reaction may be carried out at a temperature of 120 to 260° C. The reaction temperature is preferably from 160 to 220° C.
[0042] If the reaction temperature is outside the range defined above, particularly, below 120° C., it is difficult to expect effective chain extension reactions of the polyamide salts, making it impossible to obtain a high molecular weight of the prepolymer. Meanwhile, if the reaction temperature exceeds 260° C., the polyamide salts undergo side reactions, such as cyclization and coloration, making it impossible to achieve high quality of the prepolymer.
[0043] In step (a), the reaction is carried out in the presence of water in an amount of 5 to 50% by weight with respect to the weight of the polyamide salts. The water is preferably present in an amount of 10 to 35% by weight, based on the weight of the polyamide salts.
[0044] If the water content is outside the range defined above, particularly, less than 5% by weight, the prepolymer precipitates rapidly, making it difficult to obtain a high molecular weight of the prepolymer. Meanwhile, if the water content exceeds 50% by weight, large amounts of by-products are produced. The by-products prevent the forward reaction from proceeding, making it difficult to obtain a high molecular weight of the prepolymer.
[0045] The inert gas used in step (b) is not particularly limited. Any gas that does not participate in the chain extension reactions of the prepolymer may be used as the inert gas, and examples thereof include nitrogen, helium, argon and carbon dioxide.
[0046] In step (b), the molar ratio of the inert gas to water in the mixed fluid is 0.1-50:1. The inert gas and water are preferably mixed in a molar ratio of 1-30:1.
[0047] If the molar ratio is outside the range defined above, particularly, the moles of the inert gas are 50 times larger than those of water, the polyamide prepolymer undergoes side reactions, such as cyclization and coloration, making it impossible to achieve high quality of the semi-furanic copolyamide. Meanwhile, if the moles of the inert gas are 0.1 times smaller than those of water, large amounts of by-products are produced. The by-products hinder effective chain extension reactions of the prepolymer, making it difficult to obtain a high molecular weight of the semi-furanic copolyamide.
[0048] In step (b), the reaction may be carried out at a temperature of 150 to 300° C. The reaction temperature is preferably from 200 to 280° C.
[0049] When solid-state polymerization is performed using the mixed fluid of inert gas and water in step (b) to increase the molecular weight of the prepolymer, the reaction temperature is considered a very important factor. Particularly, if the reaction temperature is lower than 150° C., it is difficult to expect effective chain extension reactions of the prepolymer, making it impossible to obtain a high molecular weight of the semi-furanic copolyamide. At a low reaction temperature, a long reaction time is disadvantageously required to obtain a high molecular weight of the copolyamide. If the reaction temperature is higher than 300° C., the prepolymer undergoes side reactions, such as cyclization and coloration, other than chain extension reactions, and is melted due to its low molecular weight, making it difficult to achieve high quaintly of the semi-furanic copolyamide.
[0050] The present invention also provides a bioplastic including the semi-furanic copolyamide.
[0051] The semi-furanic copolyamide of the present invention has a intrinsic viscosity of 0.5 dL/g and can replace fossil fuels due to its very good thermal stability. In addition, the semi-furanic copolyamide of the present invention is suitable for use as an environmentally friendly bioplastic.
[0052] The present invention will be explained in detail with reference to the following examples, including preparative examples and an experimental example.
[0053] However, these examples are provided for illustrative purposes only and are not intended to limit the invention.
EXAMPLES
Preparative Example 1
Preparation of Polyamide 4,F Salt
[0054] 176.3 g of 1,4-butanediamine was dissolved in 1.6 L of distilled water, and then 312.2 g of 1,4-furandicarboxylic acid (FDCA) was slowly added thereto with stirring. The reaction was allowed to proceed to obtain a polyamide 4,F solution. The polyamide 4,F solution was cooled to room temperature. 3.5 L of ethanol was added to the polyamide 4,F solution with stirring to precipitate polyamide 4,F salt.
[0055] The precipitated polyamide 4,F salt was filtered through a filter paper, washed with cold ethanol, and dried in a vacuum oven at 60° C. for 48 hr.
Preparative Example 2
Preparation of Polyamide 4,6 Salt
[0056] 176.3 g of 1,4-butanediamine was dissolved in 1,400 g of methanol, and then 292.2 g of adipic acid was slowly added thereto with stirring at 60° C. The reaction was allowed to proceed to obtain a polyamide 4,6 solution. The solution was cooled to room temperature to precipitate polyamide 4,6 salt. The precipitate was filtered, washed with cold methanol, and dried in a vacuum oven at 60° C. for 48 hr.
Example 1
Preparation of Semi-Furanic Copolyamide-1
[0057]
[0058] Step 1: Preparation of Semi-Furanic Copolyamide Prepolymer
[0059] In this step, copolyamide 4,F/4,6 including polyamide 4,F and polyamide 4,6 in a molar ratio of 1:9 was prepared. First, 33 g of polyamide 4,F prepared in Preparative Example 1, 277 g of the polyamide 4,6 salt prepared in Preparative Example 2, and 31 g of water were fed into a 1.2 L stirred autoclave made of stainless steel (Grade 316) and stirred in a nitrogen atmosphere with increasing reaction temperature from 25° C. to 170° C. over 1 hr. Subsequently, the reaction temperature was increased from 170° C. to 220° C. over 4 hr and from 220° C. to 270° C. over 3 hr to prepare a prepolymer.
[0060] Step 2: Preparation of Semi-Furanic Copolyamide
[0061] The prepolymer prepared in step 1 was pulverized into a powder having a size of 250-500 μm. The prepolymer powder was fed into a tubular solid-state polymerization reactor made of stainless steel (Grade 316). Thereafter, the reaction was carried out in a solid state at a temperature of 200° C. for 24 hr while allowing nitrogen and water in a molar ratio 2:1 to flow at a rate of 3 L/min into the solid-state polymerization reactor, followed by cooling to obtain the title copolyamide.
Example 2
Preparation of Semi-Furanic Copolyamide-2
[0062] The title copolyamide was obtained in the same manner as in Example 1, except that the internal reaction temperature of the solid-state polymerization reactor in step 2 was raised to 220° C. instead of 200° C.
Example 3
Preparation of Semi-Furanic Copolyamide-3
[0063] The title copolyamide was obtained in the same manner as in Example 1, except that the internal reaction temperature of the solid-state polymerization reactor in step 2 was raised to 240° C. instead of 200° C.
Experimental Example 1
Analysis of the Semi-Furanic Copolyamides
[0064] The following experiments were conducted to analyze the characteristics of the semi-furanic copolyamides prepared in Examples 1-3.
[0065] (1) Measurement of Intrinsic Viscosities
[0066] Samples of the copolyamides prepared after solid-state polymerization in Examples 1-3 were dried in a vacuum oven whose temperature was maintained at 80° C. for 24 hr. The intrinsic viscosities of the copolyamides were measured to evaluate how much the molecular weights of the copolyamides were increased after solid-state polymerization.
[0067] The intrinsic viscosities of the copolyamides were measured using a viscosity measuring system (AVS370, Schott Instrument) employing an Ubbelohde viscometer under the conditions specified in ISO 307.
[0068] Results
[0069] As shown in FIG. 1 , the intrinsic viscosities of the copolyamides 4,F/4,6, which were prepared from the prepolymer having an intrinsic viscosity of 0.395 dL/g by solid-state polymerization at 200, 220 and 240° C. for 48 hr in Examples 1-3, were 0.538, 0.576 and 0.758 dL/g, respectively, indicating that the intrinsic viscosities of the copolyamides are 36.2%, 45.8% and 91.9% higher than the intrinsic viscosity of the prepolymer, respectively.
[0070] These results confirm that solid-state polymerization significantly increases the molecular weights of the copolyamides 4,F/4,6.
[0071] (2) Measurement of Degrees of Crystallinity of the Copolyamides
[0072] The Tm values and degrees of crystallinity of the copolyamides after drying were measured using a differential scanning calorimeter (DSC, Texas Instrument).
[0073] Results
[0074] The melting point and heat of fusion of the copolyamide prepared in Example 2 were investigated using a differential scanning calorimeter (DSC). As shown in FIG. 2 , the melting point and heat of fusion of the copolyamide after solid-state polymerization at 240° C. for 24 hr were 296° C. and 101 J/g at the first scan, respectively, and were 275° C. and 74 J/g at the second scan, respectively. These results confirm that the copolyamide is semi-crystalline.
[0075] (3) Measurement of Thermal Stability
[0076] 5 mg of each of the copolyamide samples prepared in Examples 1-3 was introduced into a pan, heated at a rate of 10° C./min from 30° C. to 360° C. under a nitrogen atmosphere of 50 ml/min (first heating), cooled at a rate of 10° C./min to 30° C., and heated at a rate of 10° C./min to 360° C. (second heating). The melting point and heat of fusion of the copolyamide were determined based on the data measured under the second heating conditions. The temperatures at which weight loss reached 5% and 10% were measured using a thermogravimetric analyzer (TGA, Texas Instrument). After 5 mg of each of the copolyamide samples was introduced into a pan, the measurements were done with increasing temperature at a rate of 10° C./min from 30° C. to 700° C. under a nitrogen atmosphere of 50 ml/min.
[0077] Results
[0078] The thermal stability of the copolyamide prepared by polymerization at 220° C. for 6 hr in Example 2 was evaluated using TGA. The results are shown in FIG. 3 . As shown in FIG. 3 , the copolyamide lost 5% of its weight at 371° C. and 10% of its weight at 389° C., demonstrating good thermal stability of the copolyamide 4,F/4,6.
[0079] These results lead to the conclusion that the semi-furanic copolyamide can replace fossil fuels due to its good thermal stability and is suitable for use as an environmentally friendly bioplastic. | Disclosed is a method for preparing a semi-furanic copolyamide containing at least one furanic dicarboxylic acid moiety and at least one aliphatic diamine moiety in the backbone. The method is based on solid-state polymerization. Particularly, the method uses a biomass-derived furanic dicarboxylic acid as a raw material. A semi-furanic copolyamide prepared by the method has molecular weight and color levels that are practically required in industrial applications. In addition, the semi-furanic copolyamide can replace fossil fuels due to its good thermal stability and is suitable for use as an environmentally friendly bioplastic. | 2 |
FIELD AND BACKGROUND OF THE INVENTION
The invention relates to irrigation apparatus and particularly to such apparatus which includes pulsators. The invention is especially useful with respect to dripper-type irrigation apparatus, and is therefore described below with respect to this application.
The growing use of artificial bedding in nurseries and open fields, and particularly the use of soils with very low water retaining capacity, have created a need for irrigation apparatus having very low discharge rates, of the order 0.1-0.3 liters per hour. Such low discharge rates allow the water to travel by capillary action, and thus increase the water retaining capacity of the plant growing media. Providing low water discharge rates also effects significant savings of water and fertilizer. The use of pulsator devices, such as described in U.S. Pat. Nos. 4,781,217 and 4,949,747 of Peretz Rosenberg or 4,955,539 of G. Ruttenberg, have been found to allow lower discharge rates to be used permitting significant savings of water and fertilizer.
One recent technique for using pulsators to lower the water discharge rate, described in U.S. Pat. No. 5,353,993, includes a feeder line for supplying the water and a dripper line connected to the feeder line via a plurality of spaced pulsator devices. However, using two separate lines is expensive and cumbersome, and moreover, requires drippers with small passages.
OBJECTS AND BRIEF SUMMARY OF THE INVENTION
An object of the present invention is to provide irrigation apparatus having advantages in the above respects as will be described more particularly below.
According to one aspect of the present invention, there is provided irrigation apparatus comprising: a feeder line connectible to a source of pressurized water; an outer line of larger diameter than, and enclosing, the feeder line to define an annular water chamber between the outer line and the feeder line; the outer line including a plurality of irrigation devices spaced along its length communicating with the water chamber; and a plurality of pulsator devices spaced along the length of the feeder line and connecting the feeder line to the water chamber.
According to further features in the described preferred embodiment, the outer line is constituted of a plurality of outer pipes spaced along the length of, and enclosing, the feeder line, each of the outer pipes including end walls to define an annular water chamber between the respective outer pipe and the feeder line.
According to still further features in the described preferred embodiment, the outer pipes are dripper pipes, and the irrigation devices are water drippers. Also, the feeder line includes a plurality of feeder pipes, one for each of the outer pipes, and a plurality of connectors connecting each feeder pipe to the adjacent feeder pipe and pulsator device.
As will be described more particularly below, irrigation apparatus constructed in accordance with the foregoing features is relatively simple to apply in the field since it requires deployment of only a single line, rather than two separate lines. Moreover, since the inner feeder pipe is within, and therefore occupies a substantial volume of, the outer dripper pipe, the annular water chamber produced between the two pipes is of relatively low volume, thereby permitting larger passageways in the dripper devices, or in microsprinkers if used as the irrigation devices. Primarily for the latter reason, irrigation apparatus constructed in accordance with the foregoing features may employ standard, conventional drippers which can be produced and assembled in volume and at relatively low cost.
Further features and advantages of the invention will be apparent from the description below.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:
FIG. 1 illustrates one form of irrigation apparatus constructed in accordance with the present invention;
FIG. 2 is an enlarged fragmentary view of the apparatus of FIG. 1; and
FIG. 3 illustrates another type of irrigation apparatus constructed in accordance with the present invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
The irrigation apparatus illustrated in FIGS. 1 and 2 includes a plurality of irrigation pipe assemblies of like construction each generally designated 2, connected together at their ends by T-connectors 3. As will be described more particularly below, each irrigation pipe assembly 2 includes a plurality of irrigation devices, in this case water drippers. A plurality of pulsators 4, connected between the T-connectors 3 and the irrigation pipe assemblies 2, supply water in the form of pulses, and in parallel paths, to the irrigation devices within the pipe assemblies 2.
The pulsator devices 4 may be of any of the known constructions, such as described in the previously-cited Rosenberg and Ruttenberg patents. The details of the construction and operation of such pulsator devices are therefore not set forth herein since they do not form a part of the present invention.
The construction of each of the irrigation pipe assemblies 2 is more particularly seen in FIG. 2. Each irrigation pipe assembly 2 includes an inner feeder pipe 20 and an outer pipe 21 of larger diameter than pipe 20 to define an annular water chamber 22 between the two pipes. The outer pipe 21 carries a number of irrigation devices, in this case drippers 23, in communication with the water chamber 22.
Each end of each irrigation pipe assembly 2 is closed by an end cap 24 including a transversely-extending end wall 24a, an axially-extending collar 24b attached to the outer pipe 21, and a hollow stem 24c extending centrally through end wall 24a. Another collar 25 attached to the inner feeder pipe 20 is secured between its outer collar 24b and inner hollow stem 24c to thereby close the respective end of the water chamber 22 defined between the two pipes 20, 21.
The T-connectors 3 includes three legs 31, 32, 33. Legs 31, 32 are coaxial to each other and to the axes of the two adjacent pipe assemblies 2, and receive the hollow stems 24c of the two adjacent pipe assemblies. Leg 33 is perpendicular to legs 31, 32, and receives the inlet end 41 of the pulsator device 4. The outlet end 42 of the pulsator device is connected by a tube 43 to the water chamber 22 of the next adjacent pipe assembly 2. The water within the annular water chambers 22 is discharged via the dripper devices 23 carried by the outer pipes 21.
It will be seen that legs 31, 32 of the T-connectors 3 connect all the feeder pipes 20 to form a common feeder line. One end of the feeder line is connectible to a source of pressurized water, and the opposite end of the feeder line is closed. It will also be seen that the outer pipes 21 of the pipe assemblies 2, being of larger diameter than the feeder pipes 20, define annular water chambers between the two pipes 20, 21 in each pipe assembly 2, which water chambers are closed by the end caps 24.
It will be further seen that the pulsator devices 4, having their inlet ends connected to the T-connectors 3 between pipe assemblies 2 and their outer ends connected by tubes 43 to the annular water chamber 22 of the next adjacent pipe assembly, define parallel paths for the water to flow from the feeder pipes 20 to the water chambers 22. The pulsator devices 4 thus direct the water, in the form of pulses, from the feeder pipes 20 to the water chambers 22.
Since the pulsator devices pass the water into the water chambers 22 intermittently in the form of pulses, rather than continuously, and since the volume of the annular water chambers 22 is relatively small (being the difference between the volume defined by the inner surface of the outer pipe 21 and the outer surface of the inner feeder pipe 20), the illustrated construction permits very low discharge rates to be produced from the dripper devices 23 even though such driper devices have relatively large passageways and thereby a low sensitivity to clogging.
The dripper devices 23 may be any of the known constructions with or without pressure-compensation, e.g., as described in U.S. Pat. Nos. 3,981,452, 4,281,798, 4,307,841, 4,687,143 or 5,236,130. However, if pressure-compensated pulsators are used, each section of the line defined by a pipe assembly 2 becomes pressure compensated, thereby obviating the need for pressure compensation in the dripper devices.
FIG. 3 illustrates a system as described above with respect to FIGS. 1 and 2, in which the dripper devices carried by the outer tubes 21 are off-line dripper devices, as shown at 23', attachable in discharge openings formed in the outer tubes 21 of the pipe assemblies 2. Except for this difference, the structure and operation of the apparatus illustrated in FIG. 3 is the same as described above with respect to FIGS. 1 and 2, and therefore corresponding reference numerals have been used to identify corresponding parts.
While the irrigation apparatus of the present invention is particularly useful with dripper irrigation devices, it may also be used with other types of irrigation device, such as microsprinklers. Many other variations, modifications and applications of the will be apparent. | Irrigation apparatus includes a feeder line connectible to a source of pressurized water, and an outer line of larger diameter than, and enclosing, the feeder line to define an annular water chamber between them. The outer line includes a plurality of irrigation devices spaced along its length communicating with the water chamber. A plurality of pulsator devices are spaced along the length of the feeder line and connect the feeder line to the water chamber. | 0 |
STATEMENT OF GOVERNMENT INTEREST
The invention described herein may be manufactured and used by or for the Government for governmental purposes without the payment of any royalty thereon.
CROSS REFERENCE TO RELATED APPLICATION
The tapered guide pins used herein, such as 31 and 32, FIG. 1, are similar to the guide pins disclosed in my co-pending patent application entitled, "Easy Change Wheel Assembly".
BACKGROUND OF THE INVENTION
This invention relates generally to the wheel art and, more particularly, to a quick change wheel assembly for a wheeled vehicle.
The current method of mounting a tire-mounted wheel (or "rim") on an automobile, truck or other vehicle concludes with the step of tightening nuts on lugs (or studs) not only to assure that the wheel is secured to the lugs, but also to assure that the wheel does not wobble, even if secure. Nevertheless, there is the well known tendency of overtightening for an added measure of security, thereby creating the future problem of untightening. This problem is compounded with the advent of power driven impact tools which invariably are used in garages and service stations to speed up the wheel change process. The net effect is that most lug nuts are fastened too tightly to be loosened by the aged, the handicapped, the weakened, and by the average female. Further, the reluctance of most service stations to provide roadside assistance places these individuals in jeopardy.
I have invented a unique wheel assembly that cannot be overtightened, and that permits quick change of the tire-mounted wheel member thereof, even by the aged, the handicapped, the weakened, and the average female. Thereby, I have significantly advanced the state-of-the art.
SUMMARY OF THE INVENTION
My invention pertains to a demountable wheel assembly for a vehicle with a tire (not shown) mounted on the wheel member which, in its preferred embodiment, permits the very quick change and/or removal of the tire mounted wheel member from the axle-retained hub member by almost anyone, including the weak, the handicapped, the aged, and the average female. The assembly incorporates fundamental and unique features which include, but are not limited to: tapered nuts partially embedded in the wheel member; headless lug bolts; permanent magnets partially embedded in the axle-retained hub member; and, a brace-shaped driver to use in tightening and untightening the headless lug bolts.
Accordingly, the principal object of this invention is to teach the structure of my above-described novel wheel assembly, by providing a preferred embodiment thereof.
This principal object, as well as related objects, of this invention will become readily apparent after a consideration of the description of the invention, together with reference to the Figures of the drawings.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded view of a preferred embodiment of my inventive wheel assembly, in perspective, partially schematic, and in simplified form, showing the invention in its working environment;
FIG. 2 is a perspective view, in simplified form, partially schematic and partially fragmented, of a representative extension of one of my unique nuts;
FIG. 3 is a perspective view, in simplified form, of a representative one of my novel headless bolts together with my specially structured bolt driver; and
FIG. 4 is a perspective view, partially in cross section, partially fragmented, and partially in schematic form, of the lower portion of my wheel member, my hub member, and a representative one of my headless bolts.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference to FIGS. 1 and 4, therein is shown, in simplified form and in two views, the preferred embodiment 10 of my invention.
In the most basic and generic structural form, my inventive demountable wheel assembly 10, which is for use with an axle (such as 100, FIG. 1), comprises:
a. a wheel hub 11;
b. a wheel 12 that is configurated and is dimensioned to fit over and to complement with the wheel hub 11, with the wheel 12 fitted over, complementing, and abutting with the wheel hub 11;
c. and, means (generally designated 20) for releasably connecting the wheel 12 to the wheel hub 11, such that the wheel 12 can be and is releasably connected to the wheel hub, and where this means 20 includes:
(1) a plurality of tapered and threaded cavities (such as 21A-24A, inclusive, FIG. 1) in the wheel hub 11;
(2) a plurality of threaded nuts (such as 21-24, inclusive, FIG. 1) that are affixed to the wheel 12, with one nut for each one of the plurality of threaded cavities in the wheel hub 11, and with each nut partially embedded (i.e., with the top exposed) in the wheel 12, and also with each nut having affixed thereto an extension (such as representative ones 23B, FIG. 2 and FIG. 4) which is tapered and threaded complementarily to a corresponding cavity in the wheel hub 11, and also with each nut and its extension aligned with their corresponding cavity;
(3) and, a plurality of headless bolts (such as representative ones 25, FIG. 1 and FIG. 4), with each bolt having a first slotted end (such as 25A for representative headless bolt, FIG. 1) and a second tapered and threaded end (such as 25B for representative bolt 25, FIGS. 1 and 3), and with one headless bolt for each one of the plurality of threaded nuts 21-24, inclusive, FIG. 1, and its corresponding cavity 21A-24A, inclusive, FIG. 1, with the threaded second end of each bolt having threads that are complementary to the threads of its corresponding threaded nut, threaded nut extension, and threaded cavity. Of course, as will be explained later herein, each bolt threadedly engages its corresponding threaded nut, threaded nut extension, and threaded cavity when the wheel 11 is releasably connected to the wheel hub 12.
Still with reference to FIGS. 1 and 4, my demountable wheel assembly preferably also includes means, generally designated 30, for aligning the wheel hub 11 and the wheel 12 when releasably connecting them, so that each threaded nut with its threaded extension and its corresponding threaded cavity are in registration to permit driving of the appropriate headless bolt therethrough and therein. This aligning means 30 includes: a plurality of tapered guide pins (such as representative one 31 and 32, FIG. 1) that are affixed to, and project outwardly from, the wheel hub 11; and, a plurality of openings (such as representative ones 31A and 32A) in the wheel 12, with one corresponding opening for each one of the plurality of guide pins, and with each hole aligned with, and shaped and dimensioned to accept, its corresponding guide pin.
Now, with reference to FIG. 3, therein is shown representative headless bolt 25, and the means 40 for driving each one of the headless, slotted, threaded bolts, such as 25, into (and out of) threaded engagement with that bolt's corresponding threaded nut, threaded nut extention, and threaded cavity. As can be seen, the driving means 40 comprises a brace-shaped driver 41 having a driving end 42 that is configurated and dimensioned to fit over the first slotted end (such as 25A) of each volt (such as 25), and also having across the driving end 42 a ridge 43 that is complementarily shaped to fit into, and to engage with, the slot (such as 25C) of the slotted first end of each bolt.
With reference to FIGS. 1 and 4, my demountable wheel assembly 10 preferably also includes a first magnetic means, generally designated 50, for releasably holding the wheel 12 to the wheel hub 11 if the wheel 12 is made of magnetically attractable material (i.e., any material with extremely high magnetic perimeability which reacts strongly in a magnetic field, such as iron, steel, nickel, and the like). This first magnetic means 50 comprises a plurality of exposed permanent magnets, such as 51-54, inclusive, that are partially embedded in the wheel hub 11 and are disposed facing the inner side of the wheel.
If, however, the wheel 12 is made of a non-magnetic material (e.g., plastic, reinforced plastic, and the like), and the wheel-hub is made of a magnetically attractable material (as defined above) then, in that event, my wheel assembly 10 would not and does not include the first magnetic means 50, but rather includes a second magnetic means 60 for releasably holding the wheel 11 and the wheel hub 12 together. This means 60 comprises a plurality of exposed permanent magnets, such as 61-64, inclusive (shown in FIG. 1 in phantom), that are partially embedded in the wheel 12 and are disposed facing the wheel hub 11.
It is to be noted as a matter of preference, and not of limitation: that the plurality of tapered and threaded cavities 21A-24A, inclusive, FIG. 1, in the wheel hub 11 are four (4) in number; that the plurality of tapered guide pins 31 and 32, FIG. 1, are two (2) in number; that the brace-shaped driver 41, FIG. 3, has a short driving span "L" (i.e., driving arm or torque arm); that the plurality of magnets of the first magnetic means 51-54, inclusive, FIG. 1, if used, are four (4) in number; and, that the plurality of magnets of the second magnetic means 61-64, inclusive, FIG. 1, if used, are four (4) in number.
It is also to be noted and remembered that, although the wheel hub 11 is axle-retained, the means (such as 200, FIGS. 1 and 4) for retaining the hub 11 to the vehicular axle (such as 100, FIGS. 1 and 4) does not constitute a part of this invention; and, therefore, is not described or claimed.
MANNER OF OPERATION AND OF USE OF THE INVENTION
The manner of operation and of use of my inventive quick change wheel assembly 10 can be easily ascertained by any person of ordinary skill in the art from the foregoing description, coupled with reference to the FIGS. of the drawings.
For others, the following explanation is made:
Firstly, the wheel 12 with a tire (not shown) mounted on it is guided over and onto the axle-retained wheel hub 11 by use of the guide pins 31 and 32 and the corresponding complementary guide pin holes 31A and 32A, with the pins being inserted into their respective holes. As this is being done, the magnets (of either the first magnetic means 50, or of the second magnetic means 60, whichever means is appropriately used) draw and releasably hold the wheel and the wheel hub together, thereby freeing both hands.
Then, each of the plurality of headless bolts, such as 25 and 26, is manually inserted into its respective corresponding threaded nut, such as 23 for bolt 25 and 21 for bolt 26, and is driven into and through the respective corresponding threaded nut and threaded nut extension, such as 23 and 23B for bolt 25, and into its respective threaded cavity, such as 23A for bolt 25, by, and with the use of, the brace-shaped bolt driver 41, by engaging the slot in the first end of each bolt, such as slot 25C in first end 25A of bolt 25, with the complementarily configurated and dimensional ridge 43 at the driving end 42 of the bolt driver and rotating the driver 41, thereby seating each bolt in its respective cavity and releasably connecting the wheel to the axle-retained wheel hub. It is to be remembered that the driver 41 has a short span "L" to the drive handle that reduces the leverage that can be placed on the bolts and, thereby, overtightening of the bolts is prevented.
To remove the wheel 12 from the axle-retained wheel hub 11, the above sequence is reversed.
CONCLUSION
It is abundantly clear from all of the foregoing, and from the Figures of the drawings, that the desired principal object of the invention, as well as other related objects of the invention, have been achieved.
It is to be noted that, although there have been described and shown the fundamental and unique features of my invention as applied to a particular preferred embodiment, various other embodiments, variations, adaptations, substitutions, additions, omissions, and the like may occur to, and can be made by, those of ordinary skill in the art, without departing from the spirit of my invention. For example, in appropriate circumstances the first and second magnetic means may be used simultaneously, either in registration with each other (i.e, with first magnetic means 50 aligned with second magnetic means 60), or not. | A demountable wheel assembly for a vehicle which comprises an axle-retained wheel hub and a wheel, on which a tire is mounted, which are quickly releasably connectable to, or separable from each other, even by the weak, the aged, and the handicapped. Guide pins on the wheel hub align the tire mounted-wheel, while exposed permanent magnets partially embedded in the wheel hub draw and hold the wheel, thereby freeing the hands. Headless bolts are driven by a brace-shaped driver through threaded bolt nuts that are partially embedded in the wheel; through threaded, tapered extensions behind the nuts; and into threaded, tapered cavities in the wheel hub. Overtightening of the bolts is prevented by the short-span of the bolt driver. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to improvements in a process for polymerizing a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein by using an organic peroxide as the catalyst.
2. Description of the Prior Art
In the prior art, there are a number of well-known processes for the production of styrene polymers on an industrial scale. For example, styrene polymers can be produced simply by heating a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein. Alternatively, they can also be produced by adding an organic peroxide (for example, benzoyl peroxide) to the aforesaid monomer and subjecting the resulting reaction mixture to polymerization.
According to the recent trend of the market, high-molecular-weight styrene polymers are preferred with a view to improving the mechanical and thermal strength of styrene resins. One means of achieving such improved resin performance is to increase the average molecular weight of styrene polymers. This can be realized either by reducing the polymerization temperature or by decreasing the amount of polymerization initiator added. However, since there is a conflicting relationship between the polymerization rate and the average molecular weight of the resulting polymer, it is generally difficult to produce styrene polymers having a high average molecular weight at a high polymerization rate, that is, with high productivity.
In order to solve these problems, a number of processes have been proposed. More specifically, Japanese Patent Publication No. 797/1977 discloses a process which comprises effecting bulk or solution polymerization by using 2,5-dimethyl-2,5-di(tert-butylperoxy)hexyne-3 as the catalyst; Japanese Patent Publication No. 42834/1977 discloses a process which comprises effecting continuous polymerization by using 2,5-dimethyl-2,5-di(benzoylperoxy)hexane, 2,5-dimethyl-2,5-di(tert-butylperoxy)hexane or the like as the catalyst and keeping the contents of the polymerization zone in such a mixed state as to make them substantially homogeneous; and Japanes Patent Laid-Open No. 107994/1979 discloses a process which comprises effecting suspension or bulk-suspension polymerization by using 1,1-bis(tert-butylperoxy)cyclohexane or 1,1-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane as the catalyst.
These prior art processes are based on the technological conception that, in order to improve the mechanical and thermal strength of styrene resins, efforts should be concentrated solely on the preparation of high-molecular-weight styrene polymers in the polymerization step. In practice, however, the high molecular weight of the styrene resins which have been formed into molded articles are important in achieving the desired mechanical and thermal strength. In conventional processes for the production of styrene polymers, the styrene polymer prepared in the polymerization step is subjected to thermal history during the course of after-treatments such as the removal of volatiles and the incorporation of additives, and further heated in the molding step. Thus, the fact is that its average molecular weight is considerably reduced in consequence. Accordingly, in order to produce molded articles having a high average molecular weight, it is most desirable from an industrial point of view to not only achieve a high average molecular weight in the polymerization step but also minimize the reduction in average molecular weight during the course extending from the completion of the polymerization to the fabrication of molded articles.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process for continuously polymerizing a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein to produce high-molecular-weight styrene polymers which can give molded articles having high mechanical and thermal strength.
It is another object of the present invention to provide a process for the production of high-molecular-weight styrene polymers which show no appreciable reduction in average molecular weight during the course of after-treatments following the polymerization step, such as the removal of volatiles and the incorporation of additives, and during the course of forming them into molded articles.
It is still another object of the present invention to provide a process for the production of high-molecular-weight styrene polymers which can enhance their productivity.
The above objects of the present invention are accomplished by a process for continuously polymerizing a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein by using, as the catalyst, an organic peroxide of the general formula ##STR2## where R 1 and R 2 are the same or different radicals selected from the group consisting of hydrogen, alkyl radicals of from 1 to 5 carbon atoms, and phenyl.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The styrene monomers which can be used in the practice of the present invention include styrene, α-methylstyrene and the like as well as their derivatives having one or more additional substituents on the benzene nucleus (for example, p-bromostyrene, p-methylstyrene, p-chlorostyrene, o-bromostyrene and the like). These styrene monomers may be used alone or in admixture. Moreover, copolymerizable monomers such as acrylonitrile, methacrylate esters and the like can be added to these styrene monomers.
The rubber-like polymer which is used in the production of high-impact polystyrene according to the process of the present invention can be any of the rubber-like polymers in common use for that purpose, and typical examples thereof include polybutadiene, copolymers of butadiene and styrene, acrylonitrile, methyl methacrylate or the like, natural rubber, polychloroprene, isoprene-isobutylene copolymer, ethylene-propylene copolymer, ethylene-propylene-diene copolymer and the like.
The amount of rubber-like polymer used is generally in the range of from 1 to 15 parts by weight and preferably from 5 to 10 parts by weight per 100 parts by weight of the styrene monomer.
The organic peroxides which can be used in the practice of the present invention include, for example, tert-butylperoxymaleic acid, methylperoxymaleic acid, isopentylperoxymaleic acid, phenylperoxymaleic acid, methyl pentylperoxymaleate, tert-butyl phenylperoxymaleate, methyl tert-butylperoxymaleate, phenyl tert-butylperoxymaleate and the like.
The amount of organic peroxide used is generally in the range of from 0.003 to 0.3% by weight and preferably from 0.003 to 0.1% by weight based on the weight of the styrene monomer used alone or the weight of the styrene monomer used in conjunction with the rubber-like polymer dissolved therein.
The above-mentioned organic peroxides may be used alone or in admixture. Moreover, they can also be used in admixture with at least one conventional organic peroxide such as benzoyl peroxide, tert-butyl perbenzoate, tert-butyl peroxide or the like.
In the practice of the present invention, the above-defined organic peroxide is added to a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein and the resulting reaction mixture is subjected to continuous polymerization. More specifically, this continuous polymerization is usually carried out by supplying the reaction mixture to the polymerization zone at a fixed rate and withdrawing a part of the reaction mixture from the polymerization zone at a fixed rate, whereby the amount of reaction mixture present in the polymerization zone is always kept on a constant level.
Moreover, in carrying out the continuous polymerization according to the process of the present invention, the reaction mixture present in the polymerization zone should be in such a mixed state that a flow of the complete mixing type is established, and not in a heterogeneous state (for example, in the form of an emulsion or suspension). Such a flow of the complete mixing type can be realized by adopting a polymerizer of the stirred tank reactor type.
Thus, it is preferable to maintain such a mixed state as to make the reaction mixture substantially homogeneous. More specifically, the expression "such a mixed state as to make the reaction mixture substantially homogeneous" means that, when the reaction mixture is sampled from different portions of the polymerization zone, its variation in the conversion of the styrene monomer into a polymer is within 5% and preferably within 3%.
No particular limitation is placed on the manner in which such a mixed state as to make the reaction mixture substantially homogeneous is maintained. Usually, this can be done by agitating the reaction mixture with the aid of a screw type agitator, anchor type agitator, ribbon type agitator, turbine type agitator or the like, by circulating the reaction mixture with the aid of a pump or the like which is provided outside the polymerization zone, or by combinations thereof.
The most preferred embodiments of the present invention can be achieved by satisfying all of the following requirements:
(1) an organic peroxide of the general formula (I) should be used as the catalsyt,
(2) the reaction mixture present in the polymerization zone should be kept in such a mixed state as to make it substantially homogeneous, and
(3) the polymerization should be carried out continuously, Thus, even though continuous polymerization is carried out in a complete mixing manner the objects of the present invention cannot be accomplished if conventional organic peroxides other than those of the general formula (I) are used as the catalyst. Similarly, even though an organic peroxide of the general formula (I) is used as the catalyst, the objects of the present invention cannot be accomplished by such polymerization techniques as emulsion polymerization, suspension polymerization and batch-wise bulk polymerization. In this case, the beneficial effects of the present invention are produced only by solution polymerization or continuous bulk polymerization. In particular, the best results are obtained when continuous bulk polymerization or solution polymerization is carried out in such a manner as to make the reaction mixture substantially homogeneous.
In the practice of the present invention, the polymerization temperature is generally not lower than 100° C. and preferably in the range of 100° to 170° C.
The feed material which is continuously supplied to the polymerization zone in the practice of the present invention may comprise only a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein, or may comprise a partial polymerization product of such a monomer. Moreover, the polymerization of a styrene monomer can be carried out in the presence or absence of a solvent.
Where desired, any of the solvents which are in common use for purposes of solution polymerization and other polymerization techniques (for example, benzene, toluene, ethylbenzene and the like) can be used. The amount of solvent used is generally not greater than 100 parts by weight and preferably not greater than 60 parts by weight per 100 parts by weight of the styrene monomer.
Furthermore, water may be present in the polymerization zone, so long as the reaction mixture is not brought into a heterogeneous state (for example, into the form of an emulsion or the like).
In the practice of the present invention, no particular limitation is placed on the conversion of the styrene monomer into a polymer. However, the conversion is suitably adjusted so as to fall within the range of from 20 to 90%, preferably from 25 to 70% and more preferably from 25 to 60% based on the amount of the styrene monomer used alone or the amount of the styrene monomer used in conjunction with the rubber-like polymer dissolved therein, though it also depends on the number of polymerizers of the agitated vessel type.
According to the process of the present invention, a styrene polymer having a high average molecular weight can be produced in the polymerization step without decreasing its yield per unit time, and the average molecular weight of the styrene polymer formed into molded articles can be kept high by minimizing the reduction in molecular weight during the course extending from the completion of the polymerization to the fabrication of the molded articles.
Generally, when an organic peroxide is used in the polymerization of a styrene monomer, the color properties of molded articles formed from the resulting polymer are poor in many cases. According to the process of the present invention, however, the high average molecular weight and productivity of the polymer are maintained and, at the same time, the color properties of molded articles formed therefrom are very good.
Thus, the process of the present invention is of very great industrial utility in that it can impart excellent performance characteristics to styrene polymers useful as molding materials and can bring about a marked reduction in production cost by increasing the yield of the styrene polymers per unit time.
The present invention will be more fully understood by reference to the following examples. However, these examples are intended merely to illustrate the practice of the intention and are not be construed to limit the scope of the invention.
EXAMPLE 1
A feed material was prepared by dissolving 0.040 part by weight of tert-butylperoxymaleic acid (a product of Nippon Fats and Oils Co.) in 100 parts by weight of styrene. A cylindrical reactor having a capacity of 9.6 liters was provided and the above feed material was continuously supplied thereto through its lower inlet at a rate of 4.8 liters per hour, whereby an average residence time of 2 hours was established. In order to keep the reactor filled with the reaction mixture, a part of the reaction mixture present therein was continuously withdrawn through its upper outlet.
Using a screw type agitator, the reaction mixture present in the reactor was agitated and mixed so that the reaction system would be homogeneous. Moreover, the internal temperature of the reactor was maintained at 130° C.
Ten hours (equal to five times the average residence time) after the start of the continuous polymerization, 2-g samples of the reaction mixture were withdrawn through the sampling valves provided in the lower, middle and upper parts of the reactor. Each of these samples was dissolved in 30 ml of methyl ethyl ketone and the resulting solution was added dropwise to 300 ml of methyl alcohol to form a white precipitate of polystyrene. The polystyrene obtained by drying this white precipitate was dissolved in toluene and its intrinsic viscosity was measured at 30° C. As a result, the intrinsic viscosity of the molded piece was found to be 1.10.
The conversion of the polystyrene obtained by drying the above white precipitate was 45.7, 45.3 and 45.5% for the samples taken from the lower, middle and upper parts of the reactor, respectively.
The reaction mixture continuously withdrawn through the upper outlet of the reactor was subjected to a treatment for the removal of volatiles, in which any unreacted monomer was removed by vacuum distillation. Thereafter, the polystyrene resin thus obtained was pelletized.
Using an ordinary injection molding machine, the above polystyrene resin pellets were molded at 220° C. to form an ASTM test piece. This molded piece was colorless and transparent and showed very excellent color properties. One g of the molded piece was dissolved in 30 ml of methyl ethyl ketone and the resulting solution was added dropwise to 300 ml of methyl alcohol to form a white precipitate. The intrinsic viscosity of this polystyrene was 1.15. The polystyrene obtained by drying this white precipitate was dissolved in toluene and its intrinsic viscosity was measured at 30° C. As a result, the intrinsic viscosity of the molded piece was found to be 1.10.
COMPARATIVE EXAMPLE 1
Using the same reactor as in Example 1, styrene was continuously polymerized in the same manner as described in Example 1 except that the use of tert-butylperoxymaleic acid was omitted. The resulting polystyrene was pelletized and then formed into a molded piece. The analytical results of samples taken from the lower, middle and upper parts of the reactor were in close agreement, and the conversion into polystyrene was 27.3% on the average. When measured in the same manner as described in Example 1, the intrinsic viscosity of the molded piece was 0.94.
COMPARATIVE EXAMPLE 2
A feed material was prepared by dissolving 0.027 part by weight of tert-butyl perbenzoate in 100 parts by weight of styrene. Then, styrene was polymerized in the same manner as described in Example 1 except that the above feed material was used in place of the feed material of Example 1. The resulting polystyrene was formed into a molded piece. The analytical results of samples taken from the lower, middle and upper parts of the reactor were in close agreement, and the conversion into polystyrene was 33.2% on the average. When measured in the same manner as described in Example 1, the intrinsic viscosity of the molded piece was 0.90.
EXAMPLE 2
A feed material was prepared by dissolving 5 parts by weight of polybutadiene in 95 parts by weight of styrene and then dissolving 0.05 part by weight of tert-butylperoxymaleic acid in 100 parts by weight of the resulting solution. Using the same reactor as in Example 1, the above feed material was subjected to continuous polymerization in the same manner as described in Example 1.
Similarly to Example 1, 2-g samples of the reaction mixture were withdrawn through the sampling valves provided in the lower, middle and upper parts of the reactor. Each of these samples was dissolved in 30 ml of toluene and the resulting solution was added dropwise to 300 ml of methyl alcohol to form a white precipitate of the polymer so formed. With regard to the conversion into polystyrene of the styrene included in the feed material, the analytical results of the samples taken from the lower, middle and upper parts of the reactor were in close agreement, and their average value was 46.5%.
Similarly to Example 1, the reaction mixture withdrawn from the reactor was subjected to a treatment for the removal of volatiles. The high-impact polystyrene resin thus obtained was pelletized and then formed into a molded piece. One g of this molded piece was homogeneously dispersed in 50 ml of methyl ethyl ketone and then centrifuged at 12,000 rpm for 30 minutes, whereby the polybutadiene and the polystyrene grafted thereon were separated in the form of an insoluble gel. The supernatant liquid was added dropwise to 500 ml of methyl alcohol to form a white precipitate of the polystyrene separated from the insoluble gel. The intrinsic viscosity of the polystyrene as polymerized was 1.10 and that of the molded piece was 1.06.
EXAMPLE 3
Using the same reactor as in Example 1, styrene was continuously polymerized in the same manner as described in Example 1 except that phenylperoxymaleic acid was used in place of the tert-butylperoxymaleic acid. The resulting polystyrene was pelletized and then formed into a molded piece. The analytical results of samples taken from the lower, middle and upper parts of the reactor were in close agreement, and the conversion into polystyrene was 43.4% on the average. The intrinsic viscosity of the polystyrene as polymerized was 1.04 and that of the molded piece was 1.00.
EXAMPLE 4
A feed material was prepared by dissolving 0.040 part by weight of methyl pentylperoxymaleate in 100 parts by weight of styrene. Using the same reactor as in Example 1, the above feed material was subjected to continuous polymerization in the same manner as described in Example 1. The resulting polystyrene was formed into a molded piece. The analytical results of samples taken from the lower, middle and upper parts of the reactor were in close agreement, and the conversion into polystyrene was 43.0% on the average. The Intrinsic viscosity of the polystyrene as polymerized was 1.02 and that of the molded piece was 0.98. | A process for polymerizing a styrene monomer or a styrene monomer having a rubber-like polymer dissolved therein by using, as the catalyst, an organic peroxide of the formula ##STR1## where R 1 and R 2 are the same or different radicals selected from the group consisting of hydrogen, alkyl radicals of from 1 to 5 carbon atoms, and phenyl. Preferably, the polymerization is continuously carried out by bulk or solution polymerization while the reaction mixture present in the polymerization zone is kept in such a mixed state as to make it substantially homogeneous. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to German Patent Application No. 10 2015 225 557.3, filed Dec. 17, 2015, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to a cosmetic agent for temporarily shaping keratin fibers, and in particular human hair.
BACKGROUND
[0003] Temporarily creating hair styles for an extended period of up to several days generally requires the use of setting active ingredients. Hair treatment agents that are used to temporarily impart shape to the hair therefore play an important role. Corresponding agents for temporary reshaping usually comprise synthetic polymers and/or waxes serving as the setting active ingredient. Agents for supporting the temporary shaping of hair can be formulated in the form of hair spray, hair wax, hair gel, or hair foam, for example.
[0004] The most important property of an agent for temporarily reshaping hair, hereafter also referred to as a styling agent, is to give the treated fibers the strongest hold possible in the newly modeled shape, which is to say a shape that has been imparted to the hair. This is also referred to as strong styling hold or a high degree of hold of the styling agent. The styling hold is essentially determined by the nature and amount of the setting active ingredient that is used, although further components of the styling agent may also have an influence
[0005] In addition to a high degree of hold, styling agents must satisfy a whole host of additional requirements. These can be broken down in approximate terms into properties of the hair, properties of the individual formulation, such as properties of the foam, of the gel, or of the sprayed aerosol, and properties that relate to the handling of the styling agent, wherein the properties of the hair are particularly important. In particular moisture resistance, low tack, and a balanced conditioning effect shall be mentioned. Moreover, a styling agent should be universally suitable for all hair types to an extent as great as possible, and be gentle on the hair and skin.
[0006] In order to meet the diverse requirements, a number of synthetic polymers have already been developed as setting active ingredients, which are used in styling agents. The polymers can be divided into cationic, anionic, non-ionic and amphoteric setting polymers. As an alternative or in addition, waxes are used as setting active ingredients. Ideally, the polymers and/or waxes form a polymer film when applied to the hair, or a film that gives the hair style a strong hold on the one hand, but on the other hand is sufficiently flexible so as not to break under stress.
[0007] Styling products that are present in the form of emulsions can moreover have instabilities in the form of synereses, which have the undesirable effect of resulting in a short shelf life.
BRIEF SUMMARY
[0008] Cosmetic agents for temporarily shaping keratin fibers and methods for temporarily shaping keratin fibers are provided. In accordance with an embodiment, a cosmetic agent for temporarily shaping keratin fibers comprises: (a) at least one wax having a melting point above about 37° C. in a total amount of about 1 to about 30 wt. %; (b) at least one emulsifier in a total amount of about 0.5 to about 20 wt. %; (c) at least one cellulose ether in a total amount of about 0.01 to about 3 wt. %; (d) propionic acid and/or salts of propionic acid in a total amount of about 0.01 to about 2 wt. %; and (e) water in a total amount of about 5 to about 90 wt. %, wherein the weight percent is based in each case on the total weight of the cosmetic agent.
[0009] In accordance with another embodiment, a method for temporarily shaping keratin fibers is provided. The method comprises providing a cosmetic agent comprising: (a) at least one wax having a melting point above about 37° C. in a total amount of about 1 to about 30 wt. %; (b) at least one emulsifier in a total amount of about 0.5 to about 20 wt. %; (c) at least one cellulose ether in a total amount of about 0.01 to about 3 wt. %; (d) propionic acid and/or salts of propionic acid in a total amount of about 0.01 to about 2 wt. %; and (e) water in a total amount of about 5 to about 90 wt. %, wherein the weight percent is based in each case on the total weight of the cosmetic agent. The method further comprises applying the cosmetic agent to the keratin fibers.
DETAILED DESCRIPTION
[0010] The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.
[0011] Shelf-stable, wax-containing cosmetic agents for temporarily shaping keratin fibers are provided herein.
[0012] In this regard, a cosmetic agent for temporarily shaping keratin fibers comprises:
(a) at least one wax having a melting point above about 37° C. in a total amount of about 1 to about 30 wt. %; (b) at least one emulsifier in a total amount of about 0.5 to about 20 wt. %; (c) at least one cellulose ether in a total amount of about 0.01 to about 3 wt. %; (d) propionic acid and/or salt(s) of propionic acid in a total amount of about 0.01 to about 2 wt. %; and (e) water in a total amount of about 5 to about 90 wt. %,
wherein the weight information is based in each case on the total weight of the cosmetic agent.
[0018] Cosmetic agents for temporarily shaping human hair are also referred to as styling agents. The present disclosure relates in particular to styling agents such as hair waxes, pastes, lotions or clays. The product form “clay” refers to high viscosity, wax-like cosmetic agents containing clay compounds (such as kaolin), among other things.
[0019] Surprisingly, it was found within the scope contemplated herein that adding propionic acid and/or salt(s) of propionic acid to a cosmetic agent for temporarily reshaping keratin fibers, and in particular human hair, helped increase the physical stability of cosmetic agents in the form of emulsions, and that these agents exhibit no phase separation (syneresis).
[0020] Moreover, the microbiological stability of the cosmetic agents was increased.
[0021] Other properties that are usually required of cosmetic agents for temporarily shaping keratin fibers such as long-term hold, stiffness and low tack are preserved.
[0022] As contemplated herein, the term “keratin fibers” comprises furs, wool and feathers, but in particular human hair.
[0023] The cosmetic agent comprises at least one natural or synthetic wax having a melting point of above about 37° C. as component (a). The cosmetic agent comprises the at least one wax in a total amount of about 1 to about 30 wt. %, preferably about 2 to about 25 wt. %, and more preferably about 2.5 to about 20 wt. %, based on the total weight of the cosmetic agent.
[0024] Natural or synthetic waxes that can be used include solid paraffins or isoparaffins, plant-based waxes such as candelilla wax, carnauba wax, esparto grass wax, Japan wax, cork wax, sugar cane wax, ouricury wax, montan wax, sunflower wax, fruit waxes, and animal waxes, such as beeswaxes and other insect waxes, cetaceum, shellac wax, wool fat and rump fat, furthermore mineral waxes such as ceresin and ozokerite, or petrochemical waxes, such as petrolatum, paraffin waxes, microwaxes made of polyethylene or polypropylene, and polyethylene glycol waxes. It may be advantageous to use hydrogenated waxes. Furthermore, it is also possible to use chemically modified waxes, in particular the hard waxes, such as montan ester waxes, sasol waxes and hydrogenated jojoba waxes.
[0025] Also suitable are the triglycerides of saturated and optionally hydroxylated C16-30 fatty acids, such as hydrogenated triglyceride fats (hydrogenated palm oil, hydrogenated coconut oil, hydrogenated castor oil), glyceryl tribehenate or glyceryltri-12-hydroxy stearate, furthermore synthetic full esters of fatty acids and glycols (such as Syncrowachs®) or polyols having 2 to 6 carbon atoms, fatty acid monoalkanol amides including a C12-22 acyl group and a C2-4 alkanol group, esters of saturated and/or unsaturated, branched and/or unbranched alkane carboxylic acids having a chain length of 1 to 80 carbon atoms and saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 1 to 80 carbon atoms, including, for example, synthetic fatty acid/fatty alcohol esters such as stearyl stearate or cetyl palmitate, esters of aromatic carboxylic acids, dicarboxylic acids or hydroxycarboxylic acids (such as 12-hydroxystearic acid), and saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 1 to 80 carbon atoms, lactides of long-chain hydroxycarboxylic acids, and full esters of fatty alcohols and dicarboxylic and tricarboxylic acids, such as dicetyl succinate or dicetyl/distearyl adipate, and mixtures of these substances.
[0026] The wax components can also be selected from the group of the esters of saturated, unbranched alkane carboxylic acids having a chain length of 14 to 44 carbon atoms and saturated, unbranched alcohols having a chain length of 14 to 44 carbon atoms, provided the wax component or the collectivity of the wax components is solid at room temperature. The wax components can be selected, for example, from the group consisting of the C16-36 alkyl stearates, the C10-40 alkyl stearates, the C2-40 alkyl isostearates, the C20-40 dialkyl esters of dimer acids, the C18-38 alkyl hydroxystearoyl stearates, the C20-40 alkyl erucates, and furthermore C30-50 alkyl beeswax and cetearyl behenate can be used. Silicone waxes, such as stearyl trimethylsilane/stearyl alcohol, are also optionally advantageous. Preferred wax components are the esters of saturated, monohydric C20 to C60 alcohols and saturated C8 to C30 monocarboxylic acids, preferably in particular a C20 to C40 alkyl stearate, which is available from Koster Keunen Inc. by the name Kesterwachs® K82H.
[0027] Natural, chemically modified and synthetic waxes can be used alone or in combination. The teaching contemplated herein thus also comprises the combined use of multiple waxes. Furthermore, a number of wax mixtures, optionally blended with further additives, is commercially available. Examples of mixtures that can be used include those by the designations “Spezialwachs 7686 OE” (mixture of cetyl palmitate, beeswax, microcrystalline wax and polyethylene having a melting point of 73 to 75° C.; manufacturer: Kahl & Co), Polywax® GP 200 (a mixture of stearyl alcohol and polyethylene glycol stearate having a melting point of 47 to 51° C.; manufacturer: Croda) and “Weichceresin® FL 400” (a paraffin jelly/liquid paraffin/wax mixture having a melting point of 50 to 54° C.; manufacturer: Parafluid Mineraldgesellschaft).
[0028] The wax (a) is preferably selected from carnauba wax (INCI: Copernicia Cerifera Cera), Myrica Cerifera Fruit Wax (INCI), Rhus Verniciflua Peel Cera (INCI), beeswax (INCI: Beeswax), Petrolatum (INCI), microcrystalline wax, and in particular mixtures thereof.
[0029] The wax (a) is particularly preferably a mixture of a plant-based wax, in particular carnauba wax (INCI: Copernicia Cerifera Cera), beeswax (INCI: Beeswax) and Petrolatum (INCI).
[0030] The wax or the wax components should be solid at about 25° C. and should melt around >about 37° C.
[0031] The agent comprises at least one emulsifier as the further essential component (b). In principle, anionic, cationic, non-ionic and ampholytic surface-active compounds which are suitable for use on the human body can be used as emulsifiers. The ampholytic surface-active compounds comprise zwitterionic surface-active compounds and ampholytes. Non-ionic emulsifiers are preferred.
[0032] Non-ionic emulsifiers that can be used include in particular addition products of ethylene oxide to linear fatty alcohols, to fatty acids, to fatty acid alkanolamides, to fatty acid monoglycerides, to sorbitan fatty acid monoesters, to fatty acid glycerides, to methyl glucoside monofatty acid esters, to polydimethyl siloxanes, and mixtures thereof.
[0033] The at least one emulsifier (b) is preferably selected from non-ionic emulsifiers such as addition products of about 2 to about 50 moles ethylene oxide to linear fatty alcohols having 8 to 30, preferably 12 to 18 carbon atoms, addition products of about 2 to about 50 moles ethylene oxide and about 1 to about 5 moles propylene oxide to linear fatty alcohols having 8 to 30, preferably 12 to 18 carbon atoms, addition products of about 2 to about 100 moles ethylene oxide to linear fatty acids having 12 to 18 carbon atoms, and mixtures thereof.
[0034] Examples of preferred emulsifiers (b) are compounds having the INCI names Steareth-2, Steareth-21, Oleth-10, PEG-100 Stearate or PPG-5-Ceteth-20, and in particular combinations thereof.
[0035] Likewise preferred emulsifiers (b) are the esters of fatty acids having 12 to 22 carbon atoms with saccharides. In particular the monoesters and/or diesters of sucrose with stearic acid and/or palmitic acids are preferably used. Examples of particularly preferred emulsifiers are compounds having the INCI names Sucrose Stearate, Sucrose Distearate, or mixtures thereof.
[0036] Further preferred emulsifiers (b) are linear fatty acids having 12 to 22 carbon atoms and mixtures thereof. The linear fatty acids can be present in neutralized and/or non-neutralized form, depending on the pH value. Preferably, non-neutralized palmitic acid and/or stearic acid are used as emulsifiers (b).
[0037] Likewise preferred emulsifiers (b) are addition products of about 2 to about 20 moles ethylene oxide to beeswax, such as in particular the compounds having the INCI names PEG-6 Beeswax, PEG-8 Beeswax, PEG-12 Beeswax or PEG-20 Beeswax. PEG-8 Beeswax is particularly preferred from this class of emulsifiers.
[0038] Another class of emulsifiers (b) that can preferably be used is the monoesters of fatty acids having 12 to 22 carbon atoms with glycerol. In particular the monoesters of glycerol with stearic acid and/or palmitic acids are preferably used. Examples of particularly preferred emulsifiers are compounds having the INCI names Glyceryl Stearate, Glyceryl Palmitate, or mixtures thereof.
[0039] In an exceptionally preferred embodiment, the emulsifier (b) is selected from the group consisting of linear fatty acids having 12 to 22 carbon atoms, monoesters of fatty acids having 12 to 22 carbon atoms with glycerol, addition products of about 2 to about 20 moles ethylene oxide to beeswax, and mixtures thereof.
[0040] The cosmetic agent comprises the at least one emulsifier in a total amount of about 0.5 to about 20 wt. %, preferably about 2 to about 25 wt. %, and more preferably about 2.5 to about 20 wt. %, based on the total weight of the cosmetic agent.
[0041] The cosmetic agent furthermore comprises a cellulose ether as the essential component (c). The amount of cellulose ether, based on the total amount of cosmetic agent, is about 0.01 to about 3 wt. %.
[0042] It is preferred that the cellulose ether is selected from the group consisting of methyl cellulose, ethyl cellulose, propyl cellulose, methylethyl cellulose, carboxymethyl cellulose, ethyl carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl hydroxyethyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl hydroxyethyl cellulose, methyl ethyl hydroxyethyl cellulose, and mixtures thereof. Cellulose ethers that are preferably used are hydroxyethyl cellulose and hydroxypropyl cellulose. In a preferred embodiment, the cellulose ether comprises hydroxyethyl cellulose. In a particularly preferred embodiment, the cellulose ether is hydroxyethyl cellulose.
[0043] Preferred cosmetic agents, based on the weight thereof, comprise the cellulose ether or ethers in a total amount of about 0.025 to about 2 wt. %, and more preferably in a total amount of about 0.05 to about 1 wt. %.
[0044] The cosmetic agent furthermore comprises propionic acid and/or salt(s) of propionic acid as the essential component (d). Preferably one or more propionic acid salts are used, wherein the use within certain narrow quantity ranges is particularly effective.
[0045] For this purpose, among other things the alkali metal salts sodium propionate, potassium propionate, as well as ammonium propionate, magnesium propionate, calcium propionate, zinc propionate, iron propionate and manganese propionate have proven to be particularly suitable. Preferred cosmetic agents comprise salt(s) from the group consisting of sodium propionate, potassium propionate, as well as ammonium propionate, magnesium propionate, calcium propionate, zinc propionate, iron propionate and manganese propionate in a total amount of about 0.01 to about 2 wt. %, preferably about 0.1 to about 1.75 wt. %, and in particular about 0.5 to about 1.5 wt. %, in each case based on the weight of the agent. Particularly preferred salts of propionic acid are selected from sodium propionate, potassium propionate, calcium propionate and mixtures thereof.
[0046] Particularly preferred cosmetic agents, based on the weight thereof, comprise about 0.01 to about 2 wt. %, preferably about 0.1 to about 1.75 wt. %, and in particular about 0.5 to about 1.5 wt. % calcium propionate. It may be preferred that component (d) is calcium propionate.
[0047] The cosmetic agent comprises water. Preferred cosmetic agents comprise water as the cosmetic carrier. In these embodiments, the cosmetic agent comprises water as the main component. The water content of the cosmetic agents is about 5 to about 90 wt. %, preferably about 15 to about 80 wt. %, and more preferably about 40 to about 75 wt. %, based on the total weight of the cosmetic agent.
[0048] The cosmetic agent can furthermore comprise at least one film-forming polymer that is different from the wax component (a). Examples are cationic, anionic, non-ionic or amphoteric polymers. The cosmetic agent can comprise the at least one film-forming polymer (f) in a total amount of about 1 to about 60 wt. %, preferably about 2 to about 50 wt. %, and more preferably about 5 to about 40 wt. %, based on the total weight of the cosmetic agent.
[0049] Examples include acrylamide/ammonium acrylate copolymer, acrylamides/DMAPA acrylates/methoxy PEG methacrylate copolymer, acrylamidopropyltrimonium chloride/acrylamide copolymer, acrylamidopropyltrimonium chloride/acrylates copolymer, acrylates/acetoacetoxyethyl methacrylate copolymer, acrylates/acrylamide copolymer, acrylates/ammonium methacrylate copolymer, acrylates/t-butylacrylamide copolymer, acrylates copolymer, acrylates/C1-2 succinates/hydroxyacrylates copolymer, acrylates/lauryl acrylate/stearyl acrylate/ethylamine oxide methacrylate copolymer, acrylates/octylacrylamide copolymer, acrylates/octylacrylamide/diphenyl amodimethicone copolymer, acrylates/stearyl acrylate/ethylamine oxide methacrylate copolymer, acrylates/VA copolymer, acrylates/VP copolymer, adipic acid/diethylenetriamine copolymer, adipic acid/dimethylaminohydroxypropyl diethylenetriamine copolymer, adipic acid/epoxypropyl diethylenetriamine copolymer, adipic acid/isophthalic acid/neopentyl glycol/trimethylolpropane copolymer, allyl stearate/VA copolymer, aminoethylacrylate phosphate/acrylates copolymer, aminoethylpropanediol-acrylates/acrylamide copolymer, aminoethylpropanediol-AMPD-acrylates/diacetoneacrylamide copolymer, ammonium VA/acrylates copolymer, AMPD-acrylates/diacetoneacrylamide copolymer, AMP-acrylates/allyl methacrylate copolymer, AMP-acrylates/C1-18 alkyl acrylates/C1-8 alkyl acrylamide copolymer, AMP-acrylates/diacetoneacrylamide copolymer, AMP-acrylates/dimethylaminoethylmethacrylate copolymer, Bacillus/rice bran extract/soybean extract ferment filtrate, bis-butyloxyamodimethicone/PEG-60 copolymer, butyl acrylate/ethylhexyl methacrylate copolymer, butyl acrylate/hydroxypropyl dimethicone acrylate copolymer, butylated PVP, butyl ester of ethylene/MA copolymer, butyl ester of PVM/MA copolymer, calcium/sodium PVM/MA copolymer, corn starch/acrylamide/sodium acrylate copolymer, diethylene glycolamine/epichlorohydrin/piperazine copolymer, dimethicone crosspolymer, diphenyl amodimethicone, ethyl ester of PVM/MA copolymer, hydrolyzed wheat protein/PVP crosspolymer, isobutylene/ethylmaleimide/hydroxyethylmaleimide copolymer, isobutylene/MA copolymer, isobutylmethacrylate/bis-hydroxypropyl dimethicone acrylate copolymer, isopropyl ester of PVM/MA copolymer, lauryl acrylate crosspolymer, lauryl methacrylate/glycol dimethacrylate crosspolymer, MEA-sulfite, methacrylic acid/sodium acrylamidomethyl propane sulfonate copolymer, methacryloyl ethyl betaine/acrylates copolymer, octylacrylamide/acrylates/butylaminoethyl methacrylate copolymer, PEG/PPG-25/25 dimethicone/acrylates copolymer, PEG-8/SMDI copolymer, polyacrylamide, polyacrylate-6, polybeta-alanine/glutaric acid crosspolymer, polybutylene terephthalate, polyester-1, polyethylacrylate, polyethylene terephthalate, polymethacryloyl ethyl betaine, polypentaerythrityl terephthalate, polyperfluoroperhydrophenanthrene, Polyquaternium-1, Polyquaternium-2, Polyquaternium-4, Polyquaternium-5, Polyquaternium-6, Polyquaternium-7, Polyquaternium-8, Polyquaternium-9, Polyquaternium-10, Polyquaternium-11, Polyquaternium-12, Polyquaternium-13, Polyquaternium-14, Polyquaternium-15, Polyquaternium-16, Polyquaternium-17, Polyquaternium-18, Polyquaternium-19, Polyquaternium-20, Polyquaternium-22, Polyquaternium-24, Polyquaternium-27, Polyquaternium-28, Polyquaternium-29, Polyquaternium-30, Polyquaternium-31, Polyquaternium-32, Polyquaternium-33, Polyquaternium-34, Polyquaternium-35, Polyquaternium-36, Polyquaternium-37, Polyquaternium-39, Polyquaternium-45, Polyquaternium-46, Polyquaternium-47, Polyquaternium-48, Polyquaternium-49, Polyquaternium-50, Polyquaternium-55, Polyquaternium-56, Polysilicone-9, Polyurethane-1, Polyurethane-6, Polyurethane-10, polyvinyl acetate, polyvinyl butyral, polyvinylcaprolactam, polyvinylformamide, polyvinyl imidazolinium acetate, polyvinyl methyl ether, potassium butyl ester of PVM/MA copolymer, potassium ethyl ester of PVM/MA copolymer, PPG-70 polyglyceryl-10 ether, PPG-12/SMDI copolymer, PPG-51/SMDI copolymer, PPG-10 sorbitol, PVM/MA copolymer, PVP, PVP/VA/itaconic acid copolymer, PVP/VA/vinyl propionate copolymer, rhizobian gum, rosin acrylate, shellac, sodium butyl ester of PVM/MA copolymer, sodium ethyl ester of PVM/MA copolymer, sodium polyacrylate, sterculia urens gum, terephthalic acid/isophthalic acid/sodium isophthalic acid sulfonate/glycol copolymer, trimethylolpropane triacrylate, trimethylsiloxysilylcarbamoyl pullulan, VA/crotonates copolymer, VA/crotonates/methacryloxybenzophenone-1 copolymer, VA/crotonates/vinyl neodecanoate copolymer, VA/crotonates/vinyl propionate copolymer, VA/DBM copolymer, VA/vinyl butyl benzoate/crotonates copolymer, vinylamine/vinyl alcohol copolymer, vinyl caprolactam/VP/dimethylaminoethyl methacrylate copolymer, VP/acrylates/lauryl methacrylate copolymer, VP/dimethylaminoethylmethacrylate copolymer, VP/DMAPA acrylates copolymer, VP/hexadecene copolymer, VP/VA Copolymer, VP/vinyl caprolactam/DMAPA acrylates copolymer, yeast palmitate or styrene/VP copolymer.
[0050] Furthermore, siloxanes are suitable as film-forming polymers. These siloxanes can either be water-soluble or water-insoluble. Both volatile and non-volatile siloxanes are suitable, wherein non-volatile siloxanes shall be understood to mean those compounds having a boiling point above about 200° C. at normal pressure. Preferred siloxanes are polydialkylsiloxanes, such as polydimethylsiloxane, polyalkylarylsiloxanes, such as polyphenylmethylsiloxane, ethoxylated polydialkylsiloxanes, and polydialkylsiloxanes containing amine and/or hydroxy groups. Glycosidically substituted silicones may also be used.
[0051] Homopolyacrylic acid (INCI: Carbomer), which is commercially available in different embodiments under the name Carbopol®, is also a suitable film-forming polymer.
[0052] The film-forming polymer is preferably selected from vinylpyrrolidone-containing polymers. The film-forming polymer is particularly preferably selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer, Vinyl Caprolactam/VP/Dimethylaminoethyl Methacrylate Copolymer (INCI), VP/DMAPA Acrylates Copolymer (INCI) and mixtures thereof.
[0053] A film-forming polymer that is likewise preferred is the Octylacrylamide/Acrylates/Butylaminoethyl Methacrylate Copolymer (INCI), which is sold by AkzoNobel under the designation “Amphomer®.”
[0054] In particular nourishing components, such as oils, should be mentioned as further suitable auxiliary agents and additives.
[0055] Suitable oils are selected from among the esters of the linear or branched, saturated or unsaturated fatty alcohols having 2 to 30 carbon atoms with linear or branched, saturated or unsaturated fatty acids having 2 to 30 carbon atoms, which may be hydroxylated. These include cetyl-2-ethylhexanoate, 2-hexyldecyl stearate (for example, Eutanol® G 16 S), 2-hexyldecyl laurate, isodecyl neopentanoate, isononyl isononanoate, 2-ethylhexyl palmitate (for example, Cegesoft® C 24) and 2-ethylhexyl stearate (for example Cetiol® 868). Likewise preferred are isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, isooctyl stearate, isononyl stearate, isocetyl stearate, isononyl isononanoate, isotridecyl isononanoate, cetearyl isononanoate, 2-ethylhexyl laurate, 2-ethylhexyl isostearate, 2-ethylhexyl cocoate, 2-octyldodecyl palmitate, butyloctanoic acid-2-butyl octanoate, diisotridecyl acetate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate, ethylene glycol dioleate, and ethylene glycol dipalmitate. Cetyl-2-ethylhexanoate is particularly preferred.
[0056] Further preferred oils are selected from natural and synthetic hydrocarbons, particularly preferably from mineral oils, paraffin oils, C 18 to C 30 isoparaffins, in particular isoeicosane, polyisobutene and polydecene, which are available under the designation Emery® 3004, 3006, 3010 or under the designation Ethylflo® from Albemarle or Nexbase® 2004G from Nestle, for example, and further selected from C 8 to C 16 isoparaffins, in particular from isodecane, isododecane, isotetradeane and isohexadecane, and mixtures thereof, as well as 1,3-bis(2-ethylhexyl)cyclohexane (available under the trade name Cetiol® S from BASF, for example).
[0057] Further preferred oils are selected from the benzoic acid esters of linear or branched C8-22 alkanols. Particularly preferred are benzoic acid-C12-C15-alkyl esters, for example available as the commercial product Finsolv® TN, benzoic acid isostearyl esters, for example available as the commercial product Finsolv® SB, ethylhexyl benzoate, for example available as the commercial product Finsolv® EB, and benzoic acid octyldodecyl esters, for example available as the commercial product Finsolv® BOD.
[0058] Further preferred oils are selected from fatty alcohols having 6 to 30 carbon atoms, which are unsaturated, or branched and saturated, or branched and unsaturated. The branched alcohols are frequently also referred to as Guerbet alcohols since they can be obtained by way of the Guerbet reaction. Preferred alcohol oils are 2-hexyldecanol (Eutanol® G 16), 2-octyldodecanol (Eutanol® G), 2-ethylhexyl alcohol and isostearyl alcohol.
[0059] Further preferred oils are selected from mixtures of Guerbet alcohols and Guerbet alcohol esters, for example the commercial product Cetiol® PGL (2-hexyldecanol and 2-hexyldecyl laurate).
[0060] Further preferred cosmetic oils are selected from the triglycerides (=triple esters of glycerol) of linear or branched, saturated or unsaturated, optionally hydroxylated C8-30 fatty acids. The use of natural oils can be particularly preferred, such as amaranth seed oil, apricot kernel oil, argan oil, avocado oil, babassu oil, cottonseed oil, borage seed oil, camelina oil, thistle oil, peanut oil, pomegranate seed oil, grapefruit seed oil, hemp oil, hazelnut oil, elderberry seed oil, currant seed oil, jojoba oil, linseed oil, macadamia nut oil, corn oil, almond oil, marula oil, evening primrose oil, olive oil, palm oil, palm kernel oil, Brazil nut oil, pecan nut oil, peach kernel oil, rapeseed oil, castor oil, sea buckthorn pulp oil, sea buckthorn kernel oil, sesame oil, soy bean oil, sunflower oil, grape seed oil, walnut oil, wild rose oil, wheat germ oil, and the liquid components of coconut oil, and the like. However, synthetic triglyceride oils, in particular capric/caprylic triglycerides, such as the commercial products Myritol® 318, Myritol® 331 (BASF) or Miglyol® 812 (Hüls) comprising unbranched fatty acid esters and glyceryl triisostearol with branched fatty acid esters are also preferred.
[0061] Further preferred cosmetic oils are selected from the dicarboxylic acid esters of linear or branched C2 to C10 alkanols, in particular diisopropyl adipate, di-n-butyl adipate, di-(2-ethylhexyl) adipate, dioctyl adipate, diethyl-/di-n-butyl/dioctyl sebacate, diisopropyl sebacate, dioctyl malate, dioctyl maleate, dicaprylyl maleate, diisooctyl succinate, di-2-ethylhexyl succinate, and di-(2-hexyldecyl) succinate.
[0062] Further preferred cosmetics oils are selected from the addition products of 1 to 5 propylene oxide units to monohydric or polyhydric C8-22 alkanols, such as octanol, decanol, decanediol, lauryl alcohol, myristyl alcohol, and stearyl alcohol, for example PPG-2 myristyl ether and PPG-3 myristyl ether (Witconol® APM).
[0063] Further preferred cosmetic oils are selected from the addition products of at least 6 ethylene oxide units and/or propylene oxide units to monohydric or polyhydric C3-22 alkanols, such as glycerol, butanol, butanediol, myristyl alcohol and stearyl alcohol, which may optionally be esterified, such as PPG-14 butyl ether (Ucon Fluid® AP), PPG-9 butyl ether (Breox® B25), PPG-10 butanediol (Macol® 57), PPG-15 stearyl ether (Arlamol® E), and glycereth-7-diisononanoate.
[0064] Further preferred cosmetic oils are selected from the C8 to C22 fatty alcohol esters of monovalent or polyvalent C2 to C7 hydroxycarboxylic acids, in particular the esters of glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, and salicylic acid. Such esters based on linear C14/15 alkanols, such as C12 to C15 alkyl lactate, and of C12/13 alkanols branched at the 2-position, may be purchased under the trademark Cosmacol® from Nordmann, Rassmann GmbH & Co., Hamburg, in particular the commercial products Cosmacol® ESI, Cosmacol® EMI, and Cosmacol® ETI.
[0065] Further preferred cosmetic oils are selected from the symmetric, asymmetric or cyclic esters of carbonic acid with C 3-22 alkanols, C 3-22 alkane diols or C 3-22 alkane triols, such as dicaprylyl carbonate (Cetiol® CC), or the esters according to the teaching of DE 19756454 A1, and in particular glycerol carbonate.
[0066] Further cosmetic oils that may be preferred are selected from the esters of dimers of unsaturated C 12 to C 22 fatty acids (dimer fatty acids) comprising monohydric linear, branched or cyclic C 2 to C 18 alkanols or polyhydric linear or branched C 2 to C 6 alkanols.
[0067] Further cosmetic oils that are suitable are selected from silicone oils, which include, for example, dialkyl and alkyaryl siloxanes, such as cyclopentasiloxane, cyclohexasiloxane, dimethylpolysiloxane and methylphenylpolysiloxane, but also hexamethyldisiloxane, octamethyltrisiloxane and decamethyltetrasiloxane. Volatile silicone oils, which may be cyclic, can be preferred, such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane, and mixtures thereof, as they can be found in the commercial products DC 244, 245, 344 and 345 from Dow Corning, for example. Volatile linear silicone oils are likewise suitable, in particular hexamethyldisiloxane (L 2 ), octamethyltrisiloxane (L 3 ), decamethyltetrasiloxane (L 4 ), and arbitrary mixtures of two and three of L 2 , L 3 and/or L 4 , preferably mixtures such as those present, for example, in the commercial products DC 2-1184, Dow Corning® 200 (0.65 cSt) and Dow Corning® 200 (1.5 cSt) from Dow Corning. Preferred non-volatile silicone oils are selected from higher molecular weight linear dimethylpolysiloxanes, commercially available, for example, under the designation Dow Corning® 190, Dow Corning® 200 Fluid having kinematic viscosities (25° C.) in the range of 5 to 100 cSt, preferably 5 to 50 cSt, or 5 to 10 cSt, and dimethylpolysiloxane having a kinematic viscosity (25° C.) of approximately 350 cSt.
[0068] It may be exceptionally preferred to use mixtures of the aforementioned oils.
[0069] The agent can also include at least one protein hydrolysate and/or one of the derivatives thereof, for example, as a nourishing component. Protein hydrolysates are product mixtures that are obtained by the acidically, basically or enzymatically catalyzed degradation of proteins. The term “protein hydrolysates” shall also be understood to cover total hydrolysates and individual amino acids and the derivatives thereof, as well as mixtures of different amino acids. The molecular weight of the protein hydrolysates that can be used ranges between about 75, the molecular weight for glycine, and about 200,000; the molecular weight is preferably about 75 to about 50,000, and especially particularly preferably about 75 to about 20,000 daltons.
[0070] The agent can furthermore include at least one vitamin, a provitamin, a vitamin precursor and/or one of the derivatives thereof as a nourishing component. Vitamins, provitamins and vitamin precursors that are usually assigned to the groups A, B, C, E, F and H are preferred.
[0071] To set the pH, the cosmetic agent can furthermore comprise neutralizers or pH setting agents. Examples of neutralizers that are used in cosmetic agents are primary amino alcohols such as Aminomethyl Propanol (INCI), which is commercially available under the designation AMP-ULTRA® PC, for example, such as AMP-ULTRA® PC 2000.
[0072] The agents can furthermore comprise additional cosmetically acceptable preservatives. One example of a preservative that can preferably be used is 2-phenoxyethanol.
[0073] The cosmetic agent contemplated herein can be formulated in the forms customary for the temporary shaping of hair, for example as a wax, paste, lotion or clay. The cosmetic agents are preferably offered in jars or crucibles.
[0074] An exemplary embodiment also relates to the cosmetic, non-therapeutic use of cosmetic agents contemplated herein for temporarily shaping keratin fibers, and in particular human hair, and to a method for temporarily reshaping keratin fibers, and in particular human hair, in which the cosmetic agent is applied to keratin fibers.
[0075] An exemplary embodiment also relates to the use of propionic acid and/or salts of propionic acid in a cosmetic agent for temporarily reshaping keratin fibers, and in particular human hair, which is preferably present in the form of an emulsion, for increasing the physical stability of the cosmetic agent. Preferably, cosmetic agents contemplated herein are used.
[0076] Tabular Overview
[0077] The composition of several preferred cosmetic agents can be derived from the following tables (information as solids content and in percent by weight based on the total weight of the cosmetic agent, unless indicated otherwise).
[0000] Formula 1 Formula 2 Formula 3 (a) Wax 1-30 2-25 2.5-20 (b) Emulsifier 0.5-20 0.75-17.5 1-15 (c) Cellulose ether 0.01-3 0.0225-2 0.05-1 (d) Propionic acid and/or 0.01-2 0.1-1.75 0.5-1.5 salt(s) of propionic acid (e) Water 5-90 15-80 40-75 Misc. to make up to make up to make up to 100 to 100 to 100 Formula 1a Formula 2a Formula 3a (a) Wax 1-30 2-25 2.5-20 (b) Emulsifier 0.5-20 0.75-17.5 1-15 (c) Cellulose ether 0.01-3 0.0225-2 0.05-1 (d) Propionic acid and/or 0.01-2 0.1-1.75 0.5-1.5 salt(s) of propionic acid (e) Water 5-90 15-80 40-75 (f) Film-forming polymer 1-60 2-50 5-40 Misc. to make up to make up to make up to 100 to 100 to 100 Formula 1b Formula 2b Formula 3b (a) Plant-based wax and/or 1-30 2-25 2.5-20 beeswax and/or petrolatum (b) Emulsifier 0.5-20 0.75-17.5 1-15 (c) Hydroxyethyl cellulose 0.01-3 0.0225-2 0.05-1 (d) Salt(s) of propionic acid 0.01-2 0.1-1.75 0.5-1.5 (e) Water 5-90 15-80 40-75 (f) Non-ionic and/or 0 or 1-60 0 or 2-50 0 or 5-40 amphoteric film-forming polymer Misc. to make up to make up to make up to 100 to 100 to 100 Formula 1c Formula 2c Formula 3c (a) Plant-based wax and/or 1-30 2-25 2.5-20 beeswax and/or petrolatum (b) Non-ionic emulsifier 0.5-20 0.75-17.5 1-15 (c) Hydroxyethyl cellulose 0.01-3 0.0225-2 0.05-1 (d) Salt(s) of propionic acid 0.01-2 0.1-1.75 0.5-1.5 (e) Water 5-90 15-80 40-75 (f) Vinylpyrrolidone- 0 or 1-60 0 or 2-50 0 or 5-40 containing polymer and/or Octylacrylamide/Acrylates/ Butylaminoethyl Methacrylate Copolymer (INCI) Misc. to make up to make up to make up to 100 to 100 to 100 Formula 1d Formula 2d Formula 3d (a) Plant-based wax and/or 1-30 2-25 2.5-20 beeswax and/or petrolatum (b) Linear fatty acids 0.5-20 0.75-17.5 1-15 having 12 to 22 carbon atoms and/or monoesters of fatty acids having 12 to 22 carbon atoms with glycerol and/or addition products of 2 to 20 moles ethylene oxide to beeswax (d) Hydroxyethyl cellulose 0.01-3 0.0225-2 0.05-1 (e) Ca salt of propionic acid 0.01-2 0.1-1.75 0.5-1.5 (e) Water 5-90 15-80 40-75 (f) Vinylpyrrolidone- 0 or 1-60 0 or 2-50 0 or 5-40 containing polymer and/or Octylacrylamide/Acrylates/ Butylaminoethyl Methacrylate Copolymer (INCI) Misc. to make up to make up to make up to 100 to 100 to 100
“Misc” shall be understood to mean further customary components of cosmetic agents for temporarily shaping keratin fibers, such as perfumes/aromatic substances, pH-setting agents and/or nourishing components.
EXAMPLES
[0078] The following cosmetic agents were produced:
[0000]
Example 1
Component/raw material
INCI name
(% by weight)
Carnauba wax
Copernicia Cerifera Cera
7.5
Beeswax
Beeswax
7.5
Petrolatum
Petrolatum
4
Hydroxyethyl cellulose
Hydroxyethylcellulose
0.1
Calcium propionate
Calcium Propionate
1
Glyceryl monostearate
Glyceryl Stearate
5
Ethoxylated beeswax (8EO)
PEG-8 Beeswax
1
Palmitic acid
Palmitic Acid
1
Stearic acid
Stearic Acid
1
Isopropyl myristate
Isopropyl Myristate
5.6
2-amino-2-methylpropanol
Aminomethyl Propanol
0.25
Dyes
0.077
2-Phenoxyethanol
Phenoxyethanol
0.8
Perfume
Perfume (Fragrance)
1.7
Water
Aqua (Water)
to make 100
[0079] The quantity information in the tables is provided in % by weight of the respective raw material, based on the total agent.
[0080] The cosmetic agent 1 was physically and microbiologically stable over a period of 12 weeks at various temperatures (room temperature, 0° C., 45° C., −10° C.).
[0081] All produced cosmetic agents exhibited outstanding application and distribution properties in the hair and showed no residue on the treated hair.
[0082] While at least one exemplary embodiment has been presented in the foregoing detailed description of the invention, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment or exemplary embodiments are only examples, and are not intended to limit the scope, applicability, or configuration of the invention in any way. Rather, the foregoing detailed description will provide those skilled in the art with a convenient road map for implementing an exemplary embodiment of the invention. It being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope of the invention as set forth in the appended claims. | A shelf-stable cosmetic agent for temporarily shaping keratin fibers, and in particular human hair, having improved protection against phase separation and having increased microbiological stability is provided. | 0 |
[0001] Continuation in part of application number 09/733,527 which was filed Dec. 11, 2000.
FIELD OF THE INVENTION
[0002] The invention relates to the general field of powder metallurgy and compression molding with particular reference to forming complex structures.
BACKGROUND OF THE INVENTION
[0003] The production of metal or ceramic components using powder injection molding (PIM) processes is well known. The powder is mixed with the binder to produce a mixture that can be molded into the desired part. The binder must have suitable flow properties to permit injection into a tooling cavity and forming of the part. The molded part is usually an oversized replica of the final part. It is subjected to debinding where the binder is removed without disturbing the powder orientation. After the binder is removed, the part is subjected to sintering process that results in part densification to a desired level.
[0004] The parts produced by PIM may be complex in geometry. They also tend to be made of a single material. For example, an orthodontic bracket can be made of 316L stainless steel using PIM technology.
[0005] There is, however, a need for objects, formed by PIM, that contain multiple parts, each of which is a different material whose properties differ from those of its immediate neighbors. The prior art practice has been to form each such part separately and to then combine them in the finished product using costly welding operations or mechanical fitting methods to bond these different parts of different materials together.
[0006] The basic approach that the present invention takes to solving this problem is schematically illustrated in FIGS. 1 a and 1 b . In FIG. 1 a , 11 and 12 represent two green objects having different physical properties and formed by PIM. FIG. 1 b shows the same two objects, after sintering, joined to form a single object. In the prior art, the interface 13 between 11 and 12 was usually a weld (i.e. a different material from either 11 or 12 ). Alternately, a simple press fit between the 11 and 12 might have sufficed so that the final object was not a continuous body.
[0007] An obvious improvement over welding or similar approaches would appear to have been to sinter 11 and 12 while they were in contact with one another. In practice, such an approach has usually not succeeded due to a failure of the two parts to properly bond during sintering. The present invention teaches how problems of this sort can be overcome so that different parts made of materials having different physical properties can be integrated to form a single continuous body.
[0008] A routine search of the prior art was performed with the following reference of interest being found: In “Composite parts by powder injection molding”, Advances in powder metallurgy and particulate materials, vol. 5, pp 19-171 to 19-178, 1996, Andrea Pest et al. discuss the problems of sintering together parts that comprise more than one material. They show that control of shrinkage during sintering is important but other factors (to be discussed below) are not mentioned.
SUMMARY OF THE INVENTION
[0009] It has been an object of the present invention to provide a process for the formation of a continuous body having multiple parts, each with different physical properties and/or different functional properties, there being no connecting material (such as solder or glue) between any of the parts.
[0010] This object have been achieved by using powder injection molding together with careful control of the relative shrinkage rates of the various parts. Additionally, for the case where it is the physical properties that differ between parts, care is taken to ensure that only certain selected physical properties are allowed to differ between the parts while others may be altered through relatively small changes in the composition of the feedstocks used.
[0011] Another object has been to provide a process for forming, in a single integrated operation, an object that is contained within an enclosure while not being attached to said enclosure.
[0012] This object has been achieved by means of powder injection molding wherein the shrinkage rate of the object is caused to be substantially greater than that of the enclosure. As a result, after sintering, the object is found to have detached itself from the enclosure, being free to move around therein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] [0013]FIGS. 1 a and 1 b illustrate two contiguous parts, made of different materials, before and after sintering, respectively.
[0014] [0014]FIGS. 2 a and 2 b show steps in the process of the present invention.
[0015] [0015]FIG. 3 is an isometric view of the object seen in cross-section in FIG. 2 b.
[0016] [0016]FIG. 4 is a plan view of an object that has three parts, one non-magnetic, one a hard magnet, and one a soft magnet.
[0017] [0017]FIG. 5 is a cross-section taken through the center of FIG. 4.
[0018] FIGS. 6 to 8 illustrate steps in the process of the second embodiment wherein an object is formed inside an enclosure.
[0019] [0019]FIG. 9 shows a cutting tool formed through application of the present invention.
[0020] [0020]FIG. 10 shows a wire die formed through application of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] This invention describes a novel method of manufacturing multi-material components using powder injection molding processes. Injection molding of different-material articles is an economically attractive method for manufacturing finished articles of commercial values due to its high production capacity and net shape capability.
[0022] As is well known to those skilled in the art, the basic procedure for forming sintered articles is to first provide the required material in powdered form. This powder is then mixed with lubricants and binders to form a feedstock. Essentially any organic material which will decompose under elevated temperatures without leaving an undesired residue that will be detrimental to the properties of the metal articles, can be used. Preferred materials are various organic polymers such as stearic acids, micropulvar wax, paraffin wax and polyethylene. Stearic acid serves as a lubricant while all the other materials may be used as binders. The amount and nature of the binder/lubricant that is added to the powder will determine the viscosity of the feedstock and the amount of shrinkage that will occur during sintering.
[0023] Once the feedstock has been prepared, it is injected into a suitable mold. The resulting ‘green’ object is then ejected from the mold. It has sufficient mechanical strength to retain its shape during handling while the binder is removed by heating or through use of a solvent. The resulting ‘skeleton’ is then placed in a sintering furnace and, typically, heated at a temperature between about 1,200 and 1,350° C. for between about 30 and 180 minutes in hydrogen or vacuum.
[0024] As already noted, attempts to form single objects containing parts made of different materials have usually been limited to forming the parts separately and joining them together later. This has been because green parts made of different materials could not be relied upon to always bond properly during the sintering process.
[0025] The present invention teaches that failure to bond during sintering comes about because (i) the shrinkage of the parts differs one from the other by more than a critical amount and (ii) certain physical properties differ between the parts.
[0026] By the same token, certain other physical properties may be quite different between the parts with little or no effect on bonding.
[0027] Physical properties that need to be the same or similar if good bonding is to occur include (but are not limited to) coefficient of thermal expansion and melting point, while properties that may differ without affecting bonding include (but are not limited to) electrical conductivity, magnetic coercivity, dielectric constant, thermal conductivity, Young's modulus, hardness, and reflectivity.
[0028] In cases that are well suited to the practice of the present invention it will not be necessary for the composition of two powders to vary one from another by very much. Typically, the two mixtures would differ in chemical composition by less than about 25 percent of all ingredients.
[0029] Additionally, it is important that the powders that were used to form the feedstocks of the two parts share similar characteristics such as particle shape, texture, and size distribution. The tap densities of the two powders should not differ by more than about 30% while the mean particle size for both powders should be in the range of about 1 to 40 microns.
[0030] As an example, if one part needs to be soft material (say low carbon iron), and another part is to be a hard material such as high carbon iron, then alloying the low carbon iron with specific amount of carbon will enhance hardenability and meet the requirement of high carbon iron. In so doing, both powders are still similar and have similar shrinkage rates. This will give rise to good bonding between the two materials while having different properties.
[0031] Similarly, if one material is low carbon iron and another is stainless steel, then blending the master alloy of the stainless steel with an appropriate amount of iron powder to form the required stainless steel composition can bring the overall powder characteristics closer to each other. For example, if two materials are 316L Stainless Steel and low carbon iron. Then the approach is to blend one third of master alloy of 316L with two-third of low carbon iron to form the actual 316L composition.
[0032] Note that molding of a two-material article can be achieved in one tooling of one or several cavities in a single barrel machine of one material first. The molded article is transferred to another tooling in another single barrel machine of another material to form the desired article though a manual pick-and-place operation or by using a robotic arm. The molding process can also be carried out on a twin-barrel injection machine to mold a complete article with two materials within a single tooling.
1 st Embodiment
[0033] We will illustrate this embodiment through reference to FIGS. 2 a and 2 b , but it should be understood that the process that we disclose is independent of the shape, form, size, etc. of the structure that is formed.
[0034] The first step is the preparation of a first feedstock. This is accomplished by adding lubricants and binders (as discussed earlier) to a mixture of powders. The latter consist, by weight, of about 0.05 percent carbon, about 15 percent chromium, about 0.5 percent manganese, about 0.5 percent silicon, about 0.3 percent niobium, about 4 percent nickel, and about 80 percent iron. Using a suitable mold, this first feedstock is compression molded to form first green part 21 , as shown in FIG. 2 a . This happens to have a cylindrical shape with 22 representing the hollow center.
[0035] Then, a second feedstock is formed by adding lubricants and binders to a mixture of powders consisting, by weight, of about 0.05 percent carbon, about 15 percent chromium, about 0.5 percent manganese, about 0.5 percent silicon, about 0.3 percent niobium, about 14 percent nickel, and about 70 percent iron. It is important that the lubricants and binders are present in concentrations that ensure that, after sintering, the difference in the amounts the two feedstocks shrink is less than about 1% of total shrinkage experienced by either one.
[0036] We note here that although the two feedstocks have the same composition except that 10% of iron has been replaced by an additional 10% of nickel. This relatively small change in chemical composition leaves the key physical properties associated with successful sintering unchanged but introduces a significant change in the magnetic properties.
[0037] Next, first green part 21 is transferred to a second mold into which is then injected a sufficient quantity of the second feedstock to complete the structure shown in FIG. 2 b through the placement of 23 around ring 21 .
[0038] Once the final ‘compound’ green object has been formed, all lubricants/binders are removed, in ways discussed earlier, resulting in a powder skeleton which can then be sintered so that it becomes a continuous body having both magnetic and non-magnetic parts. Because of the compositions of the originals powders from which the two feedstocks were formed, part 21 of FIG. 2 b that derived from the first feedstock is magnetic while part 23 that derived from the second feedstock is not. In this particular example the magnetic part has a maximum permeability (μ max) between about 800 and 1,500.
[0039] In FIG. 3 we show an isometric view of the object seen in FIG. 2 b with the addition of rod 33 which is free to move back and forth through hole 22 . If rod 33 is magnetic, its position relative to hole 22 could be controlled by means of an applied magnetic field generated by an external coil (not shown). Since part 21 is of a magnetic material, it will act as a core for concentrating this applied field. Rod 33 could be formed separately or it could be formed in situ as part of an integrated manufacturing process, using the method to be described later under the second embodiment.
[0040] As already implied, the formation of a continuous body having multiple parts, each with different properties, need not be limited to two such parts. In FIG. 4 we show a plan view of an object having three parts, each with different properties. All parts are concentric rings. At the center of the structure is opening 44 that is surrounded by inner ring 43 . Ring 43 is non-magnetic. It is surrounded by ring 41 that is a soft magnet. Its inner portion has the same thickness as ring 43 . Ring 41 also has an outer portion that is thicker than ring 43 , causing it to have an inside sidewall 52 which can be seen in the cross-sectional view shown in FIG. 5. Aligned with, and touching, this sidewall is intermediate ring 42 which is a hard magnet. In this context, the term soft magnet refers to a material having a low coercivity with high magnetic saturation while the term hard magnet refers to a material having a high coercivity.
[0041] The structure seen in FIGS. 4 and 5 is made by fitting hard magnet 42 (made separately) into the integral part after 41 and 43 have been formed. The reason for adding a ring of magnetically hard material to a structure that is similar to that seen in FIG. 3 is to be able to provide a permanent bias for the applied external magnetic field.
2nd Embodiment
[0042] In this embodiment we disclose a process for forming, in a single integrated operation, one object that is enclosed by another with the inner object not being attached to the outer object. As for the first embodiment, the process is illustrated through an example but it will be understood that it is applicable to any shaped object inside any shaped enclosure.
[0043] In FIG. 6 we show, in schematic representation, an object that has been formed through PIM. As part of the process for its formation, the quantity and quality of the binders/lubricants were chosen so that, after sintering, the green form of 61 would shrink by a relatively large amount (typically between about 20 and 50%).
[0044] Referring now to FIG. 7 we show enclosure 71 that has been formed by fully surrounding 61 with material from a second feedstock for which binders/lubricants were chosen so that, after sintering, the green form of 71 would shrink by a relatively small amount (typically between about 10 and 20%) Regardless of the absolute shrinkages associated with parts 61 and 71 , it is a key requirement of the process that the difference between the two shrinkage rates be at least 10%.
[0045] After the removal of all lubricants and binders from the object seen in FIG. 7, the resulting powder skeleton is sintered (between about 1,200 and 1,380° C. for between about 30 and 180 minutes in vacuum or in hydrogen for ferrous alloy steels. Because of the larger shrinkage rate of 61 relative to 71 , the structure after sintering has the appearance shown in FIG. 8 where part 81 (originally 61 ) is seen to have become detached from 71 enabling it to move freely inside interior space 82 . An example of a structure of this type is an electrostatic motor (unfinished at this stage) in which 71 will ultimately serve as the stator and 81 as the rotor. In the prior art, such structures had to be made using a sacrificial layer to effect the detachment of 81 from 71 .
Functional Properties
[0046] In the foregoing discussion we were concerned with combining, in a single continuous structure, two or more parts that had different physical properties. The same principles that are taught there may also be applied to structures having two or more parts that differ in their functional properties. By functional properties we mean properties that are application related. Although functional properties derive from physical and chemical properties, they are often a subtle blend of the latter and the adjective used to describe them will depend on the application for which they are intended. Thus, a given electrical resistivity may be considered to be low when the application is for a resistor and high when the application is for a conductor. Functional properties are therefore harder to define but a definition must be provided for them to be meaningful.
[0047] We list below, as examples, a series of functional properties that are pertinent to the present invention, together with their definitions. It will be realized that this list is not complete and other functional properties could also be given to parts of a continuous structure without departing from the spirit of the invention. In most cases these definitions are precise but, occasionally, they must, of necessity, be of a descriptive rather than a quantitative nature:
[0048] magnetic—ferromagnetic
[0049] corrosion resistant—As defined in the ASTMG157-98 Standard Guide for Evaluating the Corrosion Properties of Wrought Iron and Nickel-Based Corrosion Resistant Alloys for the Chemical Process Industries. Examples of materials that have good corrosion resistance include (but not limited to) Pure Nickel, Nickel-Copper (eg Monel 400, Monel K-500), Nickel-Chromium (eg Inconel 617, Inconel 625) Nickel-Iron-Chromium (eg Incoloy DS, Incoloy 825), and Nickel-based superalloys (eg Nimonic 80A)
[0050] controlled porosity—this manifests itself as a relative density, with a density 90-100% of the pore-free material being considered High and densities of 50-90% being considered Low
[0051] high thermal conductivity—greater than about 100 W/m. K
[0052] high density—greater than about 9,000 kg/m 3
[0053] high strength—tensile greater than about 900 Mpa, yield greater than about 700 MPa.
[0054] low thermal expansion—less than about 12×10 −6 K −1
[0055] wear resistant—having a hardness value less than about 50 HRC
[0056] high elastic modulus—greater than 200 GPa
[0057] high damping capacity—loss of 25% or more of stored energy per cycle
[0058] good machinability—using AISI 1212 as a guide, steel is rated 100% with a value in excess of 50% being considered good
[0059] highly fatigue resistant—able to withstand at least 10 8 cycles of alternating standard and zero loads
[0060] high hardness—greater than 50 HRC
[0061] high toughness—Based on Charpy or Izod testing, toughness is defined as the energy per unit volume that can be absorbed by a material up to the point of fracture. High toughness implies a value greater than about _____ joules/m 3
[0062] high melting point—greater than about 1600° C. (iron melts at 1537° C.).
[0063] oxidation resistant—as for corrosion resistant above, but limited to oxygen as the corrosive agent
[0064] easy joinability—based on experience but includes materials such as copper, silver, and gold.
[0065] It follows from our earlier discussion of processes for forming continuous bodies having multiple parts, each of which has a different set of physical properties, that these same processes may be adapted to forming continuous bodies having multiple parts, each of which has a different set of functional properties. While in the general case these bodies will comprise more than two functional parts, we take note here of a special case in which only two functionally different parts are involved, said two different functions being particularly difficult and/or expensive to combine in a single continuous body when processes of the prior art are used for their manufacture.
[0066] The following lists some examples of functional pairs of this type, it being understood that other functional pairs could be added to this list without departing from the spirit of the invention:
[0067] magnetic-corrosion resistant, controlled porosity-high thermal conductivity, high density-high strength, high thermal conductivity-low thermal expansion, wear resistant-high toughness, controlled porosity-high strength, high elastic modulus-high damping capacity, high strength-good machinability, controlled porosity-highly fatigue resistant, magnetic-non-magnetic, high hardness-high toughness, wear resistant-oxidation resistant, easy joinability-corrosion resistant, and low internal stress-controlled porosity.
[0068] To further illustrate the application of the present invention to the manufacture of structures having two parts that would ordinarily be difficult to combine in a single continuous structure, we now describe two additional embodiments of the present invention.
3rd Embodiment
[0069] In this embodiment we disclose a process and structure for forming a cutting tool. As in the first and second embodiments, the process of the third embodiment begins with the provision of two mixtures of powdered materials. One the these mixtures will, after sintering, be well suited for use as a handle while the other, also after sintering, will have excellent properties for use as a cutting edge.
[0070] The mixture that is intended to become the handle is selected from materials such as iron, and all iron-based alloys (such as carbon steels, low-alloyed steels and stainless steels). See, for example, Metals Handbook, Volume 1, 10 th edition 1990.
[0071] Possible materials for the mixture that will become the cutting edge are all tool steels, including water-hardening steels (Type W), shock-resisting steels (Type S), cold-work steels (Type O, A, D and H), hot-work steels (Type H), High speed steels (Type T and M), mold steels (Type P) and tungsten carbide. Details on the classification of tool steels may be found in in the AISI (American Iron and Steel Institute) handbook.
[0072] Lubricants and binders are added to each mixture to form feedstocks, a key requirement being that the amount that said feedstocks will shrink after sintering differs one from the other by less than about 1%. Then, the appropriate feedstock is compression molded to form a green part having the shape of a handle (shown schematically as 92 in FIG. 9) which is then transferred to a second mold into which is injected a sufficient quantity of the other feedstock for forming an extension to the green part in the shape of a cutting edge (shown schematically as 91 in FIG. 9).
[0073] After removal of all lubricants and binders (thereby forming a powder skeleton), the latter is sintered, as discussed earlier, to become the cutting tool.
4 th Embodiment
[0074] In this embodiment we disclose a process and structure for forming a wire die. As in the previous embodiments, the process of the fourth embodiment begins with the provision of two mixtures of powdered materials. One the these mixtures will, after sintering, be well suited for use as a handle and is selected from the group consisting of iron, and all iron-based alloys (such as carbon steels, low-alloyed steels and stainless steels) while the other will be well suited to serve as a die, being selected from the group consisting of all tool steels, including water-hardening steels (Type W), shock-resisting steels (Type S), cold-work steels (Type O, A, D and H), hot-work steels (Type H), High speed steels (Type T and M), mold steels (Type P), and tungsten carbide.
[0075] Also as before, lubricants and binders are added to these mixtures to form feedstocks which, after sintering, will shrink by amounts that differ one from one another by less than about 1%.
[0076] Additionally, a third feedstock is provided that has the key property that, after sintering, it will shrink an amount that exceeds the amount that the first two feedstocks shrink by at least 10%. In this case the feedstock can be made from just binders, including waxes such as paraffin wax and thermoplastics such as polyethylene.
[0077] The appropriate feedstock is then compression molded to form a green part having the shape of a handle (see 92 in FIG. 10), following which it is transferred to a second mold into which is injected a sufficient quantity of the third feedstock to add to the green part an extension having a cylindrical pin-cushion shape (see 94 in FIG. 10). This modified green part is then transferred to a third mold into which is injected a sufficient quantity of the last feedstock to surround the pin-cushion shaped extension (see 93 in FIG. 10).
[0078] All lubricants and binders are then removed so that the green part becomes a powder skeleton which can be sintered to become a solid continuous material. After sintering, the residue of materials that were originally part of the third feedstock can be removed by mechanical and/or chemical means, resulting in formation of the die cavity (shown schematically as 94 in FIG. 10).
[0079] While the invention has been particularly shown and described with reference to the preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the spirit and scope of the invention. | The invention shows how powder injection molding may be used to form a continuous body having multiple parts, each of which has different functional properties such as corrosion resistance or hardness, there being no connective materials such as solder or glue between the parts. This is accomplished through careful control of the relative shrinkage rates of these various parts. Although there is no limit to how many parts with different functional properties can make up an object, special attention is paid to certain pairs of functional properties that are difficult and/or expensive to combine in a single object when other manufacturing means are used. | 1 |
BACKGROUND OF THE INVENTION
[0001] The subject invention relates to a flexible duct liner insulation specifically designed for lining sheet metal ducts in air conditioning, heating and ventilating systems. More particularly, the subject invention relates to a flexible duct liner insulation of biosoluble glass fibers bonded together with a formaldehyde-free acrylic binder resin wherein the binder resin cures without coloration of the duct liner insulation and an interior airstream surface of the duct liner insulation is coated with a white acrylic latex water and dirt repellant coating containing an antimicrobial agent.
[0002] Sheet metal ducts of air conditioning, heating and ventilating systems are normally lined with flexible glass fiber duct liner insulations that are coated on the interior with acrylic latex coatings. These duct liner insulations control both sound and thermal transmissions within and through the air conditioning, heating and ventilating systems to reduce transmitted noise and conserve energy. The preparation and/or subsequent processing of these duct liner insulations often involves handling steps, e.g. cutting, that result in cut or broken fibers which may be inhaled. Accordingly, the formation of the glass fibers in these duct liner insulations from glass compositions that exhibit high degrees of biosolubility, i.e. glass compositions that are rapidly solubilized in biological fluids, is desirable. However, in addition to being biosoluble such glass fibers should be: strong to minimize glass fiber breakage so that the insulation duct liners made with the glass fibers recover substantially to their pre-compressed thickness after compression packaging; moisture resistant so that the glass fibers do not appreciably weaken when the insulation duct liners are stored in humid conditions; and made from glass compositions that are easy and economical to process.
[0003] The glass fibers within and forming these duct liner insulations are normally bonded together at their points of intersection by phenol/formaldehyde binding resins. While these binding resins are economical and can be extended with urea prior to use as a binder, the industry's desire to minimize volatile organic compound emissions (VOCs) to provide a cleaner environment and the presence of increasingly stringent federal regulations makes the use of binders with reduced VOCs in these duct liner insulations desirable. In addition, when these phenol/formaldehyde binder resins are cured they impart a color to the insulation blanket cores of the duct liner insulations, e.g. a yellow color that is not aesthetically pleasing. Thus, there has been a need to utilize binders in these insulation blanket cores: that reduce or eliminate unwanted VOCs, that can be easily applied to the glass fibers forming the insulation blanket cores, that are cost effective, and that do not color the insulation blanket cores.
SUMMARY OF THE INVENTION
[0004] The glass fiber duct liner insulation of the subject invention, for lining sheet metal ducts in air conditioning, heating and ventilating systems, includes a flexible blanket of biosoluble glass fibers exhibiting a biodisolution rate in excess of 150 ng/cm 2 /hr. The glass fibers of the blanket forming the core of the duct liner insulation of the subject invention are bonded together at their points of intersection by a formaldehyde-free, thermosetting, acrylic acid-based latex binder resin that cures without coloration of the blanket. A major surface of the blanket, adapted to be an interior surface of the duct liner insulation over which an airstream is to be conveyed by a duct system, is coated with a white, acrylic latex, water and dirt repellant, erosion resistant, coating that contains an antimicrobial agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] [0005]FIG. 1 is a partial perspective view of the duct liner insulation of the subject invention installed in a sheet metal duct of an air conditioning, heating and ventilating system.
[0006] [0006]FIG. 2 is an enlarged detail of the encircled portion of FIG. 1.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0007] [0007]FIG. 1 shows a sheet metal duct 20 lined with the flexible duct liner insulation 22 of the subject invention. The duct liner insulation 22 includes a glass fiber insulation blanket core 24 and a coating 26 on and coextensive with an inner major surface 28 of the glass fiber blanket core. Typically, the duct liner insulation 22 is secured to an interior surface of the sheet metal duct 20 by adhesively bonding an outer major surface 30 of the blanket core 24 to the interior surface of the sheet metal duct and by passing conventional mechanical fastener pins (not shown) through the duct liner insulation 22 and into the sheet metal duct.
[0008] The glass fiber blanket core 24 is flexible and typically has a density between about 1 (0.37 Kg/m 3 ) and about 4 pound/ft 3 (1.5 Kg/m 3 ). The glass fiber blanket core 24 is between ½ of an inch (13 mm) and 2 inches (51 mm) in thickness; between 34 inches (864 mm) and 60 inches ( 1524 mm) in width; and about 50 feet (15 lineal meters) to 200 feet (61 lineal meters) in length. The glass fibers of the glass fiber blanket core 24 are made from a glass composition that exhibits a biodisolution rate in excess of 150 ng/cm 2 /hr. While other suitable glass compositions may be used to form glass fibers of the duct liner insulation 22 with the required physical properties, preferred glass compositions used to form the glass fibers of the duct liner insulation 22 are disclosed in U.S. Pat. No. 5,945,360, issued Aug. 31, 1999 (hereinafter referred to as the “'360 patent”) and the disclosure of that patent is hereby incorporated herein in its entirety by reference. The preferred glass compositions of the '360 patent may be used in pot and marble, flame attenuation glass fiberization processes.
[0009] The preferred glass compositions of the '360 patent have high temperature viscosity (HTV) and liquidus which are suitable for production of glass fibers in the pot and marble process. Such glass compositions generally must have an HTV (10 3 poise) of 1800° F. to 2100° F., preferably 1900° F. to 2000° F., exhibit a liquidus which is minimally about 350° F., preferably 425° F., and preferably, 500° F. or lower than the HTV. These characteristics are necessary to prepare glass fibers economically on a continuous basis. The preferred glass composition must fall within the following range of compositions, in mol percent:
SiO 2 66-69.7 Al 2 O 3 0-2.2 RO 7-18 R 2 O 9-20 B 2 O 3 0-7.1
[0010] where R 2 O is an alkali metal oxide and RO is an alkaline earth metal oxide. R 2 O is preferably Na 2 O in most substantial part, while RO may be MgO and/or CaO, preferably both, in a molar ratio of MgO/CaO of 1:3 to 3:1, more preferably 2:3 to 3:2. The chemical behavior of the glass is dictated by three ratios which the glass composition must meet, C(acid), C(bio), and C(moist). These ratios are defined compositionally as follows, all amounts being in mol percent:
C (acid)=[SiO 2 ]/([Al 2 O 3 ]+B 2 O 3 ]+[R 2 O]+[RO])
C (bio)=([SiO 2 ]+[Al 2 O 3 ])/([B 2 O 3 ]+[R 2 O]+[RO])
C (moist)=([SiO 2 ]+[Al 2 O 3 ]+(B 2 0 3 ])/([R 2 O]+[RO]).
[0011] In these ratios, C(acid) is the ratio which pertains to chemical resistance in acid environments, C(bio) is the ratio which is most closely linked to biosolubility, and C(moist) is the ratio which relates to the retention of properties in moist environments. It is desired that C(acid) and C(moist) be as large as possible, while C(bio) should be as low as possible. At the same time, the HTV (10 3 poise) and liquidus of the overall composition must be suitable for glass fiber processing in the pot and marble flame attenuation process [a difference, ΔT, between HTV (10 3 poise) and liquidus in excess of 350° F.]. It has been found that pot and marble glass of high biosolubility made by flame attenuated processes maintain other necessary physical properties, while yet maintaining other necessary physical properties such as chemical resistance and moisture resistance, is obtained when C(acid)≧1.95, C(bio)≦2.30, and C(moist)≧2.40.
[0012] Preferably, the biosoluble glass fibers used in the glass fiber blanket core 24 have a composition which falls within the following ranges (in mol percent):
SiO 2 66-69.0 Al 2 O 3 0-2.2 RO 7-16 R 2 O 9-19 B 2 O 3 0-7.1
[0013] Most preferably, the biosoluble glass fibers used in the glass fiber blanket core have a composition which falls within the following ranges (in mol percent):
SiO 2 66-68.25 Al 2 O 3 0-2.2 RO 7-13 R 2 O 11-18 B 2 O 3 0-7.1
[0014] With respect to the performance characteristics of the glass fibers used in the glass fiber blanket core 24 , it is preferred that C(acid) be greater than or equal to 2.00; C(bio) be less than or equal to 2.23, more preferably, less than or equal to 2.20; and that C(moist) be greater than or equal to 2.46, more preferably greater than or equal to 2.50, most preferably greater than or equal to 2.60. As discussed previously, it is most desirable that C(acid) and C(moist) values be as high as possible. For example, C(moist) values of 3.00 or greater are particularly preferred. It should also be noted that the various C-ratios are independent in the sense that a more preferred glass need not have all “more preferred” C-ratios.
[0015] The acid resistance of the fibers may be measured by battery industry standard tests. For example, a typical test involves the addition of 5 grams of nominally 3 micron diameter fiber in 50 mL of sulfuric acid having a specific gravity of 1.26. Following refluxing for 3 hours, the acid phase may be separated by filtration and analyzed for dissolved metals or other elements.
[0016] The procedure used to evaluate biodissolution rate of the fibers is similar to that described in Law et al. (1990). The procedure consists essentially of leaching a 0.5 gram aliquant of the candidate fibers in a synthetic physiological fluid, known as Gamble's fluid, or synthetic extracellular fluid (SEF) at a temperature of 37° C. and rate adjusted to achieve a ratio of flow rate to fiber surface area of 0.02 cm/hr to 0.04 cm/hr for a period of up to 1,000 hours duration. Fibers are held in a thin layer between 0.2 micron polycarbonate filter media backed by plastic support mesh and the entire assembly placed within a polycarbonate sample cell through which the fluid may be percolated. Fluid pH is regulated to 7.4+0.1 through the use of positive pressure of 5% CO 2 /95% N 2 throughout the flow system.
[0017] Elemental analysis using inductively coupled plasma spectroscopy (ICP) of fluid samples taken at specific time intervals are used to calculate the total mass of glass dissolved. From this data, an overall rate constant can be calculated for each fiber type from the relation:
k={d 0 p (1−( M/M 0 ) 0 5 )/2 t
[0018] where: k is the dissolution rate constant in SEF, d 0 the initial fiber diameter, p the initial density of the glass comprising the fiber, M 0 the initial mass of the fibers, M the final mass of the fibers (M/M 0 =the mass fraction remaining), and t the time over which the data was taken. Details of the derivation of this relation are given in Leinweber (1982) and Potter and Mattson (1991). Values for k may be reported in ng/cm 2 /hr and preferably exceed a value of 150. Replicate runs on several fibers in a given sample set show that k values are consistent to within 3 percent for a given composition.
[0019] Data obtained from the above outlined evaluation can be effectively correlated within the sample set chosen. While the mean fiber diameter of the fibers used in the lightweight insulation products of the present invention is about 1+/−0.25 microns, dissolution data used to derive k values for the glass fibers used in the lightweight glass fiber insulations of the present invention were obtained only from experimental samples of uniform 3.0 micron diameter and under identical conditions on initial sample surface area per volume of fluid per unit time, and sample permeability. Data was obtained from runs of up to 30 days to obtain an accurate representation of the long term dissolution of the fibers. Preferred biodissolution rate constants in ng/cm 2 /hr are greater than 150 ng/cm 2 /hr, preferably greater than 200 ng/cm 2 /hr, more preferably greater than 300 ng/cm 2 /hr, and most preferably greater than 400 ng/cm 2 /hr.
[0020] To the determine moisture resistance of the glass fibers, a stress corrosion test is used in which fibers are stressed by bending the fibers in a controlled humidity and temperature test chamber. Fibers which exhibit moisture resistance under these conditions take longer to break.
[0021] With respect to the preferred glass compositions used to form the glass fibers in the insulation blanket core 24 , by the term “consisting essentially of” is meant that additional ingredients may be added to the composition provided the additional ingredients do not substantially alter the nature of the composition. Substances which cause the biodissolution rate to drop below 150 ng/cm 2 /hr or which lower the ΔT to a value below 350° F. are substances which do substantially alter the composition. Preferably, the glass compositions are free of iron oxides, lead oxides, fluorine, phosphates (P 2 O 5 ), zirconia, and other expensive oxides, except as unavoidable impurities.
[0022] The primary fibers exiting from the pot in the pot and marble fiberization process are flame attenuated rather than hot gas attenuated, thus exposing the glass fibers to higher temperatures than in a rotary fiberization process. These higher temperatures cause a loss of the more volatile compounds of the glass composition from the outside of the fibers, resulting in a “shell” which has a different composition than the fiber interior. As a result, the biosolubility of glass fibers prepared from the pot and marble fiberization process is not the same as that derived from a rotary fiberization process. It should be noted that while rotary process glass compositions are in general unsuitable for pot and marble fiberization process, the reverse is not true, the preferred glass compositions of the subject invention should yield fibers prepared by the rotary process which have yet higher rates of biodissolution.
[0023] The formaldehyde-free, thermosetting, acrylic acid-based latex binder resins used in the insulation blanket core 24 can be applied with minimal processing difficulties and enable the core 24 to have good recovery. The preferred formaldehyde-free, thermosetting, acrylic acid-based binder resins cure without any coloration of the blanket by crosslinking with a poly-functional, carboxyl group-reactive curing agent. One such preferred acrylic acid-based latex binder resin is a binder that includes a polycarboxy polymer and glycerol. It is also preferred that the binder comprises a catalyst, such as an alkaline metal salt of a phosphorous-containing organic acid, most preferably sodium hypophosphite. An important aspect of the binder is that the polycarboxy polymer used in the binder in combination with the glycerol has a very low molecular weight. It is preferred that the molecular weight of the polycarboxy polymer is less than 10,000, more preferably 5000 or less, and most preferably around 3000 or less with around 2000 molecular weight giving excellent results.
[0024] The use of glycerol in combination with the low molecular weight polycarboxy polymer, preferably polyacrylic acid, has been found to avoid any formaldehyde emissions and provide a binder which cures colorless. The use of such a low molecular weight polycarboxy polymer in the binder also beneficially results in a binder which exhibits few, if any, processing difficulties when preparing the insulation blanket core 24 .
[0025] The polycarboxy polymer used in the binder comprises an organic polymer or oligomer containing more than one pendant carboxy group. The polycarboxy polymer may be a homopolymer or copolymer prepared from unsaturated carboxylic acids including but not necessarily limited to, acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, maleic acid, cinnamic acid, 2-methylmaleic acid, itaconic acid, 2-methylitaconic acid, α,β-methyleneglutaric acid, and the like. Alternatively, the polycarboxy polymer may be prepared from unsaturated anhydrides including, but not necessarily limited to, maleic anhydride, methacrylic anhydride, and the like, as well as mixtures thereof. Methods for polymerizing these acids and anhydrides are well-known in the chemical art.
[0026] The polycarboxy polymer of the binder may additionally comprise a copolymer of one or more of the aforementioned unsaturated carboxylic acids or anhydrides and one or more vinyl compounds including, but not necessarily limited to, styrene, α-methylstyrene, acrylonitrile, methacrylonitrile, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, methyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, glycidyl methacrylate, vinyl methyl ether, vinyl acetate, and the like. Methods for preparing these copolymers are well-known in the chemical art.
[0027] Preferred polycarboxy polymers for the binder comprise homopolymers and copolymers of acrylic acid.
[0028] An important aspect of the binder relates to the molecular weight of the polycarboxy polymer used in the formaldehyde-free curable aqueous binder composition. The molecular weight of the polycarboxy polymer is less than 10,000 and more preferably less than 5000. Most preferably, the molecular weight of the polycarboxy acid is about 3000, and can be even less, as a molecular weight of about 2000, e.g. 2100, is most advantageous. It has been found that when such a low molecular weight polycarboxy acid is used in the binder resin, the binder resin can be successfully employed in the processing of a glass fiber product with little difficulty with regard to sticking or balling of the glass fibers. As a result, a much more efficient process is realized and a more economical product can be obtained by the use of the binder.
[0029] The formaldehyde-free curable binder composition also contains specifically glycerol. The use of glycerol with a polycarboxy polymer such as a polyacrylic acid results in a colorless binder upon curing. This enables the insulation blanket core 24 to be white. Other crosslinking polyols, such as triethanolamine, result in a binder which is light brown, thereby coloring the final product and being unsuitable where white is the desired product color.
[0030] The ratio of the number of equivalents of carboxy, anhydride, or salts thereof of the polyacid to the number of equivalents of hydroxyl groups from the glycerol is from about 1/0.01 to about ⅓. An excess of equivalents of carboxy, anhydride, or salts thereof of the polyacid to the equivalents of hydroxyl groups from the glycerol is preferred. The more preferred ratio of the number of equivalents of carboxy, anhydride, or salts thereof in the polyacid to the number of equivalents of hydroxyl in the glycerol is from about 1/0.2 to about 1/1. The most preferred ratio of the number of equivalents of carboxy, anhydride, or salts thereof in the polyacid to the number of equivalents of hydroxyl in the glycerol is from about 1/0.4 to about 1/0.95 with a ratio of from about 1/0.6 to about 1/0.8 being even more preferred, and a ratio of from about 1/0.65 to about 1/0.75 being most preferred.
[0031] The formaldehyde-free curable aqueous binder composition also preferably contains a catalyst. Most preferably, the catalyst is a phosphorous-containing accelerator which may be a compound with a molecular weight less than about 1000 such as, for example, an alkali metal polyphosphate, an alkali metal dihydrogen phosphate, a polyphosphoric acid, and an alkyl phosphinic acid or it may be an oligomer or polymer bearing phosphorous-containing groups such as, for example, addition polymers of acrylic and/or maleic acids formed in the presence of sodium hypophosphite, addition polymers prepared from ethylenically unsaturated monomers in the presence of phosphorous salt chain transfer agents or terminators, and addition polymers containing acid-functional monomer residues such as, for example, copolymerized phosphoethyl methacrylate, and like phosphonic acid esters, and copolymerized vinyl sulfonic acid monomers, and their salts. The phosphorous-containing accelerator may be used at a level of from about 1% to about 40% by weight based on the combined weight of the polyacid and the polyol. Preferred is a level of phosphorous-containing accelerator of from about 2.5% to about 10% by weight based on the combined weight of the polyacid and the polyol. The most preferred catalyst for the binder resin is sodium hypophosphite.
[0032] The formaldehyde-free curable aqueous binder composition may contain, in addition, conventional treatment components such as, for example, emulsifiers, pigments, filler, anti-migration aids, curing agents, coalescents, wetting agents, biocides or antimicrobial agents, plasticizers, organosilanes, anti-foaming agents, waxes, and anti-oxidants.
[0033] The formaldehyde-free curable aqueous binder composition may be prepared by admixing the polyacid, the glycerol, and the phosphorous-containing accelerator using conventional mixing techniques. The carboxyl groups of the polyacid may be neutralized to an extent of less than about 35% with a fixed base before, during, or after the mixing to provide the aqueous composition. Neutralization may be partially effected during the formation of the polyacid.
[0034] The formaldehyde-free curable aqueous composition may be applied to the insulation blanket core 24 by conventional techniques, for example, by spraying the composition into the curtain of fibers as the fibers are directed toward the collection conveyor to form the insulation blanket core 24 . The insulation blanket core 24 is then passed through a curing oven where heated air is passed through the blanket to cure the resin. The blanket is slightly compressed to give the blanket a selected thickness and surface finish. Typically, the curing oven is operated at a temperature from about 150° C. to about 325° C. and, preferably, from about 180° C. to about 250° C. The cure time in the oven ranges from about ½ minute to about 3 minutes and, typically from about 1 minute to about 2½ minutes.
[0035] The formaldehyde-free, thermosetting, acrylic acid-based latex binder resin, bonding the fibers of the insulation blanket core together, cures without coloration of the insulation blanket core 24 . The major surface 28 of the insulation blanket core 24 that forms the inner or airstream surface of the duct liner insulation 20 and, preferably, both the major surface 28 of the insulation blanket core 24 and the lateral and end edges of the insulation blanket core 24 are coated with a white acrylic water and dirt repelling coating 26 that contains an antimicrobial agent. Accordingly, the preferred glass fiber duct liner insulation 20 appears white.
[0036] Typical coating compositions used in the coating 26 comprise aqueous acrylic emulsions with catalysts to initiate cross-linking of the compositions in response to the application of heat such as but not limited to an aqueous acrylic emulsion with catalysts to initiate cross-linking in response to the application of heat sold by Tanner Chemical under the trade designation 9985 White FP. These coating compositions can be formulated to vary their elasticity, abrasion resistance, rigidity, density, flammability, water resistance, color, etc. These coating compositions may also include ingredients, such as but not limited to pigments, inert fillers, fire retardant particulate additives, antimicrobial agents, organic or inorganic biocides, bactericides, fungicides, rheology modifiers, water repellents, surfactants and curing catalysts. In the preferred embodiment of the subject invention, the coating is white and includes a white pigment such as but not limited to titanium dioxide and an antimicorbial agent.
[0037] A typical froth coating used to coat the glass fiber insulation blanket core 24 includes:
Weight Percent Aqueous Acrylic Latex Emulsion 20-90 (Not Pressure Sensitive) Curing Catalyst 0.1-1.0 Froth Aids 1-10 Foam Stabilizer 1-5 Mineral Filler, including 0-60 Flame Retardants Color Pigments 1-6 Rheology Control Thickener 1-6 Antimicrobial agent 0.1-0.3
[0038] Final solids content is from about 20 to about 85 weight percent. The application viscosity is about 500 to about 15,000 centipoise. Froth density is measured as a “cup weight”, i.e. the weight of frothed coating composition in a 16 ounce paper cup, level full. A cup weight of about 55 to about 255 grams is typical.
[0039] The coating 26 may be a single layer coating or a multilayered coating. When the coating 26 is a multilayered coating, each discrete layer of the coating can be specifically formulated to better perform a specific function. For example, a first discrete layer of the coating can be formulated to be more elastic than the second discrete layer to make the coating more puncture resistant while the second layer, if it is the exposed layer, can be formulated to be more abrasion resistant than the first coating layer. Thus, with the multilayered coating, there is the opportunity to make the coating 26 more tear and puncture resistant to minimize damage to the coating during the packaging, shipment, handling and installation of the insulation sheets.
[0040] Other examples of discrete coating layers which can be specifically formulated and used in the coating 26 , to provide or enhance specific performance characteristics or reduce the cost of the coating 26 , include but are not limited to, layers formulated with biocides, layers that can fulfill a specific performance characteristic that can made of less expensive coating formulations due to their location in the multilayered coating, layers with improved water resistance, and layers with reduced flammability or smoke potential.
[0041] In addition, to providing the opportunity to form different coating layers of the coating 26 from coating compositions having different formulations, the individual layers of the coating 26 can be made of different weights or thicknesses to enhance a specific performance characteristic or reduce coating costs without sacrificing performance, e.g. a discrete substrate layer can be thicker than the surface layer. The coating 26 typically ranges in dry weight from about 6 to about 20 grams per square foot. Thus, by way of example, one discrete coating layer of the coating 26 could have a dry weight of about 10 grams/sq. ft. and another discrete coating layer of the coating 26 could have a dry weight of about 4 grams/sq. ft.
[0042] The coating 26 may be applied by conventional coating techniques such as those disclosed in U.S. Pat. No. 4,990,370, issued Feb. 5, 1991, or U.S. Pat. No. 5,211,988, issued May 18, 1993, or U.S. Pat. No. 6,284,313, issued Sep. 4, 2001. The disclosures of U.S. Pat. Nos. 4,990,370; 5,211,988; and 6,284,313 are hereby incorporated herein by reference in their entirety.
[0043] In describing the invention, certain embodiments have been used to illustrate the invention and the practices thereof. However, the invention is not limited to these specific embodiments as other embodiments and modifications within the spirit of the invention will readily occur to those skilled in the art on reading this specification. Thus, the invention is not intended to be limited to the specific embodiments disclosed, but is to be limited only by the claims appended hereto. | A glass fiber duct liner, for lining sheet metal ducts in air conditioning, heating and ventilating systems, includes a flexible blanket of biosoluble glass fibers exhibiting a biodisolution rate in excess of 150 ng/cm 2 /hr. The glass fibers of the blanket are bonded together at their points of intersection by a colorless, formaldehyde-free, thermosetting, acrylic acid-based latex binder resin. A major surface of the blanket, adapted to be an interior surface of the blanket over which an airstream is to be conveyed by a duct system, is coated with a white acrylic latex water and dirt repellant coating that contains an antimicrobial agent. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a completion application of co-pending of United States Provisional Patent Application Serial No. 60/338,772, filed Dec. 4, 2001, the disclosure of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention pertains to sport boards. More particularly, the present invention concerns a shock absorbing system for a sport board. Even more particularly, the present invention concerns a universal shock absorbing system for a wide variety of sport boards.
PRIOR ART
[0004] In recent years, snowboarding, skate boarding, and water or aquatic board-related sports have continued to become increasingly popular sports. These sports have also become more competitive and demanding on both the rider and the equipment. The demand continues in recreational and competitive snow and water sports.
[0005] In any form of transportation, there is an inherent element of “shock” that is produced by changing terrain conditions that transfers energy from the terrain ground or water into the vehicle that is speeding across it. In most forms of transportation, the vehicle has been equipped with some form of “shock absorbers” to smooth out the ride and to increase performance of both the equipment and the rider. It has become essential for the vehicle to be equipped with shock absorbers except in vehicles like the snowboards, skateboards, water skis and wakeboards. The present invention, as subsequently detailed, addresses this issue.
SUMMARY OF THE INVENTION
[0006] In accordance herewith, there is provided a shock absorbing system for a sport board which comprises:
[0007] (a) a sport or sporting board, and
[0008] (b) a rocker system associated therewith.
[0009] The rocker system or rocker, generally, comprises a pair of spaced apart first and second or lower and upper, respectively, rocking members which are disposed transverse to the longitudinal access of the board. The rocking members are hingedly interconnected through suitable means to enable the rocker to rotate or pivot forward and aft.
[0010] The first or lower rocking member is integral with or otherwise affixed to the board on the upper surface thereof
[0011] The upper or second rocking member is affixed to a platform which is disposed above the board such that a space is created between the bottom of the platform and the upper surface of the board.
[0012] The upper rocking member and the lower rocking member include means for interdigitating, such as spacers or hinge members which cooperate to define a hinge. A hinge pin, or the like, interconnects the two together and defines a pivot about which the platform rotates.
[0013] In a first embodiment here, a pair of bladders or other compressible bodies are affixed to the upper surface of the board, one on each side of the hinge, in the space between the board and the platform. Thus, as the platform teeters or pivots between a forward and an aft position on the board, it will encounter one of the two bladders. Each bladder is inflatable and contains the same amount of fluid, such as air.
[0014] The bladders and hinge may be encased within a sealed shroud or the like to protect it from the elements.
[0015] It is further contemplated in the practice of the present invention that the present invention be part of an original equipment or that it be retrofitted wherein the bladders, rocker members, and platform are disposed on a mounting plate which is secured to a sports board.
[0016] For a more complete understanding of the present invention, references made to the following detailed description and accompanying drawings. In the drawings, like reference characters refer to like parts throughout the several views in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] [0017]FIG. 1 is a top view of a sports board for use in the present invention;
[0018] [0018]FIG. 2 is a side view of a sports board having the rocker system hereof mounted thereto;
[0019] [0019]FIG. 3 is a top view of a sports board having the lower rocker member mounted thereto;
[0020] [0020]FIG. 4 is a bottom review of the platform used herein having the upper rocker member mounted thereonto;
[0021] [0021]FIG. 5 is a partial side view showing the platform and the hinge pinhole;
[0022] [0022]FIG. 6 is a plan view, partly exploded, showing the hinge pin and the air bladders used herein;
[0023] [0023]FIG. 7 is a perspective view of a sleeve;
[0024] [0024]FIG. 8 depicts the rubber outer containment housing or shroud with upper and lower rubber seals and valve ports;
[0025] [0025]FIG. 9 is a front view of the upper and lower rocker members;
[0026] [0026]FIG. 9A is a front view of a spacer;
[0027] [0027]FIG. 10 is a side view of an air bladder; and
[0028] [0028]FIG. 11 is a side view of a second embodiment hereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0029] Now, in accordance with the present invention, and with reference to the drawing, in particular FIGS. 1 - 10 , there is depicted therein a sports board, generally, denoted at 16 . The sports board 16 hereof may comprise a ski board, skate board, water board, wave board, ski, or any other similar type of board which is used in various ground and aquatic sports. The present invention is contemplated for use in connection with and conjointly with any one of such type boards. Thus, the board 16 shown herein is a snowboard for illustrative purposes only. However, it is to be understood that the present invention is applicable to any other type of board such as those alluded to hereinabove.
[0030] The board 16 hereof has an upper surface 11 and a lower surface 13 . Disposed on the board 16 is a shock absorbing system or shock absorber defined by a rocker system or rocker, generally, denoted at 12 (FIG. 9). The rocker system hereof, generally, comprises:
[0031] (a) a first or lower rocker member 19 which is disposed atop the board 16 , and
[0032] (b) an upper or second rocker member 31 which interdigitates with and is hingedly connected to the lower rocker member via means for hingedly interconnecting such as a pin or hinge pin 22 .
[0033] In a first embodiment hereof, the lower rocker is secured to the upper surface 11 of the board 16 by any suitable means and, preferably, is molded integrally with the board. The lower rocker 19 , generally, comprises a transverse body disposed on the upper surface 11 of the board 16 and extending across the width thereof. The lower rocker member 19 further includes:
[0034] (a) a pair of spaced apart flanges 19 ′, 19 ″, each having an aperture formed therein, and
[0035] (b) a plurality of cylindrical sleeves 26 which are mounted onto the transverse rocker or fulcrum 19 or is integrally formed therewith.
[0036] The sleeves 26 , as noted, are cylindrical and have a hollow interior. The sleeves are co-axial with themselves and the apertures of the flanges. A plurality of spacers 27 , as shown in FIG. 9A are disposed on either side of associated sleeves 26 , as shown.
[0037] Disposed on either side of the fulcrum are compressible members 23 and 23 ′. Each compressible member is similar. The compressible members can comprise any suitable article such as a section of compressible foam, an inflatable bladder, or the like. Each of the bladders is independently inflatable with a suitable fluid such as water, air or the like. A valve member 24 associated with each bladder may be used to inflate and deflate its associated bladder, as desired. Preferably, in the practice of the present invention, each of the bladders contains the same amount of fluid so that they are substantially equal. Preferably, the bladders are air bladders. It is contemplated that the valves or valve members 24 will extend from their associated bladder through the platform 17 to facilitate accessibility thereto.
[0038] The compressible members are secured to the upper surface of the board by any suitable means such as through an anchor 30 . Alternatively, the bladders may be secured to the upper surface 11 with a nylon hook and fastener (Velcro), gluing, or the like.
[0039] As noted, the upper rocker assembly 31 is constructed similar to rocker member 19 and includes aperture flanges 31 ′ and 31 ″. The member 31 is secured to a platform 17 . The platform 17 has an upper surface 17 ′ and a lower surface 17 ″. As shown, the rocker 31 is integral with or otherwise affixed to the lower surface 17 ″. As shown in FIG. 5, the lower surface 17 ″ of the platform 17 is substantially bisected by the transverse rocker or fulcrum member 31 into a pair of identical sections. As shown in FIGS. 2 and 5, the bottom surface 17 ″ of the platform 17 tapers from the member 31 to the outer perimetral edge of the board. The taper permits the space 90 between the lower surface of the platform 17 and the upper surface 11 of the board 16 to reduce quickly when the platform and the board teeter into each other.
[0040] The upper rocker member 31 also includes a plurality of co-axial cylindrical sleeves 26 ′ integral therewith. The sleeves 26 ′ are constructed similarly to the sleeves disposed on the lower rocker member 19 and are spaced in a manner such that they will interdigitate, therewith, as shown in FIG. 9. The sleeves 26 ′ may be integrally formed with the fulcrum member 31 or may comprise a plurality of sleeves mounted thereonto. It should be noted in this regard, that the sleeves formed in the lower fulcrum member or transverse fulcrum member 16 may be integrally molded therewith, as shown in FIG. 9. Since each of the sleeves are coaxial, the hinge pin 22 can project therethrough to hingedly interconnect the platform to the lower rocker.
[0041] It is readily appreciated that the platform pivots about the pin 22 both fore and aft in the directions of the arrow A (FIG. 5).
[0042] It should be noted that the intermediate sleeves 26 and 26 ′ are optional since it is only necessary that the upper fulcrum member 31 be hingedly connected to the lower rocker member 19 so that the hinge pin 22 may project therethrough and interconnect the upper rocker to the lower rocker. Thus, only the apertured flanges 19 ′, 19 ″, 31 ′ and 31 ″ are necessary for hinged interconnection. Optionally, a plurality of wear rings or spacers 27 may be disposed between the sleeves 26 ′ to prevent wear or the like.
[0043] In order to maintain the rocker system sealed from the elements and to maintain the integrity and pressure within the bladders, it is possible to enshroud the system with a shroud or outer containment housing 33 . In order to accommodate the shroud, valve ports 25 are provided in the seal or shroud 33 . The valves 24 extend from each of the bladders and protrude through the ports 25 , from the platform 17 to enable them to be connected to a suitable source of compressed air or other fluid (not shown). A pressure gauge or the like (not shown) can be operatively affixed to the valves to measure and control the pressure within the bladders.
[0044] .As shown, a first sealing element or rim seal 20 is circumferentially disposed about the lower rocker member 19 . The rim seal 20 is used to attach a lower portion of a shroud 33 to encase the lower rocker 19 and to protect it from the elements, as explained herein below. The rim seal 20 secures a lower seal 28 associated with the shroud 33 thereto. Sealing is accomplished by snap-fitting the lower seal 28 into the lower rim seal 20 the lower seal 28 into the rim seal 20 .
[0045] Referring to FIGS. 5 and 8, secured to the lower surface of the platform and surrounding the upper rocker member is a rim seal 32 . The rim seal 32 slidingly fits into the lower rim seal 28 to effectively close off the rocker system from the elements. The shroud 33 carries the seals 28 and 29 .
[0046] Where used, the outer containment housing or shroud 33 is placed around the rocker assembly, the upper seal 29 and the lower seal 28 are snapped into the upper rim seal 32 and the lower rim seal 20 , respectively, to form a seal that will protect all the components inside from water, snow, ice, etc. The outer containment housing thus includes a bead, i.e. upper and lower seals 28 and 29 , that snaps into the rim seals all the way around the shock absorbing assembly to protect it from the elements. The outer containment housing is a continuous piece made of rubber, vinyl, nylon or other suitable water-impervious suitable material.
[0047] The shroud 33 , being attached at both its top and bottom to the rocker assembly has a sufficient extension capability to allow full range of motion of the most forward part and most aft part of the platform.
[0048] With the board and the platform joined together, there is defined a unitary shock absorbing assembly. The board and the platform are free moving parts, able to teeter in opposite directions from one another.
[0049] The user, when deploying the present invention as a snowboard is positioned on the platform, toes pointing to one lateral edge, and heals pointing to the other or opposite lateral edge, one foot forward of the fulcrum, and one foot aft of the fulcrum, and the feet at about a nominal 3°-35° angle to the length and the width of the platform, though this is dictated by the comfort desires of the user. When associated with a ski, the platform may be modified to include bindings 18 for securing a ski boot (not shown) or other footwear. like.
[0050] When used as water ski, the user has one foot forward of the fulcrum, centered on the platform and toes pointing toward the tip of the board and the other foot centered on the platform after of the fulcrum and toes pointing toward the tip of the board.
[0051] As a kneeboard, the user is in the kneeling position, as a wake board, the user is in the same position as with a snowboard.
[0052] The present invention can be used to retrofit an existing sport boards. Thus, and shown in FIG. 11 and in a second embodiment hereof, generally, denoted at 210 there is provided a mounting plate 212 to which is secured the rocker system hereof. The mounting plate 212 is dimensioned to lie atop or be superposed a sport board (not shown). The mounting plate is secured to the sport board through any suitable means, such as threaded fasteners, adhesives, and the like. In all respects the shock absorbing system is the same as in the first embodiment.
[0053] It is to be appreciated that there has been described herein a sports board which enables the user to ride on a “cushion of air” or other suitable fluid thereby softening the ride while at the same time providing a rigid toe-to-toe or heel-to-heel (edge-to-edge) ride providing improved performance. | A shock absorption system for a sports board which includes a rocker assembly for attaching the board to a raised platform which rocks forward and aft on the board. A space between the platform and the board to accommodate two independent inflated bladders which create a cushion for the platform to rock into forward and aft. The pressure inside the bladders will be at the rider's desired psi and will be sufficient for the rider to exert extreme pressures for balance, control, and maneuvers on any given terrain conditions. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. application Ser. No. 12/439,466 filed Feb. 27, 2009 now U.S. Pat. No. 7,763,873 which claims the benefit of PCT Application PCT/US2008/055096, filed Feb. 27, 2008, and U.S. Provisional Application 60/891,859, filed Feb. 27, 2007, the disclosures of which are all incorporated herein by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made with government support under CA088960 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
The present invention relates to radiotherapy systems using ions (such as protons) for the treatment of cancer and the like and, in particular, to a system providing improved treatment speed and accuracy.
External beam radiation therapy may treat a tumor within the patient by directing high-energy radiation in one or more beams toward the tumor. Recent advanced external beam radiation systems, for example, as manufactured by Tomotherapy, Inc., treat a tumor with multiple x-ray fan beams directed at the patient over an angular range of 360°. Each of the beams is comprised of individually modulated beamlets whose intensities can be controlled so that the combined effect of the beamlets, over the range of angles, allows an arbitrarily complex treatment area to be defined.
X-rays deposit energy in tissue along the entire path between the x-ray source and the exit point in the patient. While judicious selection of the angles and intensities of the x-ray beamlets can minimize radiation applied to healthy tissue outside of the tumor, inevitability of irradiating healthy tissue along the path to the tumor has suggested the use of ions such as protons as a substitute for x-ray radiation. Unlike x-rays, protons may be controlled to stop within the tissue, reducing or eliminating exit dose through healthy tissue on the far side of the tumor. Further, the dose deposited by a proton beam is not uniform along the entrance path of the beam, but rises substantially to a “Bragg peak” near a point where the proton beam stops within the tissue. The placement of Bragg peaks inside the tumor allows for improved sparing of normal tissue for proton treatments relative to x-ray treatments.
Current proton therapy systems adopt one of two general approaches. In the first approach, the proton beam is expanded to subtend the entire tumor and the energy of the protons, and hence their stopping point in the tissue, is spread in range, to roughly match the tumor depth. Precise shaping of the exposure volume is provided by a specially constructed range correction compensator which provides additional range shifting to conform the distal edge of the beam to the distal edge of the tumor. This treatment approach essentially treats the entire tumor at once and, thus, is fast and yet less precise and requires the construction of a special compensator.
In a second approach, the proton beam remains narrowly collimated in a “pencil beam” and is steered in angle and adjusted in range to deposit the dose as a small spot within the patient. The spot is moved through the tumor in successive exposures until an arbitrary tumor volume has been irradiated. This approach is potentially very accurate, but because the tumor is treated in successive exposures, is slower than the first approach. Further the small spot sizes create the risk of uneven dose placement or “cold spots” should there be patient movement between exposures.
SUMMARY OF THE INVENTION
The present invention provides a radiotherapy system usable with ion beams that uses multiple beam spot sizes to effect a precise trade-off between treatment speed and accuracy. For example, spatially larger beams may be used to treat large relatively homogenous portions of the treatment area with smaller beams providing precise delineation of edges and small dose features.
Specifically, the present invention provides an ion therapy machine that includes an ion source for producing an ion beam. The machine further provides a means for varying the lateral width of the ion beam (perpendicular to the propagation axis of the ion beam) as a function of a control signal and a means for steering the ion beam to different portions of a patient according to a control signal. A beam controller following a stored radiation plan communicates control signals to the means for varying the lateral width and the means for steering the ion beam to apply ion beams of different widths to different portions of the patient according to the treatment plan.
Thus, it is an object of one embodiment of the invention to aggregate treatment areas that may receive similar irradiation through the use of variable sized treatment beam, thus improving treatment speed or uniformity.
It is another object of one embodiment of the invention to allow precise tailoring of the beam spot sizes to different portions of the treatment volume to allow a flexible trade-off between treatment speed and treatment accuracy.
It is yet another object of one embodiment of the invention to provide a method of desensitizing the treatment to patient movement such as may create cold spots. The larger treatment beams naturally eliminate cold spots within the treatment beam and so it may not be necessary to employ longer treatment times to provide superior averaging of patient motion.
The invention may further include a means for varying an extent of the beams along their axis of travel (axial extent) when the beams are steered to different portions of the patient according to a control signal, and the beam controller may execute the stored radiation plan to communicate control signals to the means for varying an axial extent of the beam, to apply ion beams of different axial extents to different portions of the patient.
It is thus another object of one embodiment of the invention to change the axial extent of the beam to obtain similar benefits to those provided by the control of beam width.
The means for varying the lateral width of the beam (perpendicular to the beam axis) may be at least one focusing magnet set.
It is thus another object of one embodiment of the invention to allow control of beam size with reduced neutron generation as compared to scatter foils and the like.
It is another object of one embodiment of the invention to provide an efficient use of the energy of the proton beam by controlling beam width without the need to block portions of the beam.
A pair of successive quadrupole magnets may be used for focusing.
It is thus another object of one embodiment of the invention to provide a simple and reliable focusing structure for changing beam width.
The width of the ion beam may be adjusted by varying a separation of the quadrupole magnets or by varying the strength of at least one of the quadrupole magnets.
It is thus another object of one embodiment of the invention to provide a flexible beam width control allowing mechanical or electrical control methods.
Alternatively, the means for varying the lateral width of the beam may be a set of selectable different scattering foils movable into and out of the ion beam.
It is thus an object of one embodiment of the invention to provide a simple beam width control mechanism.
In one embodiment, the means for varying the lateral width of the beam may control the focusing drive signals of a dielectric wall accelerator.
It is thus another object of one embodiment of the invention to provide a system that will work with next generation ion sources.
The means for varying a lateral width may be a mechanical collimator.
It is thus an object of one embodiment of the invention to provide a system that may work with the current generation multi-leaf collimators or the like.
The means for varying the longitudinal and lateral extent of the beam may be a set of selectable mechanical scattering foils or ridge filters that may be moved into or out of the beam.
Thus it is an object of one embodiment of the invention to provide a simple method of controlling the axial extent of the beam.
The ion therapy machine may further include a radiation planning system receiving a dose plan for the patient and providing the radiation plan to the beam controller such that the radiation plan applies wider beams to portions of the patient with lower gradients in the dose plan and narrower beams to portions of the patient with higher dose gradients in the dose plan.
It is thus an object of one embodiment of the invention to provide a radiation planning technique adapted to exploit variable resolution ion beams.
Alternatively, the radiation plan may apply wider beams to portions of the patient removed from the edge of a tumor and narrower beams to portions of the patient at the edges of the tumor.
It is thus an object of one embodiment of the invention to provide a planning system that selects beam spot sizes based on relative location of the beams in the tumor.
The radiation planning system may provide a radiation plan to the beam controller to steer the beams to place Bragg peaks of the beams at distal edges of a tumor.
It is thus another object of one embodiment of the invention to provide a simple method of positioning the beams within the tumor volume.
These particular features and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view in partial phantom of an ion therapy system suitable for use with the present invention having a synchrotron ion source providing ions to multiple gantry units;
FIG. 2 is a cross-section along line 2 - 2 of FIG. 1 showing the path of the ion beam into a gantry to be directed into a patient after passage through a modulation assembly;
FIG. 3 is a block diagram of a first embodiment of the modulation assembly of FIG. 2 ;
FIGS. 4 a and 4 b are elevational views of one embodiment of an ion range shifter assembly using counter-translating wedges, showing two positions of the wedges that provide different amounts of blocking material in the path of the ion beam to control the average ion energy;
FIG. 5 is a perspective view of two rotating disks holding different scattering foils and ridge filters respectively, to control beam width and beam axial extent;
FIG. 6 is an elevational cross-section of two ridge filters of the disk of FIG. 5 such as provide different axial extents of an ion beam;
FIG. 7 is a schematic representation of a dose map for a patient, the dose map having treatment zones and showing different width beams superimposed on the dose map, and further showing the axial and lateral profiles of those beams;
FIG. 8 is a figure similar to that of FIG. 3 showing an alternative embodiment of the modulation assembly using quadrupole magnets for beam widening;
FIG. 9 is a flowchart of a treatment planning program that may work with the present invention to determine desirable beam resolution in the treatment of a patient;
FIG. 10 is a detail of the flowchart of FIG. 9 providing a step of locating the position of ion beams according to dose gradient;
FIG. 11 is a representation of a non-uniform dose map, its gradient along one axis, and a positioning of a Bragg peak of ion beams of different resolutions based on those gradients; and
FIG. 12 is a plan view of a multi-leaf collimator that may be operated to effectively control beam widths and beam locations.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIGS. 1 and 2 , an ion therapy system 10 may include a cyclotron or synchrotron 12 or other ion source providing a pencil beam 14 of ions that may be directed to a gantry unit 16 . The pencil beam 14 may be received at the gantry unit 16 along an axis 22 into an axial portion of a rotating arm 20 rotating about the axis 22 . The rotating arm 20 incorporates guiding magnet assemblies of a type known in the art to bend the pencil beam 14 radially away from the axis 22 then parallel to the axis and spaced from the axis 22 to be received by a treatment head 26 . The treatment head 26 orbits about the axis 22 with rotation of the rotating arm 20 and incorporates magnets bending the ion pencil beam 14 back toward the axis 22 to intersect the axis perpendicularly.
As will be described in more detail below, the treatment head 26 may include a modulation assembly 30 to produce a variable resolution treatment beam 24 . A patient 32 may be positioned on a support table 34 extending along the axis 22 so that the variable resolution treatment beam 24 may irradiate the patient 32 at a variety of angles 36 about the axis 22 . A cylindrical neutron shield 40 having a bore for receiving the table 34 and the rotating arm 20 may surround the gantry unit 16 to block generated neutrons.
In one embodiment, a second rotating arm (not shown) may rotate with or independently of the rotating arm 20 to support an x-ray source 42 and x-ray detector 44 opposed across the axis 22 to illuminate the patient 32 at a range of angles to provide CT imaging capabilities according techniques well-known in the art.
Referring now to FIG. 3 , the modulation assembly 30 produces the variable resolution treatment beam 24 by controlling the size, energy, and angle of the variable resolution treatment beam 24 to steer a variably sized treatment spot 54 through different locations within the patient 32 . Specifically, the modulation assembly 30 includes a global range shifter 46 controlling the average energy of the ions in the pencil beam 14 , a beam steering yoke 48 steering the pencil beam 14 in angle in one or two dimensions, a beam axial-extent controller 50 controlling a range of energies of the pencil beam 14 , and a beam width controller 52 controlling a lateral width of the pencil beam in one or two dimensions. As used herein, “lateral” will refer to a direction generally perpendicular to a propagation axis of the pencil beam 14 and axial will refer to a direction generally aligned with a propagation axis of the pencil beam 14 .
Each of the global range shifter 46 , the beam steering yoke 48 , the beam axial-extent controller 50 , and the beam width controller 52 , provides for electrical connections to a controller 65 that may control each of these elements electrically according to a stored a radiation plan 63 . The controller 65 may communicate with a computer terminal 67 for use by a physician in preparing the radiation plan 63 according to techniques that will be described further below.
Referring now to FIG. 4 , the global range shifter 46 , in one embodiment, provides a first wedge 56 and second wedge 58 in the form of identical right triangles of lateral thickness (perpendicular to the plane of the triangles) equal to at least the lateral thickness of the pencil beam 14 . The wedges 56 and 58 are mounted on opposite outer sides of a laterally extending belt 64 with the outer surfaces of the belt attached to corresponding bases of the wedges 56 and 58 . As attached, one wedge 58 is rotated with respect to the other wedge, once about an axis aligned with the attached base and once about an axis perpendicular to the attached base.
When the belt 64 is moved by motor actuator 66 the wedges 56 and 58 move in opposite directions, with the angled hypotenuses of the wedges 56 and 58 being maintained generally parallel to each other. It will be understood that in this configuration that when the pencil beam 14 passes through both of the wedges 56 and 58 it will pass through a constant amount of wedge material over the entire lateral extent of the pencil beam 14 , providing uniform energy attenuation of the photons of the pencil beam 14 . In a first position of the wedges 56 and 58 , shown in FIG. 4 a , with the wedges 56 and 58 fully overlapping in an axial direction, the combined material of the wedges 56 and 58 forms an equivalent rectangular bolus 68 having a first height 70 . In a second position of the wedges 56 and 58 , shown in FIG. 4 b , with the wedges 56 and 58 axially separated by a full amount still allowing them to overlap in the area of the pencil beam 14 , the equivalent rectangular bolus 68 has a second height 70 ′ less than the first height 70 . The height of the equivalent bolus 68 controls the average energy of the protons in the pencil beam 14 and thus movement of the wedges 56 and 58 allows control of the depth of the treatment spot 54 within the patient. The motor actuator 66 may be, for example, a stepper or servomotor as is understood in the art.
Referring again to FIG. 3 , after the pencil beam 14 has passed through the global range shifter 46 , the pencil beam 14 is received by a beam steering yoke 48 which may, for example, be a set of electromagnetic coils or opposed electrostatic plates well known for steering charged particles in one or two lateral dimensions. The beam steering yoke 48 allows the pencil beam 14 to be steered at an angle from an axis 60 perpendicular to the axis 22 about which the beam rotates. In this way the treatment spot 54 to be moved to an arbitrary lateral location within the patient 32 . Together these beam steering yokes 48 and the range shifter 46 allow the treatment spot 54 to be moved to arbitrary locations within the patient 32 .
Referring now to FIGS. 3 and 5 , the size of the treatment spot 54 , in terms of axial length, is controlled by the beam axial-extent controller 50 which varies the energies of the ions in the pencil beam 14 to create one of a number of predefined energy ranges. In one embodiment, the beam axial-extent controller 50 uses a disk 73 extending in a lateral plane and rotatable by motor 72 about an axis parallel to the axis of the pencil beam 14 , to bring various apertures 76 in the periphery of the disk into alignment with the pencil beam 14 as the disk is rotated. Each of the apertures 76 may be fitted with a different ridge filter 78 providing for a different spread of energies and thus a different axial length 75 of the treatment spot 54 .
Referring to FIG. 6 , a first axial ridge filter 78 , for example in a first aperture 76 , may have a set of triangular ridges 80 whose peaks provide a first axial thickness to reduce ions' energies to provide an average stopping point 82 in the patient 32 , and troughs having reduced thickness and allowing increased proton energy to provide an average stopping point 84 in the patient 32 . The difference between these two stopping points 82 and 84 represents the axial length 75 a of the treatment spot 54 .
For comparison, a second ridge filter 78 ′ in a different aperture 76 , may have a similar profile but with ridges of lesser amplitude whose peaks provide a first stopping point 82 ′ and whose troughs provide a second stopping point 84 ′ that are closer together to produce an axial length 75 b that is substantially shorter than the axial length 75 a . A number of different filters 78 may provide for a range of different axial lengths 75 for the treatment spot 54 .
Referring still to FIGS. 3 and 5 , the beam width controller 52 may be a similar disk 91 positioned below disk 73 and axially aligned therewith and rotatable by motor 95 to bring various apertures 90 in the periphery of the disk 91 into alignment with the pencil beam 14 . In this case, the apertures 90 may be fitted with different scattering foils 92 such as cause a lateral spreading of the pencil beam 14 by various amounts according to the material and thickness of the scattering foil to control the lateral width 94 of the treatment spot 54 .
Referring now to FIG. 7 , a radiation plan 63 describing the positioning of the multiple treatment spots 54 and their sizes may be developed with reference to a dose map 100 prepared by a physician using planning software to convert the dose map 100 to a radiation plan 63 . The dose map 100 may be prepared, for example, using a graphics terminal with the physician viewing one or more CT images of the patient to define desired doses in different zones within the volume of the patient.
A simple dose map 100 follows the outline of a tumor 99 and provides a desired uniform dose within that outline. The present invention may provide a radiation plan 63 that uses multiple treatment spots 54 a - 54 f to deliver the desired dose. Generally the axial length of the treatment spot 54 will affect the profile of the dose within the treatment spot 54 . Thus, for example, a small treatment spot 54 e will have an axial profile 102 exhibiting a well-defined Bragg peak with a sharp distal fall off whereas a large treatment spot 54 f will exhibit an axial profile 104 with a more gradual falloff being the aggregate of Bragg peaks for multiple protons of different energies. For this reason, smaller treatment spots 54 may preferentially be used near the distal edge of the tumor or at other points of high dose gradient.
The lateral width of the treatment spot 54 will also affect the lateral profile of the dose within the treatment spot 54 . In this case the lateral falloff is not determined by the Bragg peak but simply by beam spreading after collimation.
Intuitively, it will be understood from FIG. 7 that a large treatment spot 54 f may be advantageously placed roughly centered within the tumor 99 and smaller treatment spots 54 a - 54 e may be used close to the distal edge of the tumor 99 to take advantage of the sharper Bragg peak available from those smaller spots. As the gantry is rotated and axis 60 of the pencil beam 14 moves about the tumor 99 , different edges of the tumor 99 become the distal edge allowing this approach to be repeated for the entire tumor 99 to provide sharp demarcation of the outline of the tumor 99 .
This general observation may be exploited more precisely by a radiation treatment planning system implemented by program 110 executed in the terminal 67 to prepare a radiation plan 63 . Referring now to FIGS. 7 and 9 , the treatment plan may begin by receiving a dose map 100 as indicated by process block 112 generally describing a spatial extent of a portion of the patient 32 where an ion dose will be applied. In contrast to the dose map 100 of FIG. 7 , the dose map 100 more generally will include multiple zones within a dose map 100 describing variations in the intensity of the doses within those zones.
At process block 114 , a first set of beams, for example, producing large treatment spots 54 f may be fit to the dose map 100 . This fitting determines both an intensity of the different treatment spots 54 and the location of the beam treatment spot 54 . One method for locating the treatment spot 54 tries to fit as many of the treatment spots 54 into the tumor area of the dose map 100 as can be done with controlled overlapping or extending outside of the tumor 99 . The intensities may then be determined by an iterative process, for example “simulated annealing”, considering multiple exposures for different gantry angles.
Once the intensity of the large treatment spot 54 is determined, then at process block 130 smaller treatment spots 54 (for example treatment spot 54 a - e ) are positioned on the dose map 100 in gaps between the larger treatment spots 54 f . These gaps may be identified simply by creating a difference map indicating differences between the dose implemented by the large treatment spots 54 f and the desired dose of the dose map 100 , and placing the smaller treatment spots 54 a - e according to the difference map. The intensities and positions of the optimized larger treatment spots 54 f are held fixed and only the intensities of the new smaller treatment spots 54 a - e are optimized iteratively. Alternatively, the intensities and positions of the optimized larger treatment spots 54 f may be used as a starting position for renewed optimization of both the larger treatment spots 54 f and the new smaller treatment spots 54 a - e.
As illustrated by process block 132 , this process may be repeated for yet smaller treatment spots 54 g shown in FIG. 7 .
Referring now to FIGS. 10 and 11 , an alternative method of locating the treatment spots 54 , as indicated by process block 116 , determines a gradient 122 of the dose map 100 being the spatial derivative of the dose 120 along a particular treatment axis (e.g. aligned with axis 60 for each treatment fraction). For simplicity, the dose map 120 may be discretized into two or more dose levels as shown by discretized dose map 120 ′ and a discretized gradient 122 ′ developed (indicating generally gradient sign).
For example, the dose map 100 may include a first central zone 119 of lower dose 121 and an outer peripheral zone 118 of higher dose 123 . Discretized derivative values 122 ′ along axis 60 may provide for two positive going transitions 123 , a negative going transitions 124 , a positive going transition 123 , and two negative going transitions 124 (from left to right) following the discretized gradient 122 ′. These transitions 123 and 124 may be used to align the Bragg peak 126 of treatment spots 54 to provide a location of those beam spots for intensity optimization according to the following rules:
(a) place a Bragg peak 126 along the ray of a given proton beam at points where the dose gradient drops below a user-defined negative threshold (A) (or in the case of the discretized gradient 122 ′, where there are negative transitions);
(b). place a Bragg peak 126 along the ray of a given proton beam at points where the dose gradient exceeds below a user-defined negative threshold (B) (or in the case of the discretized gradient 122 ′, where there are positive transitions) after there has been at least one peak placed per (a) above.
The height of the peaks 124 may also be matched to the steepness of the Bragg peaks 124 of the different sizes of treatment spots 54 which, as noted, before, tend to vary with the treatment spot 54 size.
Once locations of treatment spot 54 are fixed, the intensities may be optimized as described before or by iterative techniques such as Simulated Annealing or Gradient Based Optimization Techniques beams at multiple angles. Multiple delivery angles, for example over 360 degrees, and control of the intensity of the beam spots will then build up the dose to match the dose map 100 . By selecting a beam range prior to iteration, the iteration process is much simplified.
Alternatively or in addition, the above technique of locating the Bragg peaks of the treatment spots 54 may be used on an “ex ante” basis and an optimization program 117 may then be run in which the dose produced by the ex ante placement is compared to the desired dose. The deficiency in the dose is then used to place additional treatment spots 54 . In this way locations that did not receive a sufficient amount of dose from the first pass are filled in with spots that are added based on the difference.
Referring now to FIG. 8 , in an alternative embodiment of the modulation assembly 30 , axial range shifter 46 may be followed by a first and second quadrupole magnet 152 and 154 rotated along axis 60 at 90 degrees with respect to each other. The pencil beam 14 passing through the successive quadrupole magnets 152 and 154 is expanded into a diverging fan beam. The width of this diverging fan beam may be controlled by changing the separation of the quadrupole magnets 152 and 154 by a mechanical focusing assembly 158 , and/or by control of the strength of the magnets in one or both quadrupole magnets 152 and 154 by controlling an electromagnetic current according to signals from the controller 65 .
The variable resolution treatment beam 24 from the quadrupole magnets 152 and 154 is then received by the beam axial-extent controller 50 and then steered by beam steering yoke 48 as described before.
Referring now to FIG. 12 , control of the beam width and its location may, in an alternate embodiment, be accomplished by a multi-leaf collimator 160 having individually controllable leaves 162 which may be moved into or out of a fan beam 164 to create apertures 166 defining beam widths 168 and, by their offset from a center of the fan beam 164 , may control the positioning of the beam within the patient 32 . Thus one mechanism may provide both for steering and beam width control, the separate control signals being combined to produce control signals for selection of particular shutters for opening and/or closing. A shutter system suitable for this use is described in U.S. Pat. No. 5,668,371 described above. Although only a single aperture 166 is shown, in the simplest embodiment, this technique may be used to produce simultaneous multiple apertures (not shown) of different widths for concurrent treatment using the same axial extent or variable axial extent provided by corresponding range shifters for each aperture, again as taught in U.S. Pat. No. 5,668,371.
Generally, the invention anticipates that the source of protons may also be a dielectric wall accelerator. As is understood in the art a dielectric wall accelerator provides a linear acceleration of charged particles through the use of successively applied electrostatic fields that serve to accelerate the charged particles as they move through the dielectric wall accelerator. Energy modulation may be obtained by simply controlling the degree of acceleration of the charged particle through the switching of the electrostatic fields and their timing. The beam widths may be controlled by electronic control of focusing electrodes incorporated into the body of the dielectric wall accelerator. By deflecting the protons at the proximal end of the dielectric wall accelerator early in the acceleration process, it is believed that it should be possible to steer the proton beam. The electrodes used to control the beam width can also be used for focusing the beam spot.
Dielectric wall accelerators suitable for this purpose are described for example in “Development of a Compact Radiography Accelerator Using Dielectric Wall Accelerator Technology” by Sampayan, S. et als. Proceedings of the Particle Accelerator Conference, 2005. PAC 2005. Publication Date: 16-20 May 2005 pp: 716-718 ISBN: 0-7803-8859-3.
The present invention contemplates changing of the size of the treatment spot 54 in three dimensions: axially and in two perpendicular lateral directions. The present invention may also be used with beam spot control in only two dimensions: axial and one lateral dimension within a plane of rotation of the gantry head 26 . Under this control technique the patient may be treated on a slice-by-slice basis through a “rotate and step” scanning pattern or a helical scanning pattern of a type known in the art for x-ray tomography.
Alternatively such a system may also combine helical scanning, for example, with variable beam widths in three dimensions including along the axis about which the head 26 is rotated. Such a system would anticipate common structure in adjacent slices to provide for treatment of these structures over a longer period during multiple slices.
It is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein, but include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims. | An ion radiation therapy machine provides a steerable beam for treating a tumor within the patient where the exposure spot of the beam is controlled in width and/or length to effect a flexible trade-off between treatment speed, accuracy, and uniformity. | 0 |
TECHNICAL FIELD
The present invention relates to personal care compositions, such as haircare, cosmetic and nail compositions containing linear toughened silicone grafted polymers.
BACKGROUND OF THE INVENTION
Cosmetic compositions such as lotions, creams, emulsions, packs, make-up (e.g., foundations, lipsticks, eye shadows and the like) and hair compositions are used to improve one's outward appearance. Many personal care products use contain various resins, gums, and adhesive polymers. The polymers are used for a variety of purposes including thickening, feel properties, film-forming ability, active deposition, active penetration, hair holding, etc. Consequently there is constantly a search for developing polymers having improved properties for use in personal care product. Many of these compositions require the use of adhesive silicone grafted polymers. For example, the desire to have the hair retain a particular shape is widely held. The most common methodology for accomplishing this is the application of a styling composition to dampened hair, after shampooing and/or conditioning, or to dry, styled hair. These compositions provide temporary setting benefits and they can be removed by water or by shampooing. The materials used in the compositions to provide the setting benefits have generally been resins and have been applied in the form of mousses, gels, lotions or sprays.
Many people desire a high level of style retention, or hold, from a hair spray composition. In typical hair sprays, hold is achieved by the use of resins, such as AMPHOMER R , supplied by National Starch and Chemical Company, and GANTREZ R SP 225, supplied by GAF. In general, as hair hold for hair spray compositions is increased, the tactile feel of the hair becomes stiffer and hence, less desirable. It is desirable to provide hair spray products which could provide an improved combination of hair hold and hair feel characteristics.
Recently, it has become known to utilize silicone grafted organic backbone polymers in various personal care compositions including their use as hair setting agents in hairspray compositions and other hair styling compositions, e.g. hair tonics, lotions, rinses, mousses, etc. Silicone grafted polymers can be used to make personal care compositions with improved feel, e.g., in the case of hair sprays, increased softness relative to conventional polymeric hair setting agents.
However, it remains desirable to improve the performance of these silicone grafted polymers. It is an object of this invention to provide personal care compositions containing linear toughened silicone graft copolymers.
It is a further object of this invention to provide personal care compositions containing resins that have improved adhesive and cohesive properties thereby providing improved durability benefits (e.g., style benefits).
These and other benefits as may be apparent from the description below can be obtained by the present invention.
The present compositions can comprise, consist of, or consist essentially of any of the required or optional ingredients and/or limitations described herein.
All percentages and ratios are calculated on a weight basis unless otherwise indicated. All percentages are calculated based upon the total composition unless otherwise indicated.
All ingredient levels refer to the active level of that ingredient, and are exclusive of solvents, by-products, or other impurities that may be present in commercially available sources, unless otherwise indicated.
SUMMARY OF THE INVENTION
The present invention relates to a personal care composition comprising:
(a) a silicone grafted adhesive polymer, said polymer being characterized by an organic polymeric backbone wherein said backbone comprises
(i) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from about −120° C. to about 25° C. and
(ii) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from above about 25° C. to about 250° C.
wherein said silicone grafted adhesive polymer has silicone macromers grafted to said backbone and wherein the number average molecular weight of said silicone macromers is greater than about 1000; and
(b) a personal care carrier.
DETAILED DESCRIPTION OF THE INVENTION
The essential components of the present invention are described below. Also included is a nonexclusive description of various optional and preferred components useful in embodiments of the present invention.
Silicone Grafted Adhesive Polymer
The compositions according to the invention comprise, as an essential component, a silicone grafted adhesive polymer, said polymer being characterized by an organic polymeric backbone wherein said backbone comprises:
(a) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from about −120° C. to about 25° C. and
(b) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from above about 25° C. to about 250° C.
wherein said silicone grafted adhesive polymer has silicone macromers grafted to said backbone and wherein the number average molecular weight of said silicone macromers is greater than about 1000. This silicone containing hair styling polymer is preferably colloidally dispersed or solubilized in any applicable carrier.
The compositions hereof will generally comprise from about 0.1% to about 99%, preferably from 0.5% to about 50%, more preferably from about 1% to about 10%, by weight of the composition, of the silicone grafted polymer. It is not intended to exclude the use of higher or lower levels of the polymers, as long as an effective amount is used to provide adhesive or film-forming properties to the composition and the composition can be formulated and effectively applied for its intended purpose. By adhesive polymer what is meant is that when applied as a solution to a surface and dried, the polymer forms a film or a weld. Such a film will have adhesive and cohesive strength, as is understood by those skilled in the art.
The silicone grafted polymers are characterized by polysiloxane moieties covalently bonded to and pendant from a polymeric carbon-based backbone.
The backbone will preferably be a carbon chain derived from polymerization of ethylenically unsaturated monomers. The backbone comprises (a) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from about −120° C. to about 25° C. and (b) at least one monomer wherein when said monomer is polymerized as a homopolymer having a Tg of from above about 25° C. to about 250° C. The polysiloxane moieties can be substituted on the polymer or can be made by co-polymerization of polysiloxane-containing polymerizable monomers (e.g. ethylenically unsaturated monomers, ethers, and/or epoxides) with non-polysiloxane-containing polymerizable monomers.
The polysiloxane-grafted polymer should have a weight average molecular weight of at least about 20,000. There is no upper limit for molecular weight except that which limits applicability of the invention for practical reasons, such as processing, aesthetic characteristics, formulateability, etc. In general, the weight average molecular weight will be less than about 10,000,000, more generally less than about 5,000,000, and typically less than about 3,000,000. Preferably, the weight average molecular weight will be between about 50,000 and about 2,000,000, more preferably between about 75,000 and about 1,000,000, most preferably between about 100,000 and about 750,000.
Preferably, the adhesive hereof when dried to form a film have a Tg of at least about −20° C., more preferably at least about −5° C., so that they are not unduly sticky, or “tacky” to the touch. As used herein, the abbreviation “Tg” refers to the glass transition temperature of the backbone of the polymer, if such a transition exists for a given polymer. Preferably, the Tg is above about −20° C., more preferably above about −5° C. Preferably the adhesive polymer of the present invention has a Tg below about 60° C., more preferably below about 50° C. and most preferably below about 40° C.
The silicone grafted polymers for the compositions of the present invention comprise “silicone-containing” (or “polysiloxane-containing”) monomers, which form the silicone macromer pendant from the backbone, and non-silicone-containing monomers, which form the organic backbone of the polymer.
When used in a composition, such as a personal care composition for application to the hair or skin, the non-polysiloxane portion should permit the polymer to deposit on the intended surface, such as hair or skin.
The polysiloxane macromer should have a weight average molecular weight of at least about 1000, preferably from about 1,000 to about 50,000, more preferably from about 5,000 to about 50,000, most preferably about 8,000 to about 25,000. Organic backbones contemplated include those that are derived from polymerizable, ethylenically unsaturated monomers, including vinyl monomers, and other condensation monomers (e.g., those that polymerize to form polyamides and polyesters), ring-opening monomers (e.g., ethyl oxazoline and caprolactone), etc.
The preferred silicone grafted polymers are comprised of monomer units derived from: at least one free radically polymerizable ethylenically unsaturated monomer or monomers and at least one free radically polymerizable polysiloxane-containing ethylenically unsaturated monomer or monomers.
Vinyl Monomer Units
The silicone copolymers of the present invention comprise from about 50% to about 98%, preferably from about 60% to about 95%, and more preferably from about 70% to about 90% by weight of the vinyl monomer units.
The vinyl monomer unit is selected from copolymerizable monomers, preferably ethylenically unsaturated monomers. The vinyl monomers are selected to meet the requirements of the copolymer. By “copolymerizable”, as used herein, is meant that the vinyl monomer can be reacted with or polymerized with the polysiloxane macromonomers in a polymerization reaction using one or more conventional synthetic techniques, such as ionic, emulsion, dispersion, Ziegler-Natta, free radical, group transfer or step growth polymerization. In the present invention, monomers and macromonomers that are copolymerizable using conventional free radical initiated techniques are preferred. The term “ethylenically unsaturated” is used herein to mean a material that contains at least one polymerizable carbon-carbon double bond, which can be mono-, di-, tri- or tetra-substituted.
The monomer units can be derived from hydrophilic monomers (typically polar monomers), or mixtures of such hydrophilic monomers with hydrophobic monomers (typically low polarity monomers), provided that the solubility characteristics of the overall copolymer is achieved. As used herein, “hydrophilic monomers” means monomers which form homopolymers which are substantially water soluble; “hydrophobic monomers” means monomers which form substantially water insoluble homopolymers.
Nonlimiting classes of monomers useful herein include monomers selected from the group consisting of unsaturated alcohols, unsaturated monocarboxylic acids, unsaturated dicarboxylic acids, unsaturated anhydrides, alcohol esters of unsaturated monocarboxylic acids, alcohol esters of unsaturated dicarboxylic acids, alcohol esters of unsaturated anhydrides, alkoxylated esters of unsaturated monocarboxylic acids, alkoxylated esters of unsaturated dicarboxylic acids, alkoxylated, esters of unsaturated anhydrides, aminoalkyl esters of unsaturated monocarboxylic acids, aminoalkyl esters of unsaturated dicarboxylic acids, aminoalkyl esters of unsaturated anhydrides, amides of unsaturated monocarboxylic acids, amides of unsaturated dicarboxylic acids, amides of unsaturated anhydrides, salts of unsaturated monocarboxylic acids, salts of unsaturated dicarboxylic acids, salts of unsaturated anhydrides, unsaturated hydrocarbons, unsaturated heterocycles, and mixtures thereof.
Representative examples of such monomers include acrylic acid, methacrylic acid, N,N-dimethylacrylamide, dimethylaminoethyl methacrylate, quaternized dimethylaminoethyl methacrylate, methacrylamide, N-t-butyl acrylamide, maleic acid, maleic anhydride and its half esters, crotonic acid, itaconic acid, acrylamide, acrylate alcohols, hydroxyethyl methacrylate, diallyldimethyl ammonium chloride, vinyl pyrrolidone, vinyl ethers (such as methyl vinyl ether), maleimides, vinyl pyridine, vinyl imidazole, other polar vinyl heterocyclics, styrene sulfonate, allyl alcohol, vinyl alcohol (such as that produced by the hydrolysis of vinyl acetate after polymerization), vinyl caprolactam, acrylicor methacrylic acid esters of C 1 -C 18 alcohols, such as methanol, ethanol, methoxy ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 1-methyl-1-butanol, 3-methyl-1-butanol, 1-methyl-1-pentanol, 2-methyl-1-pentanol, 3-methyl-1-pentanol, t-butanol(2-methyl-2-propanol), cyclohexanol, neodecanol, 2-ethyl-1-butanol, 3-heptanol, benzyl alcohol, 2-octanol, 6-methyl-1-heptanol, 2ethyl-1-hexanol, 3,5-dimethyl-1-hexanol, 3,5,5-tri methyl-1-hexanol, 1-decanol, 1-dodecanol, 1-hexadecanol, 1-octa decanol, and the like, the alcohols having from about 1-18 carbon atoms with the number of carbon atoms preferably being from about 1-12; dicyclopentenyl acrylate; 4-biphenyl acrylate; pentachlorophenyl acrylate; 3,5-dimethyladamantyl acrylate; 3,5-dimethyladamentyl methacrylate; 4-methoxycarbonylphenyl methacrylate; trimethylsilyl methacrylate; styrene; alkyl substituted styrenes including alpha-methylstyrene and t-butylstyrene; vinyl esters, including vinyl acetate, vinyl neononanoate, vinyl pivalate and vinyl propionate; vinyl chloride; vinylidene chloride; vinyl toluene; alkyl vinyl ethers, including isobutyl vinyl ether and s-butyl vinyl ether; butadiene; cyclohexadiene; bicycloheptadiene; 2,3-dicarboxylmethyl-1,6-hexadiene; ethylene; propylene; indene; norbornylene; β-pinene; α-pinene; salts of acids and amines listed above, and combinations thereof. The quaternized monomers can be quaternized either before or after the copolymerization with other monomers of the graft copolymer.
Preferred monomers include acrylic acid, methacrylic acid, N,N-dimethyl acrylamide, dimethylaminoethyl methacrylate, quaternized dimethylaminoethyl methacrylate, vinyl pyrrolidone, acrylic or methacrylic acid esters of C 1 -C 18 alcohols, styrene, alpha-methylstyrene, t-butylstyrene, vinyl acetate, vinyl propionate, 2-methoxyethyl acrylate, 2-ethoxyethyl acrylate, n-butyl methacrylate, isobutyl methacrylate, t-butyl acrylate, t-butyl methacrylate, 2-ethylhexyl methacrylate, methyl methacrylate, salts of any acids and amines listed above, and mixtures thereof.
From the above descriptions, esters of acrylic and methacrylic acid that form low Tg homopolymers include, for example, 3-methoxybutyl acrylate, 2-methoxyethyl acrylate, 2-phenoxyethyl ester, 2-hydroxyethyl ester, 4-hydroxybutyl acrylate, 2-ethoxyethoxyethyl acrylate, 2-ethoxyethyl acrylate, n-butyl acrylate, dodecyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutyl acrylate, n-ethyl acrylate, n-heptyl acrylate, n-hexyl acrylate, iso-butyl acrylate, iso-decyl acrylate, iso-propyl acrylate, 3-methylbutyl acrylate, 2-methylpentyl acrylate, nonyl acrylate, octyl acrylate, 2-ethylhexyl methacrylate, n-pentyl methacrylate; Acrylamide monomers including N-dodecylacrylamide, N-octadecylacrylamide; Vinyl monomers including sec-butyl vinyl ether, butyl vinyl ether, vinyl propionate, vinyl butyrate,decylvinyl ether, methyl vinyl ether and Styrene monomers including 4-decylstyrene. Other monomers that form low Tg homopolymers include isobutylene, 1-butene, 5-methyl-1-hexene, olefinic monomers that could be hydrogenated post polymerization (after formation of copolymers), for example, isoprene, 1,2-butadiene, 1,4-butadiene.
Preferred monomers which form low Tg homopolymers include 3-methoxybutyl acrylate, 2-methoxyethyl acrylate, n-butyl acrylate, dodecyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutyl acrylate,ethyl acrylate, n-heptyl acrylate, n-hexyl acrylate, iso-butyl acrylate, iso-decyl acrylate, iso-propyl acrylate, 3-methylbutyl acrylate, 2-methylpentyl acrylate, nonyl acrylate, octyl acrylate, 2-ethylhexyl methacrylate, n-pentyl methacrylate, N-octadecylacrylamide.
Most Preferred monomers which form low Tg homopolymers include 2-methoxyethyl acrylate, n-butyl acrylate, ethyl acrylate. These low Tg monomers preferably have Tg of from about −70° C. to about 25° C., more preferably from about −60° C. to about 0° C. and most preferably from about −60° C. to about −20° C.
From the above descriptions, acrylic and methacrylic acids and esters thereof that form high Tg homopolymers include, for example, sec-butyl methacrylate, t-butyl acrylate, methyl methacrylate, isopropyl methacrylate, 2-t-butylaminoethyl methacrylate, dimethyl aminoethyl methacrylate, quaternized dimethyl aminoethyl methacrylate, 4-biphenyl acrylate, pentachlorophenyl acrylate, 3,5-dimethyladamantyl acrylate, 3,5-dimethyladamentyl methacrylate, isobornyl acrylate, trimethysilyl methacrylate, trimethylsilyl acrylate (silyl esters could be hydrolysed to form acrylic or methacrylic acids), acrylic acid, methacrylic acid, salts of acrylic and methacrylic acids; Acrylamide & methacrylamide monomers including N-butylacrytlamide, acrylamide, N-isopropylacrylamide, N-t-butylmethacrylamide; Vinyl monomers including: 2-vinylpyridine, 4-vinylpyridine, vinyl acetate, vinyl chloride, N-vinylcaprolactam, N-vinyl pyrollidone, cyclohexyl vinyl ether, vinyl alcohol, vinyl imidazole; Styrene monomers including: styrene, 4-t-butylstyrene, 2-methoxystyrene, 4-acetylstyrene, styrene sulfonate. Other monomers that form high Tg homopolymers include: diallyldimethylammonium chloride, maleimides, crotonic acid, itaconic acid, maleic anhydrides, allyl alcohol, α-pinene, β-pinene, tert-butyl styrene, α-methyl styrene, indene, norbornene, norbornylene.
Preferred monomers which form high Tg homopolymers include: t-butyl methacrylate, t-butyl acrylate, methyl methacrylate, dimethyl aminoethyl methacrylate, isopropyl methacrylate, trimethysilyl methacrylate, trimethylsilyl acrylate, acrylic acid, methacrylic acid, salts of acrylic and methacrylic acids, tert-butyl styrene, α-methyl styrene, 2-vinylpyridine, 4-vinylpyridine, N-isopropylacrylamide, N-t-butylmethacrylamide.
Most Preferred monomers which form high Tg homopolymers include: t-butyl methacrylate, t-butyl acrylate, methyl methacrylate, acrylic acid, methacrylic acid, salts of acrylic and methacrylic acids, tert-butyl styrene. These high Tg monomers preferably have Tg of from above about 25° C. to about 250° C., more preferably from about 30° C. to about 200° C., even more preferably from about 35° C. to about 150° C., and most preferably from about 40° C. to about 130° C.
Polysiloxane Macromonomer Units
The copolymers of the present invention comprise from about 2% to about 50%, preferably from about 5% to about 40%, and more preferably from about 10% to about 30%, by weight of the copolymer of polysiloxane macromonomer units.
The polysiloxane macromonomer units are copolymerizable with the vinyl monomers, said macromonomers preferably having a vinyl moiety. Either a single type of macromonomer unit or combinations or two or more macromonomer units can be utilized herein. The macromonomers are selected to meet the requirements of the copolymer. By “copolymerizable”, as used herein, is meant that the macromonomers can be reacted with or polymerized with the vinyl monomers in a polymerization reaction using one or more conventional synthetic techniques, as described above.
The polysiloxane macromonomers that are useful herein contain a polymeric portion and a copolyermizable moiety which is preferably an ethylenically unsaturated moiety. Typically, the preferred macromonomers are those that are endcapped with the vinyl moiety. By “endcapped” as used herein is meant that the vinyl moiety is at or near a terminal position of the macromonomer.
The macromonomers can be synthesized utilizing a variety of standard synthetic procedures familiar to the polymer chemist of ordinary skill in the art. Furthermore, these macromonomers can be synthesized starting from commercially available polymers. Typically, the weight average molecular weight of the macromonomer is from about 1000 to about 50,000.
Polysiloxane macromonomers are exemplified by the general formula:
X(Y) n Si(R) 3−m Z m
wherein X is a vinyl group copolymerizable with the vinyl monomer units; Y is a divalent linking group; each R is independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkylamino, phenyl, C1-C6 alkyl or alkoxy-substituted phenyl; Z is a monovalent siloxane polymeric moiety having a number average molecular weight of at least about 1000, is essentially unreactive under copolymerization conditions, and is pendant from the vinyl polymeric backbone described above; n is 0 or 1; and m is an integer from 1 to 3. The polysiloxane macromonomer has a weight average molecular weight from about 1000 to about 50,000, preferably from about 5,000 to about 30,000, more preferably from about 8,000 to about 25,000.
Preferably, the polysiloxane macromonomer has a formula selected from the following formulas:
or
X—C H 2 —(CH 2 ) s —Si(R 1 ) 3−m —Z m
or
In these structures s is an integer from 0 to 6; preferably 0, 1, or 2; more preferably 0 or 1; m is an integer from 1 to 3, preferably 1; p is 0 or 1; q is an integer from 2 to 6; each R 1 is independently selected form the group consisting of hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkylamino, phenyl, C1-C6 alkyl or alkoxy-substituted phenyl, preferably C1-C6alkyl, or C1-C6 alkyl or alkoxy-substituted phenyl, more preferably C1-C6 alkyl, even more preferably methyl, R 2 is selected from the group consisting of C1-C6 alkyl or C1-C6 alkyl substituted phenyl, preferably methyl.
n is an integer from 0 to 4, preferably 0 or 1, more preferably 0; X is
wherein R 3 is hydrogen or —COOH, preferably R 3 is hydrogen; R 4 is hydrogen, methyl or —CH 2 COOH, preferably R 4 is methyl; Z is
wherein R 5 , R 6 , and R 7 , are independently selected from hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkooxy, C2-C6 alkylamino, phenyl, C1-C6 alkyl or alkoxy-substituted phenyl, hydrogen or hydroxyl, preferably R 5 , R 6 , and R 7 are C1-C6 alkyls; more preferably methyl; and r is an integer of from about 14 to about 700, preferably about 60 to about 400, and more preferably about 100 to about 350.
Exemplary silicone grafted polymers for use in the present invention include the following, where the composition is given as weight part of monomer used in the synthesis:
(i) poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
MWt of copolymer: 210,000
Composition: t-butyl acrylate (36%), n-butyl acrylate (27%), acrylic acid (12%), methacrylic acid (10%), poly(dimethylsiloxane) (15%)
MWt of poly(dimethysiloxane): 10,000
(ii) poly(t-butyl acrylate-co-ethyl acrylate-co-acrylic acid)-graft-poly(dimethylsiloxane)
MWt of copolymer: 100,000
Composition: t-butyl acrylate (34%), ethyl acrylate (35%), acrylic acid (21%), poly(dimethylsiloxane) (10%)
MWt of poly(dimethylsiloxane): 5,000
(iii) poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid)-graft-poly(dimethylsiloxane)
Mwt of copolymer: 150,000
Composition: t-butyl acrylate (47.25%), n-butyl acrylate (22.75%), acrylic acid (20%), poly(dimethylsiloxane) (10%)
MWt of poly(dimethylsiloxane): 10,000
(iv) poly(t-butyl acrylate-co-2-methoxyethyl acrylate-co-methacrylic acid)-graft-poly(dimethylsiloxane)
MWt of copolymer: 100,000
Composition: t-butyl acrylate (27%), 2-methoxyethyl acrylate (43%), methacrylic acid (20%), poly(dimethylsiloxane) (10%)
MWt of poly(dimethylsiloxane): 15,000
(v) poly(t-butyl acrylate-co-isobornyl acrylate-co-2-methoxyethyl acrylate-co-acrylic acid)-graft-poly(dimethylsiloxane)
MWt of copolymer: 95,000
Composition: t-butyl acrylate (33%), isobornyl acrylate (17%), 2-methoxyethyl acrylate (20%), acrylic acid (20%), poly(dimethylsiloxane) (10%)
MWt of poly(dimethylsiloxane): 10,000
(vi) poly(t-butyl acrylate-co-lauryl methacrylate-co-acrylic acid)-graft-poly(dimethylsiloxane)
MWt of copolymer: 125,000
Composition: t-butyl acrylate (60%), lauryl methacrylate (10%), acrylic acid (20%), poly(dimethylsiloxane) (10%)
MWt of poly(dimethylsiloxane): 15,000
The Tg's for monomer units above can be found in The Polymer Handbook , third edition, (John Wiley & Sons, 1989) and the backbone Tg can be calculated using the method illustrated in Fundamental Principles of Polymeric Materials , second edition (John Wiley & Sons, 1993). Representative Tg's for monomers in the exemplary silicone grafted polymers described above are as follows: The Tg of t-butyl acrylate is 44.85° C.; the Tg of n-butyl acrylate is −54.15° C.; the Tg of acrylic acid is 105.85° C.; the Tg of methacrylic acid is 227.85° C.; the Tg of ethyl acrylate is −24.15° C.; the Tg of lauryl methacrylate is −65.15° C.; and the Tg of 2-methoxyethyl acrylate is −50.15° C.
The silicone grafted polymers can be synthesized by free radical polymerization of the polysiloxane-containing monomers with the non-polysiloxane-containing monomers. The synthetic procedures are in general the same as those described for the adhesive copolymer. The silicone macromer is added in to the reactor along with the “A” and “B” monomers, and the reaction proceeds as for the adhesive copolymer examples. Compared to the adhesive copolymer, it may be necessary to choose different solvents for the polymerization reaction, as apparent to one skilled in the art, to keep the monomers and polymers in solution throughout the polymerization.
Without being limited by theory, it is believed that in forming the above-described silicone grafted polymers, there is some polymer which does not incorporate the silicone graft; such polymers have a relatively low weight average molecular weight e.g., below 20,000.
Personal Care Carrier
The compositions of the present invention comprise from about 0.1% to about 99.9%, preferably from about 0.5% to about 99.0% and most preferably from about 1.0% to about 99.9% of a suitable personal care carrier. Suitable carriers are fully described in U.S. Pat. No. 5,061,481 issued Oct. 29, 1991 to Suzuki et al., incorporated by reference herein. For example, skin care carriers typically comprise oil-in-water emulsions.
Hair spray compositions typically comprise a polar solvent phase as a liquid vehicle for the silicone grafted polymer. The polar solvent phases comprise one or more polar solvents that are present in the hair care compositions at a level of from about 80% to about 99%, preferably from about 85% to about 98%, more preferably from about 90% to about 95% of the total composition.
The polar solvents essential to the present compositions are selected from the group consisting of water, C 2 -C 3 monohydric alkanols, and mixtures thereof. If present, C 3 alkanols, such as isopropanol, should be used at levels no greater than about 15% by weight of the composition, preferably no greater than about 12%, more preferably no greater than about 10%. High levels of C 3 monohydric alcohols are, undesirable in the present compositions due to potential odor issues they can create. Preferred polar solvent phases contain water, ethanol, or mixtures thereof.
Where water and alcohol mixtures are used, for instance, water-ethanol or water-isopropanol-ethanol, the water content of the compositions is generally in the range of from about 0.5% to about 99%, preferably from about 5% to about 50% by weight of the total composition. In such mixtures, the alcohol solvents are generally present in the range of from 0.5% to about 99%, preferably from about 50% to about 95%, by weight of the total composition.
In yet another aspect of this invention are provided hair styling products, such as hair spray compositions, which contain reduced levels of volatile organic solvents. A reduced volatile organic solvent hair spray composition of the present invention contains no more than 80% volatile organic solvents (which include, for example, alkanols but not water). As used herein, volatile organic solvents means solvents which have at least one carbon atom and exhibit a vapor pressure of greater than 0.1 mm Hg at 20° C.
In the reduced volatile organic solvent hair styling products hereof, the compositions generally comprise at least 10%, by weight, of water. It is also specifically contemplated that they may contain at least about 11%, 12%, 13%, 14%, 15%, or more water.
The reduced volatile organic solvent compositions hereof will comprise up to about 90%, preferably up to about 70%, more preferably up to about 60% even more preferably no more than about 50%, water; and from about 10% to about 80%, preferably from about 20% to about 80%, more preferably from about 40% to about 80%, of volatile organic solvent. It is also contemplated that the compositions can be limited to containing no more than about 75%, 65%, 55%, or other levels of volatile organic solvents.
Shampoos and rinse compositions typically comprise a volatile, nonpolar, branched chain hydrocarbon and is safe for topical application to the skin and hair. The branched chain hydrocarbon solvent hereof is present at a level of from about 0.1% to about 15%, preferably from about 0.5% to about 10%, more preferably from about 2% to about 8%, by weight of the composition. Also useful are low boiling point silicone oils.
The branched chain hydrocarbon solvent is characterized by a boiling point of at least about 105° C., preferably at least about 110° C., more preferably at least about 125° C., most preferably at least about 150° C. The boiling point is also generally about 260° C. or less, preferably about 200° C. or less. The hydrocarbon chosen should also be safe for topical application to the hair and skin.
The branched chain hydrocarbon solvents are selected from the group consisting of C 10 -C 14 branched chain hydrocarbons, and mixtures thereof, preferably C 11 -C 13 branched chain hydrocarbons, more preferably C 12 branched chain hydrocarbons. Saturated hydrocarbons are preferred, although it isn't necessarily intended to exclude unsaturated hydrocarbons.
Examples of suitable nonpolar solvents include isoparaffins of the above chain sizes. Isoparaffins are commercially available from Exxon Chemical Co. Examples include Isopar™ G (C 10 -C 11 isoparaffins), Isopar™ H and K (C 11 -C 12 isoparaffins), and Isopar™ L (C 11 -C 13 isoparaffins). The most preferred nonpolar solvent are C 12 branched chain hydrocarbons, especially isododecane. Isododecane is commercially available from Preperse, Inc. (South Plainfield, N.J., USA) as Permethyl™ 99A.
Plasticizer
The compositions hereof can optionally contain a plasticizer for the silicone grafted polymer. Any plasticizer suitable for use in hair care products or for topical application to the hair or skin can be used. A wide variety of plasticizers are known in the art. These include acetyl triethylcitrate, triethycitrate, glycerin, diisobutyl adipate, butyl stearate, and propylene glycol. Plasticizers are typically used at levels of from about 0.01% to about 10%, by weight of the composition, preferably from about 0.05% to about 3%, more preferably from about 0.05% to about 1%.
Optional Components
Adhesive Polymer
The compositions of the present invention can comprise an additional adhesive polymer. The compositions hereof will generally comprise from about 0.1% to about 15%, preferably from 0.5% to about 8%, more preferably from about 1% to about 8%, by weight of the composition, of the adhesive polymer. It is not intended to exclude the use of higher or lower levels of the polymers, as long as an effective amount is used to provide adhesive or film-forming properties to the composition and the composition can be formulated and effectively applied for its intended purpose. By adhesive polymer what is meant is that when applied as a solution to a surface and dried, the polymer forms a film. Such a film will have adhesive and cohesive strength, as is understood by those skilled in the art.
The polymeric backbone is chosen such that it is compatible with the silicone adhesive styling polymer. By “compatible” is meant is that, when placed in a suitable solvent, the polymers form a stable solution, i.e., the polymers do not compete for solubility and therefore, cause no phase separation and when the solution is dried a uniform film is formed, with no macrophase separation of the two polymers. A suitable solvent is a solvent which substantially completely dissolves the non-silicone and silicone grafted polymers at the levels described herein. The polymer blend forms a relatively clear hairspray system (% transmittance at 450 nm is generally greater than 80%). It is recognized that certain plasticizers can form cloudy films as well as incorrect neutralization levels. Therefore, this would fall outside this definition of compatibility. The compatibility can be tested by dissolving the adhesive polymer and the silicone grafted hair styling resin in a mutual solvent, and then evaporating the solvent to form a film. Incompatible polymers will form a cloudy film with poor mechanical properties, due to the large scale phase separation of the two polymers. Alternatively, after drying the polymer solution to a film, compatibility can be evaluated by measuring the Tg. Compatible polymers will have a single Tg, while incompatible polymers will exhibit two Tg's. Although compatibility can occur between two polymers of completely different structures, it is preferred that compatibility be obtained by making the composition of the non-silicone backbone of the silicone grafted polymer similar to or identical to the composition of the adhesive polymer.
The adhesive polymer should have a weight average molecular weight of at least about 20,000, preferably greater than about 25,000, more preferably greater than about 30,000, most preferably greater than about 35,000. There is no upper limit for molecular weight except that which limits applicability of the invention for practical reasons, such as processing, aesthetic characteristics, formulateability, etc. In general, the weight average molecular weight will be less than about 10,000,000, more generally less than about 5,000,000, and typically less than about 2,000,000. Preferably, the weight average molecular weight will be between about 20,000 and about 2,000,000, more preferably between about 30,000 and about 1,000,000, and most preferably between about 40,000 and about 500,000.
Preferably, the adhesive hereof when dried to form a film have a Tg of at least about −20° C., more preferably at least about 20° C., so that they are not unduly sticky, or “tacky” to the touch. As used herein, the abbreviation “tg” refers to the glass transition temperature of the backbone of the polymer. Preferably, the Tg is above about −20° C., more preferably above about 20° C.
Preferably the weight ratio of the non-silicone polymer to silicone grafted polymer ranges from about 1:10 to about 1:1, preferably from about 1:5 to about 1:1.
Exemplary adhesive polymers for use in the present invention include the following, where the numbers following the structure indicate the weight ratios of monomers as loaded into the polymerization reactor:
(i) acrylic acid/t-butyl acrylate 25/75
(ii) dimethylaminoethyl methacrylate/isobutyl methacrylate/2-ethylhexyl-methacrylate 40/40/20
(iii) t-butylacrylate/acrylic acid 65/35
(iv) polymer (ii) quaternized by treatment with methyl chloride
The adhesive polymers can be synthesized as described above such as by free radical polymerization of the monomers.
Solubility of the adhesive polymer, as described above, should be determined after neutralization, if any, as well as after addition of other ingredients that may be included in the polar solvent phase, such as surfactants, solubilizers, etc.
The present compositions can contain a wide variety of additional optional ingredients, including among them any of the types of ingredients known in the art for use in hair setting compositions, especially hair spray compositions and hair setting tonics. These ingredients include, but are not limited to, surfactants (including fluorinated surfactants and silicone copolyols), and ionic strength modifiers, propellants, hair conditioning agents (e.g., silicone fluids, fatty esters, fatty alcohols, long chain hydrocarbons, cationic surfactants, etc.).
Ionic Strength Modifier System
Optionally, the compositions of the present invention can contain an effective amount of a non-surface active ionic strength modifier system for reducing the viscosity of the hair spray composition. When used, the ionic strength modifiers will be present in the present compositions at a level of at least about 0.01%, by weight of the composition. The upper limit is dependent upon the maximum amount of the ionic strength modifiers that can be present in the particular compositions hereof such that the hair setting resin remains solubilized or dispersed. As will be understood by those skilled in the art, as the ionic strength of the composition is increased, the resin will eventually fall out of solution, or otherwise no longer remain solubilized or dispersed in the polar liquid carrier. The upper limit of the ionic strength modifier system level will vary depending upon the particular ionic strength modifiers, liquid vehicle, resin, and other ingredients present in the composition. Thus, for example, the maximum amount of the ionic strength modifiers that can be used will tend to be lower for compositions with liquid vehicles containing less water, compared to compositions with more water. Generally, the compositions will comprise about 4%, by weight, or less of the ionic strength modifiers, more generally about 2% or less, and typically about 1% or less. Preferably, the compositions hereof will comprise from about 0.01% to about 0.5%, more preferably from about 0.01% to about 0.1%, of the ionic strength modifier system.
The ionic strength modifier system comprises a mixture of monomeric cations and anions. The ions of the ionic strength modifier system hereof are non-surface active, i.e. they do not significantly reduce surface tension. For purposes hereof, non-surface active shall mean the ions, which at a 0.5% aqueous solution concentration, reduce surface tension by no more than 5.0 dynes/cm2. Generally, the ions of the ionic strength modifier system hereof will be characterized by having, at maximum, four or less carbon atoms per charge, preferably two or less carbon atoms, in any aliphatic chain or straight or branched chain organic heterochain.
The ionic strength modifier system comprises monomeric ions of the type which are products of acid-base reactions. Thus, basic and acidic ions OH − and H + do not constitute part of the ionic strength modifier system hereof, although they may be present in the composition. The ions hereof are incorporated into the composition in a form such that they can exist in the composition as free ions, i.e., in dissociated form. It is not necessary that all of the ions added exist in the composition as free ions, but must be at least partially soluble or dissociated in the composition. The ionic strength modifiers can be incorporated into the hair styling compositions, for example, by addition of soluble salts, or by addition of mixtures of acids and bases, or by a combination thereof. It is a necessary aspect of the invention that both anions and cations of the ionic strength modifier system be included in the composition.
Suitable cations for use include, for example, alkali metals, such as lithium, sodium, and potassium, and alkaline-earth metals, such as magnesium, calcium, and strontium. Preferred of the divalent cations is magnesium. Preferred monovalent metal ions are lithium, sodium, and potassium, particularly sodium and potassium. Suitable means of addition to the compositions hereof include, for example, addition as bases, e.g., hydroxides, sodium hydroxide and potassium hydroxide, and such as salts that are soluble in the liquid carrier, e.g. salts of monomeric anions such as those described below.
Other suitable cations include organic ions, such as quaternary ammonium ions and cationic amines, such as ammonium mono-, di-, and tri-ethanolamines, triethylamine, morpholine, aminomethylpropanol (AMP), aminoethylpropanediol, etc. Ammonium and the amines are preferably provided in the forms of salts, such as hydrochloride salts.
Monomeric anions that can be used include halogen ions, such as chloride, fluoride, bromide, and iodide, particularly chloride, sulfate, ethyl sulfate, methyl sulfate, cyclohexyl sulfamate, thiosulfate, toluene sulfonate, xylene sulfonate, citrate, nitrate, bicarbonate, adipate, succinate, saccharinate, benzoate, lactate, borate, isethionate, tartrate, and other monomeric anions that can exist in dissociated form in the hair styling composition. The anions can be added to the compositions hereof, for example, in the form of acids or salts which are at least partially soluble in the liquid vehicle, e.g., sodium or potassium salts of acetate, citrate, nitrate, chloride, sulfate, etc. Preferably, such salts are entirely soluble in the vehicle.
The use of ionic strength modifiers are especially useful in reduced volatile organic solvent compositions, most especially those utilizing silicone macromer-containing polymers.
Personal Care Compositions
The present invention encompasses a wide variety of personal care compositions, including shampoos, soaps, lotions, creams, antiperspirants, nail enamels, lipsticks, foundations, mascaras, sunscreens, hair spray compositions, mousses, and hair setting tonics. Compositions that will be flowable, e.g., low viscosity compositions that, preferably, are suitable for spray application as well as higher viscosity compositions are also contemplated.
Personal care carriers are suitable for use in the present invention are described in U.S. Pat. No. 5,306,485 to Robinson et al., issued Apr. 26, 1994, and U.S. Pat. No. 5,002,680 to Schmidt et al., issued Mar. 26, 1991, both of which are incorporated by reference herein. Hair spray compositions and mousses of the present invention can be dispensed from containers which are aerosol dispensers or pump spray dispensers. Such dispensers, i.e., containers, are well known to those skilled in the art and are commercially available from a variety of manufacturers, including American National Can Corp. and Continental Can Corp.
When the hair spray compositions are to be dispensed from a pressurized aerosol container, a propellant which consists of one or more of the conventionally-known aerosol propellants may be used to propel the compositions. A suitable propellant for use can be generally any liquifiable gas conventionally used for aerosol containers.
Suitable propellants for use are volatile hydrocarbon propellants which can include liquefied lower hydrocarbons of 3 to 4 carbon atoms such as propane, butane and isobutane. Other suitable propellants are hydrofluorocarbons such as 1,2-difluoroethane (Hydrofluorocarbon 152A) supplied as Dymel 152A by DuPont. Other examples of propellants are dimethylether, N-butane, isobutane, propanes, nitrogen, carbon dioxide, nitrous oxide and atmospheric gas and mixtures thereof.
The aerosol propellant may be mixed with the present compositions and the amount of propellant to be mixed is governed by normal factors well known in the aerosol art. Generally, for liquifiable propellants, the level of propellant is from about 10% to about 60% by weight of the total composition, preferably from about 15% to about 40% by weight of the total composition.
Alternatively, pressurized aerosol dispensers can be used where the propellant is separated from contact with the hair spray composition such as a two compartment can of the type sold under the tradename SEPRO from American National Can Corp.
Other suitable aerosol dispensers are those characterized by the propellant being compressed air which can be filled into the dispenser by means of a pump or equivalent device prior to use. Such dispensers are described in U.S. Pat. No. 4,077,441, Mar. 7, 1978, Olofsson and U.S. Pat. No. 4,850,577, Jul. 25, 1989, TerStege, both incorporated by reference herein, and in U.S. Ser. No. 07/839,648, Gosselin et al., filed Feb. 21, 1992, also incorporated by reference herein. Compressed air aerosol containers suitable for use are also currently marketed by The Procter & Gamble Company under their tradename VIDAL SASSOON AIRSPRAY® hair sprays.
Conventional non-aerosol pump spray dispensers, i.e., atomizers, can also be used.
Other hair styling compositions include tonics and lotions, which are typically dispensed in a conventional bottle or tube, and applied directly to the hair or first dispensed to the hand and then to the hair.
The hair styling formulations of the present invention can optionally contain conventional hair care composition adjuvants. Generally, adjuvants collectively can comprise from about 0.05% to about 5% by weight and preferably from about 0.1% to about 3%, by weight. Such conventional optional adjuvants are well known to those skilled in the art and include in addition to those discussed above, emollients; lubricants and penetrants such as various lanolin compounds; protein hydrolysates and other protein derivatives; ethylene adducts and polyoxyethylene cholesterol; dyes, tints, bleaches, reducing agents and other colorants; pH adjusting agents sunscreens; preservatives; thickening agents (e.g. polymeric thickeners, such as xanthan gum); and perfume.
Method of Making
The personal care compositions of the present invention can be made using conventional formulation and mixing techniques.
Method of Use
The compositions of the present invention are used in conventional ways to provide the personal care compositions of the present invention. Such method generally involves application of an effective amount of the product. For example, in a hair spray composition, said composition is applied to the desired dry, slightly damp, or wet hair before and/or after the hair is arranged to a desired style. The composition is then dried or allowed to dry. By “effective amount” is meant an amount sufficient to provide the desired benefits.
The following Experimentals and Examples further illustrate embodiments within the scope of the present invention. They are given solely for the purposes of illustration and are not to be construed as limitations of the present invention as many variations of the invention are possible without departing from its spirit and scope.
EXPERIMENTALS
The following synthesis exemplify silicone grafted polymers useful in the present compositions.
Polymer 1
Synthesis of Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
Place 42.75 parts of t-butyl acrylate, 27.25 parts n-butyl acrylate, 10 parts methacrylic acid, 10 parts acrylic acid, and 10 parts polydimethylsiloxane macromonomer in a roundbottom flask. Add sufficient acetone as the reaction solvent to produce a final monomer concentration of 20%. Purge the vessel with argon for approximately one hour. Following the purge, maintain a constant positive pressure on the closed reaction system with argon. Heat the reaction to 58° C. Prepare a 10% solution of azobisisobutyronitrile (0.5% by weight relative to the amount of monomer) in acetone, and add it to the reaction mixture. Maintain heat and stirring for 20 hours. Terminate the reaction by opening the reactor to atmosphere and cooling to room temperature.
The polymer solution is then precipitated in water at one part solution to 15 parts water. The resultant polymer is then redissolved in acetone. This procedure is repeated six times, with the final polymer being placed in a vacuum oven for heated drying. This completes the polymer purification process.
Polymer 2
Synthesis of Poly(t-butyl acrylate-co-n-butyl acrylate-co-methacrylic acid)-graft-poly(dimethylsiloxane)
Place 32 parts of t-butyl acrylate, 27 parts n-butyl acrylate, 21 parts methacrylic acid, and 20 parts polydimethylsiloxane macromonomer in a roundbottom flask. Add sufficient acetone as the reaction solvent to produce a final monomer concentration of 20%. Purge the vessel with argon for approximately one hour. Following the purge, maintain a constant positive pressure on the closed reaction system with argon. Heat the reaction to 58° C. Prepare a 10% solution of azobisisobutyronitrile (0.5% by weight relative to the amount of monomer) in acetone, and add it to the reaction mixture. Maintain heat and stirring for 20 hours. Terminate the reaction by opening the reactor to atmosphere and cooling to room temperature.
The polymer solution is then precipitated in water at one part solution to 15 parts water. The resultant polymer is then redissolved in acetone. This procedure is repeated six times, with the final polymer being placed in a vacuum oven for heated drying. This completes the polymer purification process.
EXAMPLES
Examples 1-4
The following examples represent nonaerosol hairspray compositions of the present invention.
Example No
Component (wt. %)
1
2
3
4
Copolymer 1
4.00
4.75
5.50
5.50
Isododecane 2
1.00
1.00
1.00
3.00
Diisopropyl butyl adipate
0.40
0.75
0.90
0.55
Sodium hydroxide 3
0.96
1.20
1.44
1.6
Perfume
0.10
0.10
0.10
0.10
Water
17.00
20.00
20.00
18.00
Ethanol 4
76.54
71.95
70.56
71.25
1 Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane).
2 PERMETHYL 99A, from Presperse, Inc., South Plainfield, NJ, USA.
3 Sodium hydroxide is 30% active.
4 SDA 40 (100% ethanol).
Example 5
Sunscreen Composition
An oil-in-water emulsion is prepared by combining the following components utilizing conventional mixing techniques.
Ingredients
Weight %
Phase A
Water
QS100
Carbomer 954 [1]
0.24
Carbomer 1342 [2]
0.16
Copolymer [3]
1.00
Disodium EDTA
0.05
Phase B
Isoarachidy Neopentanoate [4]
2.00
PVP Eicosene Copolymer [5]
2.00
Octyl Methoxycinnamate
7.50
Octocrylene
4.00
Oxybenzone
1.00
Titanium Dioxide
2.00
Cetyl Palmitate
0.75
Stearoxytrimethylsilane (and)
0.50
Stearyl Alcohol [6]
Glyceryl Tribehenate
0.75
Dimethicone
1.00
Tocopheryl Acetate
0.10
DEA-Cetyl Phosphate
0.20
Phase C
Water
2.00
Triethanolamine 99%
0.60
NaOH solution 40%
0.33
Phase D
Water
2.00
Butylene Glycol
2.00
DMDM Hydantoin (and)
0.25
Iodopropynyl Butylcarbamate[7]
dL Panthenol
1.00
Phase E
dimethylmyristamine
0.36
[1] Available as Carbopol ® 954 from B. F. Goodrich.
[2] Available as Carbopol ® 1342 from B. F. Goodrich.
[3] Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
[4] Available as Ganex V-220 from GAF Corporation.
[5] Available as DC 580 Wax from Dow Corning.
[6] Available as Synchrowax HRC from Croda.
[7] Available as Glydant Plus from Lonza.
In a suitable vessel the Phase A ingredients are dispersed in the water and heated to 75-85° C. In a separate vessel the Phase B ingredients (except DEA-Cetyl Phosphate) are combined and heated to 85-90° C. until melted. Next, the DEA-Cetyl Phosphate is added to the liquid Phase B and stirred until dissolved. This mixture is then added to Phase A to form the emulsion. The Phase C ingredients are combined until dissolved and then added to the emulsion. The emulsion is then cooled to 40-45° C. with continued mixing. In another vessel, the Phase D ingredients are heated with mixing to 40-45° C. until a clear solution is formed and this solution is then added to the emulsion. Finally, the emulsion is cooled to 35° C. and the Phase E ingredients are combined at 65° C., use an appropriate homogenizer to facilitate incorporation of the copolymer into the solvent. Phase E is the cooled to 35° C., added and mixed.
This emulsion is useful for topical application to the skin to provide protection from the harmful effects of ultraviolet radiation.
Example 6
Facial Moisturizer
A leave-on facial emulsion composition containing a cationic hydrophobic surfactant is prepared by combining the following components utilizing conventional mixing techniques.
Ingredient
Weight %
Phase A
Water
QS100
Glycerin
3.00
Cetyl Palmitate
3.00
Cetyl Alcohol
1.26
Quaternium-22
1.00
Glyceryl Monohydroxy Stearate
0.74
Dimethicone
0.60
Stearic Acid
0.55
Octyldodecyl Myristate
0.30
Potassium Hydroxide
0.20
Carbomer 1342
0.125
Tetrasodium EDTA
0.10
DMDM Hydantoin and Iodopropynyl
0.10
Butyl Carbamate
Carbomer 951
0.075
Phase B
Isododecane
4.00
Copolymer [1]
1.00
stearamine
0.36
[1] Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
In a suitable vessel the Phase A ingredients are combined to form an emulsion. Phase B is prepared by dispersing the copolymer in Isododecane (solvent) then adding the stearamine. Heat the solution to 65° C. and use an appropriate homogenizer to facilitate incorporation of the copolymer into the solvent. Cool the Phase B and mix into Phase A using conventional mixing techniques.
This emulsion is useful for application to the skin as a moisturizer.
Example 7
The following is an anti-perspirant composition representative of the present invention.
Component
Weight %
PPG 2 Myristyl Propionate
34.00%
Glyceryl C 18 -C 36 Wax Acid Ester
0.40%
Cyclomethicone
32.75%
Copolymer [1]
1.00%
dimethylmyristamine
0.50%
Aluminum Chlorohydrate
19.00%
PPG 5 Ceteth 20
7.50%
Water
1.50%
[1] Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
Mix PPG 2 Myristyl Propionate and Glyceryl C 18 -C 36 Wax Acid Ester, heat to 75° C. Disperse the Chlorohydrate. Disperse the copolymer in Cyclomethicone (solvent) then add the dimethylmyristamine. Heat the solution to 65° C. and use an appropriate homogenizer to facilitate incorporation of the copolymer into the solvent. Add the cyclomethicone mixture to the Chlorohydrate dispersion. Mix PPG 5 Ceteth 20 and the water, the add to oils, perfume and cool.
Example 8
The following is an anti-acne composition representative of the present invention.
Component
Weight %
Copolymer-Solvent Mix
Copolymer [1]
1.00%
dimethylpalmitamine
0.18%
Isopar H ® [2]
3.75%
Main Mix
Water
Q.S. to 100%
Ethanol (SDA 40)
40.00%
Carbopol 940 ®
0.75%
Triethanol Amine
1.00%
Salicylic Acid
2.00%
[1] Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
[2] C 11 -C 12 Isoparaffin, available from Exxon Chemical Co.
This product is prepared by dispersing the copolymer in Isopar H® (solvent) then adding the dimethylpalmitamine. Heat the solution to 65° C. and use an appropriate homogenizer to facilitate incorporation of the copolymer into the solvent. The other components are mixed in a separate vessel at ambient temperature. The copolymer-solvent premix is cooled (if needed) and added to the other components. This composition is useful for application to the skin to provide improve water resistance and is useful in the treatment of acne.
Example 9
The following is an anti-acne composition representative of the present invention.
Component
Weight %
Copolymer-Solvent Mix
Copolymer [1]
1.00%
dimethylpalmitamine
0.18%
Isopar H ® [2]
3.75%
Main Mix
Water
Q.S. to 100%
Ethanol (SDA 40)
20.00%
Carbopol 940 ®
0.75%
Triethanol Amine
1.00%
Ibuprofen
2.00%
[1] Poly(t-butyl acrylate-co-n-butyl acrylate-co-acrylic acid-co-methacrylic acid)-graft-poly(dimethylsiloxane)
[2] C 11 -C 12 Isoparaffin, available from Exxon Chemical Co.
This product is prepared by dispersing the copolymer in Isopar H® (solvent) then adding the dimethylpalmitamine. Heat the solution to 65° C. and use an appropriate homogenizer to facilitate incorporation of the copolymer into the solvent. The other components are mixed in a separate vessel at ambient temperature. The copolymer-solvent premix is cooled (if needed) and added to the other components. This composition is useful for application to the skin to provide improve water resistance and is useful for the analgesic effects. | Disclosed are personal care compositions, such as haircare, cosmetic and nail compositions containing linear toughened silicone grafted polymers. | 0 |
This application claims the priority and benefit of U.S. Provisional Patent Application Ser. No. 60/864,199 filed Nov. 3, 2006.
FIELD OF THE INVENTION
The present invention relates generally to the field of pets and devices that are used to feed pets. More particularly, it relates to a lidded pet dish that uses wireless technology to control selective access to the dish by multiple pets.
BACKGROUND OF THE INVENTION
In the area of data acquisition, the use of wireless communication devices is well known. For example, infrared (IR) technology and radio frequency identification (RFID) technology, in particular, are well known in the art of wireless communication devices and in the art of electronic identification methods.
RFID technology relies on the storage and remote retrieval of data by means of one or more transmission or transponder devices that are frequently called RFID “tags.” An RFID tag is a small electronic device that can be attached to or incorporated within a physical item or object for a number of different purposes. RFID tags contain micro-circuitry and antennas that enable them to receive and respond to radio frequency queries from an RFID transceiver. Passive tags require no internal power source, whereas active tags typically require a power source.
IR technology refers to the use of free-space propagation of light waves in the near infrared band as a transmission medium for communication. IR technology has advantages over RFID technology in that IR systems are generally cheaper to produce than wireless RFID links. Using IR technology, a point-to-point connection between two devices may be constructed for very low cost, with one or two emitter light-emitting diodes (LEDs). Additionally, numerous modulation methods have been developed for transmitting data using infrared signals. Modulation methods that are currently in commercial use include baseband pulsing, frequency shift keying, amplitude shift keying, phase shift keying, pulse position modulation and burst-pulse position modulation. Each of these modulation methods involves tradeoffs between cost, signal distance, signal rate and “ambient immunity”. Ambient immunity is the ability to receive information sent over infrared signals while rejecting ambient sources of light. Ambient sources of light include, for example, sunlight, fluorescent lighting and incandescent lighting.
The use of containers or dishes for feeding and watering pets is also well known. Such dishes can be used to provide a pet, or several of them, with a quantity of pet food and water. In the situation where only one pet has access to the contents of such a dish, the pet owner clearly has control over how much food is consumed by his or her pet and when that food is made available to the pet. However, in a multiple pet household, or in an animal care facility where multiple pets can be found, the control over how much food is consumed by any one pet is subject to far less accurate assessment. That is, in a multiple-pet setting, one pet may be consuming more than its “fair share” of food, thus shorting other pets of their food requirements. This problem is even more evident in a situation where, for example, a household is inhabited by a dog and a cat where the dog has access to the cat's food. In that situation, it has been observed by this inventor that dogs seem to prefer cat food which tends to be more expensive. Not only does this often result in the cat going hungry, it also results in each pet getting an incorrect diet. This situation is made worse where, for example, one pet requires that some sort of medication be added to its food and diet. In that situation, the wrong pet may be medicated and the pet that was intended to be medicated is denied its proper level of medication. While the obvious solution to these situations would be to separate the pets, such is not always easy for the pet owner to do and may have no effect since some pets, when separated, will not eat.
Another undesirable consequence of leaving pet food dishes unmonitored is that other “eaters” may, from time to time, attempt to access the pet food dishes. For example, curious infants are known to attempt to gain access the contents of pet food dishes, as will hungry rodents and pesky insects, assuming that the food dish is in such an area that it can be accessed in that fashion.
In the view of this inventor, there is a need to devise a lidded pet food dish that allows selective access to the dish contents by the particular intended pet or pets and that denies access to all other pets and other eaters.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a lidded pet food dish that allows selective access to the dish contents by one or more pets. It is another object of the present invention to provide such a lidded pet food dish whereby multiple pets may use the dish in such a way that only the food dish compartment assigned to a particular pet is accessed by that pet, and only that pet, all others being unable to access that compartment. It is still another object of the present invention to provide such a lidded pet food dish that uses currently available wireless technology to accomplish this selective accessing of the lidded pet food dish. It is yet another object of the present invention to provide such a lidded pet food dish that also includes an “override” mechanism such that the pet owner will have unfettered access to the contents of the lidded pet food dish when such is desired or required. This override mechanism could be incorporated into a device that would be operated directly on the device or remotely by the pet owner. In this fashion, the owner could check whether a given pet has eaten and, if so, how much that pet has eaten.
The device of the present invention has obtained these objects. It provides for a lidded pet food dish that uses one or more wireless or RFID tags that are associated with a like number of corresponding pets. Each pet that is fitted with an RFID tag has the ability or means to access the contents of at least one compartment of the lidded pet food dish such that the pet will have exclusive access to that compartment. The pet food dish of the present invention has at least one food compartment and a hinged lid for that compartment, the lid being movable between an open position and a closed position. The dish has a sensor in it that receives a passive or active signal from the pet's RFID tag for actuating the opening of the compartment lid. As that pet approaches the lidded pet food dish, and comes within a pre-determined distance of the dish, that pet's lidded dish compartment is made accessible by the opening of the lid. As the animal leaves the dish, the lid would close. No other pet would be able to actuate the opening of the lid of that particular compartment. The lidded food dish also has an override mechanism that allows the pet owner to open the lid of each compartment to check on the amount of food consumed and to refill the compartment as needed.
The foregoing and other advantages of the device of the present invention will be further apparent from the detailed description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram illustrating the outfitting of a first pet with a passive RFID tag in accordance with the present invention, the first pet being a dog.
FIG. 2 is a schematic diagram illustrating the outfitting of a second pet with a passive RFID tag in accordance with the present invention, the second pet being a cat.
FIG. 3 is a schematic diagram illustrating a lidded pet food dish in accordance with the present invention.
FIG. 4 is a schematic diagram illustrating the lidded pet food dish where the first pet approaches the dish.
FIG. 5 is a schematic diagram illustrating the lidded pet food dish where the second pet approaches the dish.
FIG. 6 is a schematic diagram illustrating the lidded pet food dish with a remotely-controlled override mechanism as used by the pet owner.
FIGS. 7 and 8 are a flow diagram illustrating the logic used in the circuitry in one embodiment of a lidded pet food dish in accordance with the present invention as used in a two pet situation.
DETAILED DESCRIPTION
Referring now to the drawings in detail, wherein like numbered elements refer to like elements throughout, FIGS. 1 and 2 illustrate, in schematic form, two pets with which the device of the present invention could be used. It is to be understood that, although only two pets are shown, the device of the present invention is not limited to the two-pet application. That is, any number of pets could use the device of the present invention. As shown, the first pet is a dog 2 that is outfitted with a passive RFID tag 4 , also identified as “TAG A,” that is attached to its collar. The second pet is a cat 6 that is outfitted with a similar passive RFID tag 8 that is identified as “TAG B.” It is to be understood that the passive RFID tags 4 , 8 each carries with it certain identifying information and are each “readable” by a sensor in accordance with a pre-programmed scheme as will be apparent later in this detailed description. Each RFID tag 4 , 8 , however, is readable in the same fashion, even though each contains different tag information. That is, it is to be understood that the passive RFID tags 4 , 8 could also be configured as active RFID tags, as infrared tags, or other type of tag that utilizes wireless information technology that has been used or which has yet to be used. The important purpose of the RFID tags 4 , 8 is to differentiate the access information carried by one pet from the information that is carried by the other pet or pets. It is also possible to “embed” other pertinent pet information into each tag 4 , 8 for the purpose of gaining recordable information and data about feeding times, feeding amounts, etc. that could be captured by a random access memory or flash memory component within the basic circuit disclosed later in this detailed description. Physically, the tags 4 , 8 could be configured to include a clear vinyl pocket (not shown) to include, other pet-specific information, such as the owner's name and address and the pet's name, for example.
As alluded to previously, it is also to be understood that infrared (IR) data transmission could be employed in an alternative embodiment of the tags 4 , 8 mentioned above. In the case of IR data transmission, IR light-emitting diodes can be used to emit or transmit IR radiation which is focused by a plastic lens into a narrow beam or “cone.” The beam is modulated, or switched “on” and “off” very quickly, to encode the data. The receiver, in turn, uses a photodiode to convert the received IR radiation into an electric current. The receiver is typically designed such that it responds only to the rapidly pulsing signal created by the transmitter, and filters out slowly changing IR radiation from other ambient light or heat sources. IR is a “line-of-sight” transmission method because it does not penetrate most objects, such as walls, and accordingly does not interfere with other devices in adjoining rooms. The communication that actually occurs between two devices that operate on IR principles only “simulate” duplex communication because they quickly turn the link between the two devices around.
Referring now to FIG. 3 , it illustrates a lidded pet dish, generally identified 10 , in one preferred embodiment of the present invention, this particular embodiment using RFID technology. Although the example given here, which example is given solely for the purpose of illustrating enablement of the present invention, is one where the dish 10 includes two compartments 12 , 14 , the compartments being labeled “A” and “B,” it is to be understood that other numbers of compartments could be used within the scope of the present invention. The “A” and “B” nomenclature presented here is provided to distinguish the first compartment 12 from the second compartment 14 , much in the same way as the two pets are distinguished. The two individual compartments 12 , 14 contained within the dish 10 are best illustrated in FIGS. 4 , 5 and 6 . It is also to be understood that the compartments 12 , 14 could be configured with removable inner dishes or liners (not shown) for ease in filing and cleaning the dish 10 . As with the tags, the dish 10 could also be configured to include a clear vinyl pocket (not shown) to include pet-specific information, as well, such as the pet's name, the pet's picture, and the like.
As shown in FIG. 3 , it will be seen that each compartment 12 , 14 is “lidded.” That is, each compartment 12 , 14 includes a hinged lid 22 , 24 that seats atop each compartment. The lids 22 , 24 each include a hinge 32 , 34 , respectively, which allows the lids 22 , 24 to rotate upwardly to the “open” position and downwardly to the “closed” position at the hinge 32 , 34 when a power circuit (not shown) is actuated. The power circuit would include a small direct current (DC) power supply that would operate a small DC motor attached to each hinge 32 , 34 . Such motors are well known in the art. The power supply would most conveniently be comprised of one or more DC batteries that would be housed within the dish 10 as well. The normal position for each lid 22 , 24 is in the “down” position as shown in FIG. 3 . Although not shown, it is also to be understood that each lid 22 , 24 may be fitted with a seal whereby vermin and insects are prevented from accessing the food contents 42 , 44 , respectively, of each compartment 12 , 14 when each lid is in the “down” position. This type of a seal can also assist in odor control relative to the specific food contents 42 , 44 fed to the pets. See also FIGS. 4 , 5 and 6 in this regard. While the lids 22 , 24 are shown hinged from the rear of the dish 10 , it is to be understood that the hinges 32 , 34 could be located at another part of the peripheral edge of each lid 22 , 24 and still come within the scope of the present invention. For example, the lids 22 , 24 could be hinged in a “back-to-back” configuration whereby the lids 22 , 24 would actually serve as a barrier to each pet 2 , 6 during side-by-side feeding. That is, the lid that provides access to one compartment could effectively “block” the other pet from access to that compartment to prevent one pet from “muscling in” on the other pet during feeding. The lids 22 , 24 could be alternatively configured to “swing” out of the way during feeding.
Though not shown, it is to be understood that the lids 22 , 24 could be color-coded with the respective pet tags 4 , 8 used with each of the owner's pets 2 , 6 . The same color-coding could be used with the compartments 12 , 14 as well. This color-coding scheme would assist the pet owner with easy visualization as to which pet is supposed to have access to which compartment 12 , 14 .
Returning now to the first preferred embodiment, and as is shown in FIG. 3 , it will be seen that the dish 10 also includes an electronic device 20 which is a sensor for each of the pet tags 4 , 8 . The electronic device 20 would be part of the DC electrical circuitry described above. Here again, the wireless technology used could be altered without deviating from the scope of the present invention. In this particular dish 10 , however, the electronic device 20 , or “sensor,” is intended in this first preferred embodiment to operate using RFID technology of the type that is well known in the art. As is also shown in FIGS. 3 through 6 , the sensor 20 is functionally adapted to be actuated within a given perimeter 30 about the dish 10 . The perimeter 30 is exaggerated in the given illustrations and would, in the preferred embodiment be much closer to the dish 10 than is shown, the perimeter 30 being illustrated for representation purposes only. In the preferred embodiment, the sensor 20 would “sense” a signal 26 , 28 that would respond to a pet tag 4 , 8 , respectively, when the pet 2 , 6 , approached the dish 10 at a point that is within this perimeter 30 .
More specifically, and as is shown in FIG. 4 , as the dog 2 would approach the dish 10 and be sensed to be within the perimeter 30 of operation of the dish 10 , its tag 4 would trigger a signal 26 from the sensor 20 . This would then actuate a motor (not shown) that would move the lid 22 of the “A” compartment 12 upwardly, in response to the presence of the dog 2 . This would afford the dog 2 with access to its food 42 . Note that the dog 2 would not be afforded access to the food 44 contained within the “B” compartment 14 , which is that compartment 14 used by the cat 6 . If the dog 2 wanders away from the dish 10 , the lid 22 of its food compartment 12 closes and would not re-open unless and until the dog 2 again approached the dish 10 .
If the cat 6 approaches the dish 10 , a similar action results with respect to the “B” compartment 14 . As is shown in FIG. 5 , as the cat 6 would approach the dish 10 and be sensed to be within the perimeter 30 of operation, its tag 8 would similarly trigger a signal 28 from the sensor 20 . This would then actuate a motor (also not shown) that would move the lid 24 of the “B” compartment 14 upwardly, in response to the presence of the cat 6 . This would afford the cat 6 with access to its food 44 . Note that the cat 6 would not be afforded access to the food 42 contained within the “A” compartment 12 , which is that compartment 12 used by the dog 2 . If the cat 6 wanders away from the dish 10 , the lid 24 of its food compartment 14 would close and would not re-open unless the cat 6 again approached the dish 10 .
It should be obvious to the reader that any number of dishes 10 could be used with an even greater number of pets 2 , 6 or that the dish 10 could be configured with an even greater number of compartments 12 , 14 , each corresponding to an associated pet. The precise number of pets and the precise number of compartments is not a limitation of the present invention.
It is also within the scope of the present invention that the electronic circuitry of the dish 10 be pre-programmed such that, when one lid is in the “open” position as would be intended for the pet that would be feeding from it, the open lid could move to a “closed” position if the other pet approached and attempted to aggressively feed from the wrong compartment. Other pre-programmed variations could also be incorporated within the basic design of the present invention.
One additional aspect of the present invention is that the owner be enabled to check the food or water contents 42 , 44 of each compartment 12 , 14 when such is desired or required. That is, the owner should have access to each compartment 12 , 14 to determine whether the compartment 12 , 14 needs to be cleaned and re-filled or to determine whether the pet 2 , 6 is eating and at what rate its food is being eaten. One way to provide the owner with access to the compartments 12 , 14 would be to provide, as part of the control circuitry, an override button (not shown) that would be located on top of or underneath the dish 10 and in a position where it could not be inadvertently actuated by the feeding pet 2 , 6 . This would allow the pet owner to remove the dishes for filling, cleaning, and so on, without the need for the owner to wait for pet-actuation of the dish 10 . Another way to accomplish this is illustrated in FIG. 6 which shows that the owner would be provided with a remote control device 50 , the remote control device 50 being integrated with the circuitry of the sensor 20 . The control device 50 could include, for example, actuation buttons 52 , 54 whereby the owner could selectively “open” the lids 22 , 24 , respectively, or either of them, of the dish 10 . The control device 50 could also include circuitry such that depressing one of the actuating buttons 52 , 54 a first time “opens” a lid 12 , 14 and depressing the actuating button 52 , 54 a second time “closes” the lid 12 , 14 . Alternatively, the control circuitry in the dish 10 of the present invention could include a built-in timing capability such that the lid 12 , 14 stays open for a pre-programmed period of time and then automatically re-closes the lid 12 , 14 .
As previously alluded to, an alternative preferred embodiment would use known IR technology for actuation of the dish 10 . Referring now to FIGS. 7 and 8 , these figures schematically represent the logic diagram where the sensor 20 is an IR sensing device, for example. In this scenario, the sensor 20 “searches” for the tags 4 , 8 at regular intervals. The IR sensor 20 is effectively and periodically checking the area near the dish 10 , looking for the tags 4 , 8 to appear. The lids 22 , 24 will remain closed until the sensor 20 “scans” and identifies one or the other, or both, of the tags 4 , 8 within a “read” zone 30 . As one or both of the pets 2 , 6 continues to feed, the sensor 20 will “search” for the tags 4 , 8 at an increased frequency to prevent premature closing of the respective lid 22 , 24 . When a tag leaves the vicinity, that lid closes and the dish 10 and its sensor 20 , together with its conventional circuitry (not shown), will return to “normal” searching intervals. In this scenario, the tags 4 , 8 could be active or passive devices, but would preferably be active devices. That is, the tags 4 , 8 would emit IR radiation that is “read” by the sensor 20 using any known IR technology modulation method.
It is also to be understood that, in the case of the use of IR technology, it may be necessary or desirable to use a separate sensor 20 for each pet tag 4 , 8 and its corresponding food compartment 12 , 14 . The circuitry could then be presented in a series or parallel configuration as desired or required. Further, each circuit could be a stand-alone as well.
In view of the foregoing, it will be apparent that there has been provided a new, useful and non-obvious lidded pet food dish that allows selective access to the dish contents by one or more pets; that provides such a lidded pet food dish whereby multiple pets may use the dish in such a way that only the food dish compartment assigned to a particular pet is accessed by that pet, and only that pet, all others being unable to access that compartment; that provides such a lidded pet food dish that uses currently available wireless technology to accomplish this selective accessing of the lidded pet food dish; that provides such a lidded pet food dish that also includes an “override” mechanism and circuitry such that the pet owner will have unfettered access to the contents of the lidded pet food dish when such is desired or required and wherein the override mechanism and circuitry could be incorporated into a device that would be operated directly on the lidded pet food dish or remotely by the pet owner. In this fashion, the owner could check whether a given pet has eaten and, if so, how much that pet has eaten. The owner can also re-fill the dish as may be desired or required using this override mechanism or circuitry. | A lidded pet food dish uses wireless technology to independently and selectively open one of a plurality of lidded food compartments for access by a pet. The dish discriminates between pets by means of a tag worn by each pet to allow or prevent access to a given food compartment. Electronic circuitry for this functionality is operable by any wireless technology and provides for manual system override by the pet owner as well as remote control capability. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims benefit of U.S. Provisional Application Serial Nos. 60/166,510, and 60/166,449, both filed Nov. 19, 1999, the contents of which are incorporated by reference in their entirety. Applicants also note the existence of U.S. patent application Ser. No. 09/321,931, filed May 28, 1999, now U.S. Pat. No. 6,359,249 in turn claiming priority from U.S. Provisional Patent Application Serial No. 60/095,385 filed Aug. 5, 1998, and now expired; U.S. patent application Ser. No. 09/557,896, filed Apr. 21, 2000, now abandoned and claiming priority from U.S. Pat. No. 5,742,022, filed Apr. 19, 1995, and from U.S. Pat. No. 6,066,824, filed Apr. 20, 1998, all commonly owned with this application and incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to electric welding assemblies having multiple weld gun arms for producing multiple simultaneous welds in a single pass. In particular, the present invention relates to assemblies where one arm of a multiple arm weld gun is retractable.
BACKGROUND OF THE INVENTION
Resistance welding utilizes the flow of electricity to permanently join two or more overlapping metallic work pieces to one another. Typically, the metallic work pieces are placed between two opposing electrode tips, which are on the jaws of a weld gun arm. The electrodes are then forced together until their tips contact the outer surfaces of the work pieces at a pressure sufficient to sandwich the work pieces and ensure an adequate electrical contact between the electrode tips and the work pieces. An electrical current is induced to flow from one electrode tip to the other electrode tip by way of the sandwiched work pieces. The work pieces act as conductors in the resulting electrical circuit, and resistance to the flow of electrical current at the interfaces between the metals generates heat. The affected metal of each work pieces selectively becomes molten, and interacts with molten metal of an adjacent work pieces to form a weld nugget that permanently bonds the work pieces together at the point of electrode tip contact.
A number of factors relate to the creation of a weld nugget, including the force and area of contact between the electrode tips and the work pieces, the level of current flow, the length of time the current flow lasts, degree of work pieces imperfection, and even the condition of the electrode tips themselves.
Weld guns used in manufacturing processes typically are required to make multiple consecutive welds on a given work pieces. In such a situation, devices exist for moving the work pieces between individual welds, moving the weld gun between individual welds, or both. For example, the electric welding gun may cycle through various locations, i.e. between an operational position with a work pieces and a resting position. The work pieces may be placed on a moving platform that manipulates the work pieces for a welding operation with a movable weld gun. After the work pieces is manipulated, the weld gun may move toward the work pieces to perform a weld cycle, after which the weld gun moves away from the work pieces to allow movement of the piece and manipulation of the next piece to be welded. In some applications, the weld gun must make a significant number of consecutive welds before further manipulation of the work pieces. In such applications, the amount of time required to move the weld gun to make the consecutive welds becomes a rate limiting step.
It is known to mount multiple weld gun arms to a single weld gun to decrease the amount of time required to make a significant number of consecutive welds. For example, simply adding one additional gun arm to a weld gun such that both arms are capable of simultaneous welding operation cuts the time required for performing a series of multiple consecutive welds nearly in half. Multiple arm weld guns, usually in the form of dual arm weld guns, have the advantage of being able to make several welds at one time, which decreases the cycle period of the weld gun assembly. In current multiple arm weld gun systems, artificial intelligence controls the weld gun arm position process during a weld cycle by first operationally orienting the multiple arm weld gun to the work pieces. The process includes creating welds by closing electrode tips of the weld guns about the work pieces, creating welds, reorienting the multiple arm weld gun with respect to the work pieces, and creating additional welds. Multiple arm weld guns are thus able to complete more than one weld at once, depending upon the number of weld arms on the weld gun, thereby shortening the period of time it takes to complete all the welds on a work pieces. As a result, the weld cycle period is shortened, i.e. the period of time from the beginning of one work pieces to the beginning of the next work pieces is decreased.
However, conventional multiple arm weld guns have a significant disadvantage due to their increased size over single arm assemblies, which are required to accommodate multiple arms on a weld gun. Specifically, currently known multiple arm weld guns are not suitable for welding many types of work pieces, because the multiple arm weld gun cannot make welds in spatially restricted locations of mated work pieces if the weld gun has difficulty gaining access to the work pieces where the weld is required.
One solution to the problem of the too-large-multiple arm-weld-gun is to use a second, single arm weld gun that can be accommodated in the spatially restricted space. However, this provides unsatisfactory results because of the added inefficiencies of using two weld guns. The purpose of multiple arm weld guns is to reduce the number of required weld guns, not to increase the number. The added, single arm weld gun would be similarly expensive to design, maintain, and operate as the multiple arm weld gun. In addition, the introduction of a second separate weld gun would unduly increase the cycle period because one weld gun would have to be moved out of the way in order of the other weld gun to move into its welding position.
Accordingly, there is a need to provide an improved electric welding system that minimizes or eliminates one or more the problems set forth above.
SUMMARY OF THE INVENTION
A multiple arm weld gun is provided wherein one or more weld gun arms on the multiple arm weld gun are able to retract away from a work pieces while at least one other arm remains operational, thus allowing a multiple arm weld gun to act as a single arm weld gun. As a result, once one or more weld gun arms are retracted, the remaining weld gun arms may be repositioned with respect to the work pieces in a space not previously accessible to the multiple arm weld gun before retraction of an arm. While all weld gun arms may be retractable, preferably only at least one arm is not retractable. The ability to retract all but one of the weld gun arms effectively overcomes the problem of multiple arm weld guns that are too large, without requiring the use of a separate single arm weld gun.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is perspective view of a dual arm weld gun.
FIG. 2 is a side view of a dual arm weld gun.
FIG. 3 is a side view of a second embodiment.
FIG. 4 is a side view of a third embodiment.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In all weld guns, at least one actuator is required per weld gun arm to provide the force necessary to make a weld stroke, which includes opening and closing the jaws of the weld gun arm at the spot of the weld on an engaged work pieces and providing the necessary compressive force to achieve a tight electrical contact between the electrode and the work pieces. For example, in a dual arm weld gun, at least two actuators are required, i.e. one for each weld gun arm. Any known actuators may be used, as well as any known toggle link and actuator combination. U.S. application Ser. No. 09/715,343, filed Nov., 17, 2000[Attorney docket number 65012-0063] depicts various actuators in combination with links and pivotable members, and is incorporated herein by reference in its entirety. In the present invention, the actuator also provides the force necessary to rotate a weld gun arm to a retracted position from an extended position.
Referring now to FIGS. 1 and 2, a dual arm weld gun 10 includes a first C-shaped weld gun arm 11 having a generally C-shaped fixed jaw 12 in combination with a second C-shaped weld gun arm 13 to form a multiple weld gun arm. It should be understood that more than two weld gun arms may be interconnected to form a multiple arm weld gun. Additionally, while the below description is directed primarily to only first C-shaped weld gun arm 11 , it should be understood that the description may apply to one or more arms of a multiple arm weld gun.
Fixed jaw 12 of first weld gun 11 includes a first end 14 , a second end 16 and an electrode tip 18 at a distal end of the first end 14 . Weld gun arm 11 also includes a moveable jaw 20 having a first end 22 , a second end 24 , an electrode tip 26 at a distal end of the first end 22 , and a guide 28 that is preferably linear. Linear guide structure 28 includes a guide rail 29 received in a bracket 31 , which ensures that during normal welding operation, movable jaw 20 moves only along a fixed, preset path.
Weld gun arm 11 further comprises an actuator 30 having an actuator shaft 32 connected to movable jaw 20 . In FIGS. 1 and 2, shaft 32 is fixedly connected to movable jaw 20 through connector 40 . The size and shape of connector 40 may vary as necessary to prevent unwanted interaction between shaft 32 of the actuator 30 and guide 28 . In a preferred construction, actuator 30 is a linear actuator capable of moving only in a fore and aft direction during normal operation. As such, the interconnection of shaft 32 with connector 40 and of connector 40 to movable jaw 20 limits movement of the movable jaw 20 to only a fixed, preset path that is preferably linear during normal operation.
Structurally, in the embodiment shown in FIGS. 1 and 2, fixed jaw 11 is connected to at least one mounting bracket 34 at the second end 16 of the fixed jaw 11 . Preferably, bracket 31 of the linear guide structure 28 is also connected to mounting bracket 34 at a locking joint that allows rotational movement, such as by a clutch plate 36 . Preferably, clutch plate 36 is mounted on bracket 34 having a central axis of rotation 38 defined through the center of the clutch plate 36 . As best seen in FIG. 2, both fixed and movable jaws 11 , 20 are operably connected to the clutch plate 36 for rotational movement about axis 38 . In particular, second ends 16 of fixed jaw 11 enclose portions of linear guide 28 attached to the movable jaw 20 . The connector 40 also serves to operably interconnect actuator 30 with fixed and movable jaws 11 , 20 . As a result, the entire weld gun arm, including fixed and movable jaws 11 , 20 as well as the actuator 30 and actuator shaft 32 , is functionally connected to clutch plate 36 on bracket 34 .
Under normal operation, clutch plate 34 is locked against rotation about axis 38 . As a result, a work pieces may be positioned between electrodes 18 , 26 . Movable electrode 26 on movable jaw 20 is cycled on a fixed, preset path, preferably linear, by operation of actuator 30 . In particular, actuator 30 cycles actuator shaft 32 fore and aft as necessary to accomplish welding. Since shaft 32 is operably connected to movable jaw 20 , movable jaw 20 likewise cycles fore and aft in response to movement of shaft 32 . Thus, as actuator 30 extends the actuator shaft 32 in a first direction, the distance between the electrode tips 18 , 26 decreases until the electrode tips are in an engaged position in contact with the work pieces (not shown). Electricity is passed between the electrode tips 18 , 26 and through the work pieces to create the weld nugget. This is the weld stroke. After the weld has been completed, the actuator 30 withdraws the actuator shaft 32 in a second direction to release the work pieces and return the weld gun 10 to a disengaged position, depicted in FIGS. 1 and 2. The normal weld stroke may be repeated as necessary until such time that a weld is needed in a spatially restricted portion of the work pieces. Then a retraction stroke takes place, as described below, to retract weld gun 10 to allow the remaining unencumbered weld gun arm to continue normal operation creating additional welds on the work pieces.
As necessary, the actuator 30 may withdraw the actuator shaft 32 in the disengaged direction beyond the disengaged position to provide the force necessary to rotate the weld gun arm 11 including jaws 12 and 20 to a retracted position. As noted above, all structural components of the weld gun arm 10 are operably connected to the clutch plate 36 , which is normally locked against rotation.
During a retraction stroke, the clutch plate 36 disengages, thereby allowing rotation of weld gun 10 about axis 38 , while actuator 30 provides the force necessary to rotate the gun. Clutch plate 36 may be electrically engaged and spring disengaged, or vice versa, or may use any suitable engagement and disengagement mechanism. When retraction is desired, actuator 30 withdraws actuator shaft 32 beyond the disengaged position. As actuator shaft 32 is withdrawn further toward a retracted position, not only does the actuator create a linear force along its path of movement, it also causes a downward force to be exerted on the jaws 12 , 20 . Because the actuator 30 and the plate 36 are offset from one another and the main force of the actuator does not pass through the axis 38 , the downward force exerted on jaws 12 , 20 causes rotation the plate 36 , thereby causing the weld gun 10 to rotate in a downwardly direction, as shown in phantom in FIG. 2 . As it rotates downwardly, the weld gun arm 11 is moved to a retracted position such that the arm 11 will not interfere with the remaining arm 13 as it performs additional welds in a confined space on mating work pieces. In this way, a dual arm weld gun may quickly, easily and reversibly be transformed into a single weld gun arm, or into a weld gun utilizing less than all of its weld gun arms if there are more than two arms.
In an alternative embodiment, bracket 34 further includes a cam track 50 formed at a point on bracket 34 adjacent actuator 30 or actuator shaft 32 . A cam follower 52 is affixed along the longitudinal length of the actuator shaft 32 and is slidably engaged in the cam track 50 . Cam track 50 includes a predetermined cam surface 54 along which cam follower 52 slides. In general, the cam track 50 includes two portions, but any conventional design may be employed. A first portion 56 of the cam track 50 is preferably linear and parallel to the normal position of both linear guide 28 and actuator shaft 32 . During normal operation of the actuator, cam follower 52 resides only in the first portion 56 of cam track 50 , which defines motion between engaged and disengaged positions. A second portion 58 of the cam track 50 is preferably arcuately shaped to define a path of travel for gun 10 during a retraction operation, as described more fully below. As actuator shaft is withdrawn further toward and through the retracted position, cam follower 52 moves within cam track 50 from the generally linear first portion 56 to the arcuate second portion 58 . Arcuate second portion 58 of cam track 50 is designed and shaped to cause gun 10 to rotate about axis 38 . In particular, as actuator shaft 32 is withdrawn so that cam follower 52 engages second portion 58 of the cam track 50 , all portions of weld gun 10 that are operationally connected to clutch plate 36 rotate with clutch plate 36 about axis 38 . In FIG. 1, the second portion 58 of cam track 50 angles upwardly with respect to actuator shaft 32 , thereby causing the assembly to rotate in a downwardly direction, as shown in phantom in FIG. 2 .
The weld gun 10 of FIGS. 1 and 2 utilizes a linear actuator to translate linear motion into rotation of the weld gun 10 about a rotational joint. However, other conventional types of pivoting or rotational joints are also suitable, such as joints that facilitate a linear sliding motion or a corkscrew motion.
Preferably, a single stage actuator or motor is used to provide the force and movement required for both the weld stroke and the retraction stroke by working in combination with the locking joint. Alternately, a two stage actuator or motor may be used to effect both the weld stroke and the retraction stroke. A strategically placed stop or appropriately designed cam track may also be utilized to facilitate a retraction stroke using a two stage actuator.
A retractable weld gun utilizing a two stage actuator is shown in FIG. 3. A caliper-type weld gun arm 110 is shown, representing one arm of a multiple arm weld gun. Weld gun arm 110 includes a fixed jaw 112 having a first end 114 and a second end 116 . Fixed jaw first end 114 terminates in electrode tip 118 . The weld gun arm 110 further includes a moveable jaw 120 having a first end 122 inwardly directed towards fixed jaw first end 114 , a second end 124 . Movable jaw first end 122 likewise terminates in an electrode tip 126 in a position opposed to tip 118 . Fixed and movable jaws are rotationally interconnected at a connection point 134 such that opposed electrodes 118 , 126 may rotationally move toward and away from each other during a weld stroke. Fixed jaw 112 is further connected to a mounting bracket 138 at a selectively lockable second connection point 136 . Second connection point 136 usually acts as a rigid connection point that selectively prevents rotation of fixed jaw 112 about the second connection point. However, if further retraction of gun 110 is required, second connection point 136 may be unlocked to act as a rotational connection similar to first connection point 134 , thereby allowing fixed jaw 112 to rotate about second connection point 136 , as described further below.
Weld gun arm 110 further includes an actuator 130 , preferably mounted on bracket 138 , having an actuator shaft 132 . Actuator shaft 132 is rotationally connected at a third connection point 141 to the second end 124 of the moveable jaw 120 . A stop 140 is connected to the second end 116 of the fixed jaw 112 .
Under normal operation, actuator 130 extends shaft 132 , forcing movable jaw 120 to rotate about first connection point 134 , thereby decreasing the distance between tips 118 , 126 until the electrode tips are in contact with the work pieces (not shown) in an engaged position. Electricity is passed between the electrode tips 118 , 126 and through the work pieces to create the weld nugget. This is the weld stroke. After the weld has been completed, the actuator 130 withdraws the actuator shaft 132 to a disengaged position to release the mated work pieces so that arm 110 or the work pieces may be repositioned with respect to the other. This weld stroke may be repeated until such time that a weld is needed in a spatially restricted portion of the work pieces. Then a retraction stroke takes place, as described below, after which, the remaining weld gun arm or arms may create additional welds on the work pieces.
To retract a weld gun arm, second connection point 136 selectively disengages from a rigid connection to a rotatable connection. Selective engagement and disengagement of second connection point 136 may be accomplished by any conventional means. Under normal operation, the maximum withdrawal of actuator shaft 132 , and by association, the maximum distance between electrode tips 118 , 126 , is limited by stop 140 . However, by selectively disengaging second connection point 136 , continued withdrawal of the actuator shaft 132 by the actuator 130 forces the combined fixed jaw 112 and moveable jaw 120 to rotate as a single unit about both first connection point 134 and second connection point 136 . The linear motion of the actuator 130 is thereby translated into rotational motion of the jaws 112 , 120 , causing both jaws to rotate upwardly with respect to bracket 138 in FIG. 3 . The rotation about the connections 134 , 136 effectively swings the weld gun arm away from the work pieces so that additional welds may be made on a spatially restricted portion of the work pieces.
The cam track/cam follower mechanism used in FIGS. 1 and 3 may also be adapted to bayonet style weld guns. In such a configuration, a cam follower is fixedly attached to a moveable jaw of bayonet style weld gun arm, while a cam track is located on a fixed jaw of the weld gun arm. In a first portion, the cam track is straight and guides the movable jaw along a fixed, preset preferably linear path between a disengaged and an engaged position. A second portion of the cam track is preferably angled away from the first portion, causing the movable jaw to retract in response to action of the cam follower within the cam track.
A bayonet style weld gun 210 is shown in FIG. 4 . As above, gun arm 210 is only one arm of a multiple arm weld gun. The weld gun arm 210 comprises a generally C-shaped fixed jaw 212 having a first end 214 terminating in an electrode tip 218 and a second end 216 . Fixed jaw 212 is pivotally mounted at connection point 236 to a mounting bracket 238 . The weld gun arm 210 further includes a moveable jaw 220 having a first end 222 and a second end 224 . Movable jaw first end 222 terminates in an electrode tip 226 such that tips 218 , 226 are arranged in an opposed manner. Movable jaw 220 further includes a cam follower 228 mounted on a bracket 229 as necessary such that the cam follower slidably engages a cam track 234 located on fixed jaw 212 . An actuator 230 , moving along a fixed, preset path, and preferably a linear actuator having an actuator shaft 232 , is connected to the movable jaw second end 224 to impart fore and aft motion to the movable jaw 220 .
In operation, as actuator 230 extends the actuator shaft 232 , movable jaw 220 moves generally linearly towards fixed jaw first end 214 . Movable jaw 220 is guided in its motion through the action of cam follower 228 sliding within cam track 234 . As shaft 232 moves from a disengaged to an engaged position, the distance between the electrode tips 218 , 126 decreases until the electrode tips are in contact with the work pieces (not shown). Electricity is passed between the electrode tips 218 , 226 and through the work pieces to create the weld nugget. This is the weld stroke. After the weld has been completed, the actuator 230 withdraws the actuator shaft 232 to release the work pieces and return the weld gun arm 210 to a disengaged position. This weld stroke may be repeated until such time that a weld is needed in a spatially restricted portion of the work pieces. Then a retraction stroke takes place, as described below, after which, any remaining weld gun arms may create additional welds on the mated work pieces.
As noted above, cam track 234 has two portions. A first portion 240 is generally linear and parallel to the motion of the actuator 230 , thereby describing a fixed, preset path corresponding to normal operation. The cam follower 228 slides in this portion of the cam track 234 without significantly moving the fixed jaw 212 because the fixed length cam follower 228 is moving parallel to the motion of the actuator 230 . A second portion 242 of the cam track 234 angles toward the moveable jaw 220 to cause the fixed jaw 212 to pivot about connection 232 as the fixed jaw 212 is drawn toward the movable jaw 222 . Thus, the motion of the fixed jaw 212 during the retraction stroke is defined by the shape of the cam track 234 .
Although certain preferred embodiment of the present invention have been described, the invention is not limited to the illustration described and shown herein, which are deemed to be merely illustrative of the best modes of carrying out the invention. A person of ordinary skill in the art will realize that certain modifications and variation will come within the teachings of this invention and that such modifications and variations will come within its spirit and the scope as defined by the claims. | A multiple arm weld includes at least two weld gun arms where one arm retracts away from mating work pieces while at least one other arm remains operational, thus allowing a multiple arm weld gun to act as a single arm weld gun. Once one or more weld gun arms is retracted, the remaining weld gun arms may be repositioned with respect to the work pieces in a space not previously accessible to the multiple arm weld gun before retraction of an arm. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. utility application Ser. No. 11/594,400, filed Nov. 8, 2006. Priority is claimed to application Ser. No. 11/594,400, which claims priority to U.S. provisional application No. 60/737,789, filed Nov. 17, 2005. Priority is also claimed to U.S. utility application Ser. No. 11/933,815, filed Nov. 1, 2007, which claims priority to U.S. utility application Ser. No. 11/594,400, which claims priority to U.S. provisional application No. 60/737,789. The Ser. Nos. 11/933,815, 11/594,400 and 60/737,789 applications are incorporated by reference herein, in their entirety, for all purposes.
BACKGROUND
[0002] This application relates generally to oral implant surgery. More particularly the present invention relates to a surgical guide to be used during dental implant surgery which is used to effect correct placement of a dental implant.
[0003] In the healthy non-diseased mouth with natural teeth present, there exists a biologic relationship between the root of a tooth, the crown of a tooth, the bone surrounding the root and the gingiva (soft tissue) surrounding the bone, root and crown of a tooth. In nature, the shape and contour that the gingiva or soft tissue assumes and follows is dictated by the underlying presence and shape of bone. The bone contours around a natural tooth are actually scalloped, with the bone more apical on the facial and lingual aspects of the tooth and more coronal in the inter-proximal area (between the teeth). In a healthy mouth, this scalloping effect is dictated by the cemento-enamel junction (CEJ) of the tooth which itself is also scalloped. It is this scalloping of the bony architecture which lends itself to the formation and maintenance of proper gingival contours including the inter-dental papilla (the small triangular flesh portion adjacent the gum line and located between the teeth).
[0004] However, despite best efforts of a person, or because of lack of proper dental care, it may become necessary to replace teeth completely. In these cases, dental implant procedures have proven to be an effective method of restoring both form and function in patients having missing teeth. Implants provide a structure upon which a prosthetic tooth or teeth can be attached and secured in an otherwise edentulous (non-tooth) area. In contrast to using dentures or other tooth born fixed or removable dental bridge systems, implants have the advantage of maintaining bone and not being subject to decay.
[0005] Bone support is necessary for proper placement, securement and maintenance of a dental implant. Proper bone support around an implant is also necessary for the development and maintenance of healthy gingival contours, including papilla. Bone growth around an implant follows the shape of the bone-integrating part of the implant. A primary concern in implant dentistry is the precise placement of an implant in its proper location, with appropriate and accurate angulation and rotational position at the time of implant placement surgery. Even the slightest error in implant placement can result in significant complications and or compromises in the stability of the implant, the maintenance of bone, the contours of the gingival tissues, placement of the final prosthesis, stability of the final prosthesis and the overall appearance of the patient's mouth.
[0006] Accordingly, it is desirable to provide a prefabricated dental implant surgical guide which ensures the proper placement of a dental implant or implants and its corresponding prosthesis (crown or crowns). One exemplary embodiment of the present invention allows it to be converted from a surgical guide to a dental provisional crown which can then be used to help maintain the hard (bone) and soft (gingival) tissue architecture of the mouth during the healing phase of treatment, with the end result being a final prosthesis that is stable, functional, natural looking and aesthetically pleasing in the patient's mouth.
[0007] For such applications, the prefabricated dental implant surgical guide of the present invention may be configured as a surgical guide with a tooth-shaped configuration contour (also referred to as a “tooth contour”) with a post affixed to its apical end, or with a post as an integral part of the entire guide. This embodiment of a dental implant surgical guide is placed into an initial osteotomy site (a surgical procedure in which bone is cut or prepared for the placement of a dental implant) at the time of dental implant placement surgery, but prior to final implant body placement, to ensure and or to correct proper location, angulation, and rotational position of an implant body prior to its placement.
[0008] The present invention in various embodiments is a prefabricated dental implant placement surgical guide which, in one exemplary embodiment, has a post affixed to the apical end of an anatomically correct tooth form. This tooth form can be made to represent any tooth in the mouth in order to have accurate implant placement regarding the tooth to be replaced.
[0009] At the time of initial osteotomy site preparation, a small hole is prepared into the jaw bone using conventional dental implant surgical drills. The apical post of the surgical implant guide is inserted into the osteotomy site allowing verification of proper implant placement in location, angulation, and rotational position prior to implant body placement. This is accomplished by viewing the surgical guide in place, then comparing the tooth-contoured part of the surgical guide with some facial and/or intra-oral guideline such as the adjacent teeth, gingiva, shape of the arch and lips etc. This allows for proper implant location and ultimately placement to be verified or corrected prior to implant body placement lending to a more stable, functional and esthetic prosthetic outcome. The apical post of the surgical guide can repeatedly be inserted into the osteotomy site, as the site is further developed and deepened to continuously verify proper position and location of the implant body prior to its placement. This process of trying in the surgical guide with further osteotomy site preparation is repeated until the appropriate final depth of the osteotomy site is achieved. Thus the process of the present invention provides for a verified correct position, location and angulation of the osteotomy site, all prior to final implant body placement. If improper alignment is detected during this verification process, the osteotomy site location, angulation and position can be corrected with minimal damage to the bone.
[0010] In another embodiment of the present invention, the prefabricated dental implant surgical guide can be converted into a provisional crown, a plurality of crowns, or a bridge. This is accomplished by removing the finger grip and apical post, or guide post, hollowing out the tooth contour aspect of the guide, and relining the tooth contour aspect of the surgical guide, then reversibly fastening via screw or cement, the tooth contour aspect of the surgical guide to the abutment of an implant body.
[0011] In yet another embodiment, the surgical guide comprises a set of anatomically correct tooth forms each having an apical post and finger grip. The apical posts are graduated in length thus constituting a set of surgical guides that are sequentially used as an osteotomy site is created and deepened. In this way the surgical guide set can sequentially provide guidance that the osteotomy site is being correctly prepared.
[0012] In yet another exemplary embodiment, the prefabricated dental implant surgical guide comprises an anatomically correct tooth form having a bore through the tooth form into which an adjustable and removable post is placed or threaded. The apical end of the post protrudes through the tooth form and can be lengthened by pushing or screwing the post through the bore. In this way the apical end is lengthened and can be placed into the gradually deepening osteotomy site to insure that the site is correctly prepared. The post can also be removed and an osteotomy drill passed thru the bore to allow for further preparation of the osteotomy site with the guide in place. In another embodiment of the present invention, a bottom face of the apical end of the movable post comprises a marking agent. In this embodiment, the surgical guide is placed in a desired position on the jaw bone at a proposed osteotomy site. Once the correct position of the surgical guide is established, the movable post is pressed downward to engage the bottom face of the apical end with the jaw bone thereby marking the location of the osteotomy site.
[0013] In still another exemplary embodiment, the prefabricated dental implant surgical guide comprises a number of anatomically correct tooth forms as a unitary surgical guide. In this case, for example and without limitation, a number of tooth forms can be connected and tried into a series of side by side osteotomy sites as a unit. This allows multiple dental implants to be placed side by side with verification of proper location, angulation, and rotational position.
[0014] Thus various embodiments improve the dental implant placement process and allow for proper placement of a dental implant subsequent to osteotomy site preparation. Embodiments act as a prefabricated surgical guide and improve the placement of a dental implant. Embodiments further allow sequential placement of individual prefabricated implant surgical guides to develop sequential osteotomy sites for subsequent multiple side by side implant placement during dental implant placement surgery. Additional embodiments use unitary multi-tooth prefabricated implant surgical guides during dental implant placement surgery where more than one tooth is to be replaced with a dental implant. Other embodiments use a prefabricated dental implant surgical guide having adjustable apical posts for use with deepening osteotomy sites.
[0015] These and other embodiments will become apparent to those skilled in the art upon review of the detailed description that follows.
DESCRIPTION OF THE FIGURES
[0016] FIGS. 1 a , 1 b , and 1 c illustrate a prefabricated dental implant surgical guide configured as a tooth with a static post.
[0017] FIGS. 2 a and 2 b illustrate another embodiment of a prefabricated dental implant surgical guide converted to and also used as an interim crown with posts that are removable.
[0018] FIGS. 3 a , 3 b , 3 c and 3 d illustrate a prefabricated dental implant surgical guide as a series of tooth shapes having graduated post lengths.
[0019] FIGS. 4 a , 4 b and 4 c and 4 d illustrate another embodiment as a prefabricated dental implant surgical guide having a central bore with an adjustable, removable post.
[0020] FIG. 5 illustrates an embodiment, as illustrated in FIGS. 1 a - c , 2 a - b , 3 a - d and 4 a - d being used in a multiple side by side format.
[0021] FIG. 6 illustrates another embodiment as a one piece multiple unit surgical guide.
[0022] FIGS. 7 a - c illustrate an embodiment for the purpose of marking and identifying an osteotomy site.
[0023] FIGS. 8 a - c illustrate another embodiment for the purpose of marking and identifying an osteotomy site.
[0024] FIGS. 9 a - c illustrate another embodiment for the purpose of marking and identifying an osteotomy site.
[0025] FIGS. 10 a - c illustrate another embodiment for the purpose of marking and identifying an osteotomy site.
[0026] FIGS. 11 a - c illustrate another embodiment for the purpose of marking and identifying an osteotomy site.
DETAILED DESCRIPTION
[0027] As noted above, the present invention comprises a method and apparatus for insuring correct placement of dental implants during the surgical placement process. Referring now to FIGS. 1 a , 1 b , and 1 c , the prefabricated dental implant surgical guide configured as a surgical guide with a tooth-shaped contour with a post affixed to its apical end is illustrated. The guide can be made of metal, plastic, acrylic, porcelain or some other material known to those of skill in the dental arts. Such materials will be collectively referred to herein as “dental material.” This exemplary embodiment is placed into an initial osteotomy site at the time of implant placement surgery, prior to implant body placement to ensure and or to correct the proper location, angulation, and rotational position of the implant body.
[0028] FIGS. 1 a , 1 b , and 1 c illustrate the dental implant aid in an exemplary alternative embodiment. As illustrated in FIG. 1 a , the dental implant aid, generally referred to as 40 in this figure, is configured as a one piece surgical guide with a tooth-shaped contour 42 . The tooth shaped contour 42 is further defined by its anatomical components, i.e. the incisal edge (for an anterior tooth) or occlusal table (for a posterior tooth) 30 , facial contour 31 , lingual contour 32 , interproximal aspect 33 and apical aspect 34 . Affixed to the apical end of tooth-shaped contour 42 is collar 45 which has apical post 44 extending above it. Affixed to the coronal end of tooth-shaped contour 42 is a protruding post which acts as finger grip 43 . Thus the surgical guide 40 can be held in the mouth and the tooth-shaped component contour 42 of guide 40 can be seen clearly by the surgeon during the course of surgery with out the surgeon's fingers obscuring the view.
[0029] This tooth-shaped contour 42 can be represented by any tooth shape found in the mouth (central incisors, lateral incisors, cuspids, premolars, and molars of both the upper and lower jaws) and can therefore be used as a surgical guide to verify implant body placement with respect to any tooth and its corresponding position in the mouth prior to implant placement. For example, FIG. 1 b represents a jaw bone 48 to which an osteotomy site 46 (a surgical procedure in which bone is cut or prepared for the placement of an implant) has been prepared in jaw bone 48 . As illustrated in FIGS. 1 b and 1 c , by holding finger grip 43 , the apical post 44 of implant surgical guide 40 is placed into the osteotomy site 46 so that collar 45 of implant surgical 40 rests against jaw bone 48 at the opening of osteotomy site 46 . This is done at the time of implant placement surgery, but prior to implant body placement.
[0030] By using existing intra-oral guidelines as a reference (i.e. adjacent teeth 50 , lips, shape of the arch as but several examples), the tooth contour 42 and its corresponding anatomic components of implant surgical guide 40 with apical post 44 in osteotomy site 46 , can be used to verify and/or correct the proper location, angulation, and rotational position of any implant body and it's corresponding system prior to it's insertion. This is accomplished by comparing the location, angulation, and position of the tooth shape-contour 42 and its corresponding anatomic components of the implant surgical guide 40 with some facial and/or intra-oral guideline or reference such as the adjacent teeth, gingiva, shape of the arch and lips, face etc., while apical post 44 of implant surgical guide 40 is engaged in osteotomy site 46 .
[0031] Verification of osteotomy site position, angulation, location, subsequent proper implant location and placement and proper prosthesis location, requires the tooth contour aspect 42 of implant surgical guide 40 be in proper alignment with the facial and or intra-oral guide lines or references previously noted. This alignment is verified by comparing the position of the anatomic components of tooth contour 42 , for example, the incisal edge (for an anterior tooth) or occlusal table (for a posterior tooth) 30 , facial contour 31 , lingual contour 32 , interproximal aspect 33 and apical aspect 34 of tooth contour 42 of the surgical guide 40 while engaged in the mouth with facial and or intra-oral references previously noted.
[0032] If the alignment of the anatomic components of tooth contour 42 of surgical guide 40 is in harmony with and is symmetrical to the facial and or intra-oral references previously noted, osteotomy site location, position and angulation are verified, and osteotomy site and subsequent implant placement can be completed.
[0033] If there is disharmony and/or an asymmetrical position of the anatomic components of tooth contour 42 of the implant surgical guide 40 is noted with respect to the facial and or intra-oral references previously noted, a correction as to position and location can be made and verified prior to final implant placement.
[0034] It will be apparent to those skilled in the art that, not only can different tooth shapes be represented, but also different sizes of tooth contour 42 of the prefabricated dental implant surgical guide 40 can be used to conform to the size teeth and arch form of the dental implant patient.
[0035] Referring now to FIGS. 2 a and 2 b , another alternate embodiment generally referred to as 51 is illustrated. In this embodiment, the prefabricated implant surgical guide is made of a dental material so that once implant placement has been verified and the implant body has been placed, either at the time of surgery or at a later date subsequent to healing, the surgical guide can be converted to a provisional crown as illustrated in FIGS. 2 a and 2 b.
[0036] Referring again to FIG. 2 a , apical post 24 of implant guide 51 having a collar 25 is placed into osteotomy site 46 of jaw bone 48 to verify proper implant location and angulation prior to implant body placement as previously described in FIGS. 1 a - c.
[0037] Referring now to FIG. 2 b , implant body 52 is shown having been placed into jaw bone 48 . At the time of surgery or subsequent to surgical healing, the finger grip 23 and apical post 24 of implant surgical guide 51 are removed via a cutting procedure known in the art. The tooth contour 22 of implant surgical guide 51 is then hollowed out so that a concavity 26 is formed on the internal aspect 27 of tooth contour 22 of implant guide 51 . At the time of surgery or subsequent to surgical healing utilizing either a 2-stage, 2-piece implant system, a one-stage, 2-piece implant system or a one piece, one-stage implant system, the concavity 26 of internal aspect 27 of tooth contour 22 of implant guide 51 is relined with a dental provisional material, known to those in the art (for example and without limitation, acrylic) to the abutment aspect 54 of implant body 52 to create a custom fitting, retentive provisional crown which can then be either cemented into place with some provisional dental cement (for example and without limitation zinc oxide-eugenol) or screw retained.
[0038] Referring now to FIGS. 3 a , 3 b , 3 c and 3 d , another embodiment of the prefabricated implant surgical guide, herein referred to as 53 having separate graduated apical post lengths is illustrated. In this embodiment, implant guide 53 exists in a multiple set format with apical posts 13 , 15 , and 17 , connected to tooth contours 12 , 14 , and 16 respectively via collars 7 , 9 , and 11 respectively. Tooth contours 12 , 14 and 16 are further defined by their anatomical components, that is, the incisal edge (for an anterior tooth) or occlusal table (for a posterior tooth) 1 a , 1 b and 1 c respectively, facial contours 2 a , 2 b and 2 c respectively, lingual contours 3 a , 3 b , and 3 c respectively, interproximal aspects 4 a , 4 b and 4 c respectively and apical aspects 5 a , 5 b and 5 c respectively.
[0039] The tooth-shaped contours 12 , 14 and 16 can be represented in the form of any tooth shape found in the mouth (central incisors, lateral incisors, cuspids, premolars, and molars of both the upper and lower jaws) and can therefore be used as a surgical guide to verify implant body placement with respect to any tooth and its corresponding position in the mouth prior to implant placement.
[0040] Apical posts 13 , 15 , and 17 increase in length to be used as described in FIGS. 3 a , 3 b , 3 c and 3 d . Finger grips 6 , 8 , and 10 , respectively allow for manipulation of the surgical guide during the surgical implant placement procedure.
[0041] Referring now to FIG. 3 b , the use of the embodiment of FIG. 3 a is illustrated. An initial osteotomy site 46 of minimum depth is prepared into jaw bone 48 . By placing implant guide 53 with the shortest apical post 13 first into initial osteotomy site 46 , an initial and preliminary evaluation as to proper implant position, location and angulation can be done. At this time, verification and or correction to the initial osteotomy site 46 can be done with minimal trauma to jaw bone 48 . This is accomplished by comparing the location, angulation and position of the tooth shape-contour 12 of the surgical guide 53 with some facial and/or intra-oral guideline or reference such as the adjacent teeth, gingiva, shape of the arch and lips, face etc. with apical post 13 of surgical guide 53 engaged in osteotomy site 46 .
[0042] To verify osteotomy site position, angulation, location, subsequent proper implant location, angulation and placement and ultimately proper prosthesis location, requires the tooth contour aspect 12 of implant surgical guide 53 be in proper alignment with the facial and or intra-oral guide lines or references previously stated. This alignment is verified by comparing the anatomic components of tooth contour 12 , that being the incisal edge or occlusal table 1 a , facial contour 2 a , lingual contour 3 a , interproximal aspect 4 a and apical aspect 5 a of tooth contour 12 of surgical guide 53 while engaged in the mouth with facial and or intra-oral references previously noted.
[0043] If the alignment of the anatomic components of tooth contour aspect 12 of surgical guide 53 is in harmony with and is symmetrical to the facial and or intra-oral references previously noted, osteotomy site location, position and angulation are verified and osteotomy site and subsequent implant placement can be completed.
[0044] If there is disharmony and or an asymmetrical position of the anatomic components of tooth contour aspect 12 of implant surgical guide 53 is noted with respect to the facial and or intra-oral references previously noted, a correction as to position, angulation and location of the osteotomy site can be made and verified prior to final implant placement.
[0045] As illustrated in FIGS. 3 e and 3 d , as the osteotomy site 46 is deepened and developed, the implant guide 53 with the increasing apical post lengths 15 and 17 can be tried into deepening osteotomy site 46 to further verify and or to correct the position and or angulation of osteotomy site 46 prior to final implant body placement. This is accomplished by comparing the position of tooth contours 12 , 14 , and 16 (as the osteotomy site is deepened) of guide 53 with some other facial or intra-oral reference point (i.e. other teeth, gingiva, shape of the arch, lips, face, etc.) with posts 13 , 15 , and 17 of guide 53 sequentially engaged in osteotomy site 46 . This verification process is accomplished as previously described in FIG. 3 b . In this fashion, osteotomy site 46 is gradually prepared (deepened) and continuously verified during the preparation process to ensure accuracy in final location, angulation and position of the implant body and final prosthesis prior to its placement.
[0046] Referring now to FIGS. 4 a , 4 b , 4 c and 4 d , yet another embodiment of the prefabricated dental implant surgical guide generally referred to as 70 is illustrated. Implant surgical guide 70 comprises a tooth contour 62 , collar 65 , finger grip 63 and apical post 64 . The tooth shaped contour 62 is further defined by its anatomical components: the incisal edge (for an anterior tooth) or occlusal table (for a posterior tooth) 61 , facial contour 58 , lingual contour 66 , interproximal aspect 69 and apical aspect 71 .
[0047] The tooth-shaped contour 62 can be represented by any tooth shape found in the mouth (central incisors, lateral incisors, cuspids, premolars, and molars of both the upper and lower jaws) and can therefore be used as a surgical guide to verify implant body placement with respect to any tooth and its corresponding position in the mouth prior to implant placement.
[0048] In this embodiment, the surgical guide 70 has a central bore 60 which extends the entire length of guide 70 (through tooth contour 62 and collar 65 ). This central bore 60 can be either smooth or threaded. An adjustable and removable post generally referred to as 67 , comprises a central portion 68 which is located in central bore 60 , finger grip portion 63 that extends beyond the coronal end of guide 70 and apical post portion 64 that extends beyond the apical end of guide 70 . The central post portion 68 of post 67 remains in the central bore 60 . Central post portion 68 and central bore 60 can be either smooth or threaded. If smooth, central post portion 68 of post 67 may be pushed through the central bore 60 thereby adjusting the length of apical post 64 . If threaded, central post portion 68 of post 67 may be turned through central bore 60 thereby adjusting the length of apical post 64 . In this fashion apical post portion 64 of adjustable removable post 67 can be adjusted and made shorter or longer to fit into a developing osteotomy site 46 to verify or correct final implant body location, position and angulation in jaw bone 48 prior to implant body placement.
[0049] During this process, as in other embodiments described above, proper implant location and position can be verified by comparing the position of tooth contour 62 of guide 70 with some other facial or intra-oral reference point (i.e. other teeth, gingiva, shape of the arch, lips, face, etc.) with apical post 64 of guide 70 engaged in osteotomy site 46 .
[0050] Referring now to FIG. 4 b , an osteotomy site is identified, and an initial osteotomy site 46 of minimum depth is prepared in jaw bone 48 . Surgical guide 70 is placed over osteotomy site 46 . Finger grip portion 63 of adjustable, removable post 67 is pushed or turned so that central post portion 68 of adjustable, removable post 67 moves through central bore 60 increasing the length of apical post portion 64 of adjustable, removable post 67 until it engages the base 49 of osteotomy site 46 . By comparing the position of tooth contour 62 of guide 70 with some other facial or intra-oral reference point (i.e. other teeth 50 , gingiva, shape of the arch, lips, face, etc.), with apical post portion 64 of adjustable, removable post 67 of guide 70 engaged in osteotomy site 46 , an initial verification or correction of position and or angulation of osteotomy site 46 can be done with minimal trauma to jaw bone 48 .
[0051] This is accomplished by comparing the location, angulation and position of the tooth shape-contour 62 of the surgical guide 70 with some facial and/or intra-oral guidelines or references such as the adjacent teeth, gingiva, shape of the arch and lips etc. with apical post 64 of surgical guide 70 engaged in osteotomy site 46 .
[0052] To verify osteotomy site position, angulation, location, subsequent proper implant location, angulation and placement and ultimately proper prosthesis location, requires tooth contour 62 of prefabricated dental implant surgical guide 70 be in proper alignment with the facial and or intra-oral guide lines or references previously stated. This alignment is verified by comparing the anatomic components of tooth contour 62 , that being the incisal edge or occlusal table 61 , facial contour 58 , lingual contour 66 , interproximal aspect 69 and apical aspect 71 of tooth contour 62 of surgical guide 70 while engaged in the mouth, with facial and or intra-oral references previously stated.
[0053] If the alignment of the anatomic components of tooth contour aspect 62 of surgical guide 70 is in harmony with and is symmetrical to the facial and or intra-oral references previously noted, osteotomy site location, position and angulation are verified and osteotomy site and subsequent implant placement can be completed.
[0054] If there is disharmony and or an asymmetrical position of the anatomic components of tooth contour 62 of implant surgical guide 70 is noted with respect to the facial and or intra-oral references previously noted, a correction as to position and location can be made and verified prior to final implant placement.
[0055] Referring now to FIG. 4 c , as osteotomy site 46 is further deepened, guide 70 can repeatedly be placed over osteotomy site 46 , with apical post portion 64 of adjustable, removable post 67 further lengthened into osteotomy site 46 by turning or pushing finger grip portion 63 of adjustable, removable post 67 (See FIG. 4 a ) to move central post portion 68 of adjustable, removable post 67 thru central bore 60 , thus providing a means of continuous verification and or correction of position and or angulation of osteotomy site 46 prior to final implant body placement. Again, this is accomplished by comparing the position of tooth contour 62 of guide 70 with some other facial and or intra-oral reference point (i.e. other teeth 50 , gingiva, shape of the arch, lips, face, etc.) with apical post portion 64 of adjustable, removable post 67 of guide 70 engaged in osteotomy site 46 . This verification process is accomplished as previously described in FIG. 4 b.
[0056] Referring now to FIG. 4 d , adjustable, removable post 67 can be removed from surgical guide 70 . Surgical guide 70 can be held in place in the mouth at osteotomy site 46 with a buccal and or lingual finger grip 45 . By stabilizing guide 70 with buccal and or lingual finger grip 45 , osteotomy bur 47 attached to surgical drill 59 can be placed thru central bore 60 of tooth contour 62 of implant guide 70 and activated allowing further preparation and continuous verification of osteotomy site 46 with surgical guide 70 in place in the mouth.
[0057] This verification process is accomplished as previously described in FIG. 4 b.
[0058] As more fully explained below, in another embodiment, a bottom face of the apical end of the movable post comprises a marking agent. In this embodiment, the prefabricated dental implant surgical guide is placed in a desired position on the jaw bone at a proposed osteotomy site before a hole is drilled. Once the correct position and location of the osteotomy site is established, the movable post is pressed downward to engage the bottom face of the apical end with the jaw bone thereby marking the location of the osteotomy site.
[0059] Referring now to FIG. 5 , embodiments as illustrated in FIGS. 1-4 is described when placing multiple implants in a side by side format. Initial osteotomy sites 46 a - c are identified, made and verified into jaw bone 48 as previously described. As an example, the most mesial osteotomy site 46 a could be prepared and verified or corrected as previously described. Leaving the implant guide 40 a in place, the next implant osteotomy site 46 b can be prepared and verified or corrected as previously described. Now, leaving that implant guide 40 b in place, another osteotomy site 46 c can be prepared with implant guide 40 c put in its place and verified or corrected as previously described. This type of verification process can be used to place implants side by side in a partially edentulous arch and or in a continuous fashion all the way around a completely edentulous arch. Thus all potential multi-unit side by side implant sites can be properly and accurately prepared, verified and or corrected prior to implant body placement.
[0060] FIG. 6 illustrates another embodiment of the present invention generally referred to as 72 . In this embodiment, the surgical guide is formatted as a one piece, multi-unit surgical guide having tooth contours 72 a , 72 b , and 72 c . Affixed to these tooth contours are collars 75 a , 75 b , and 75 c , apical posts 74 a , 74 b , and 74 c respectively, and corresponding finger grips 73 a , 73 b , and 73 c respectively. The purpose of this embodiment is to guide the placement of multiple, side by side implants in a multi tooth edentulous site. Although formatted as such, guide 72 can be fabricated and used as described in FIGS. 1-4 . In this embodiment, a proper guide size 72 and corresponding contour would be chosen that corresponds to the size and location of the edentulous site. Multiple initial osteotomy sites 46 a - c would be made in jaw bone 48 with apical posts 74 a , 74 b , and 74 c tried in osteotomy sites 46 a - c to verify and or correct position, angulation and location of osteotomy sites 46 a - c prior to implant body placement as previously described in FIGS. 1-4 .
[0061] As will be appreciated by those skilled in the art, the multi-unit surgical guide may use movable (adjustable) posts as previously described in place of the fixed posts illustrated in FIG. 6 .
[0062] Thus the embodiments as described may be used to guide the placement of dental implants in a single tooth format, multi tooth format and fully edentulous format.
[0063] Referring now to FIG. 7 a , another embodiment of the prefabricated dental implant surgical guide 40 is illustrated. Surgical guide 40 as depicted in FIG. 1 a , has fixed apical post 44 with bottom end face 75 and marking agent 77 on it for the purpose of marking and identifying an osteotomy site 46 .
[0064] Referring now to FIGS. 7 b and 7 c use of the embodiment of FIG. 7 a is illustrated. By holding coronal post 43 and by using tooth shaped contour 42 as a guide as previously described, osteotomy site 46 in jaw bone 48 can be located and demarcated by pressing end face 75 with marking agent 77 of fixed apical post 44 on top of jaw bone 48 leaving a mark denoting the osteotomy site 46 . Osteotomy bur 47 of surgical drill 59 can then be used to initiate osteotomy site preparation. Further preparation, verification and completion of the osteotomy site 46 via drill 59 can then be accomplished as previously described in FIGS. 1 b and 1 c.
[0065] Referring now to FIG. 8 a , another embodiment of the prefabricated dental implant surgical guide 51 is illustrated. In this embodiment, surgical guide 51 , comprises a fixed apical post 24 with bottom end face 85 and marking agent 87 on it for the purpose of marking and identifying an osteotomy site 46 .
[0066] Referring now to FIGS. 8 b and 8 c , by holding coronal post 23 and by using tooth shaped contour 22 as a guide as previously described, osteotomy site 46 in jaw bone 48 can be located and demarcated by pressing bottom end face 85 with marking agent 87 of fixed apical post 24 on top of jaw bone 48 leaving a mark denoting the osteotomy site 46 . Osteotomy bur 47 of surgical drill 59 can then be used to initiate osteotomy site preparation. Subsequent to osteotomy site preparation and implant placement, the tooth shaped contour 22 of guide 51 can be converted to a provisional crown (immediate or delayed) as previously described in FIG. 2 b.
[0067] Referring now to FIG. 9 a , yet another embodiment of the prefabricated dental implant surgical guide 53 is illustrated. Surgical guide 53 comprises a fixed apical post 13 with bottom end face 95 and marking agent 97 on it for the purpose of marking and identifying an osteotomy site 46 .
[0068] Referring now to FIGS. 9 b and 9 c , use of the surgical guide 53 is illustrated. By holding coronal post 6 and by using tooth shaped contour 12 as a guide as previously described, osteotomy site 46 in jaw bone 48 can be located and demarcated by pressing end face 95 with marking agent 97 of fixed apical post 13 on top of jaw bone 48 leaving a mark denoting the osteotomy site 46 . Osteotomy bur 47 of surgical drill 59 can then be used to initiate osteotomy site preparation. Further preparation, verification and completion of the osteotomy site 46 can then be accomplished as previously described in FIGS. 3 b , 3 c and 3 d.
[0069] Referring now to FIG. 10 a , another embodiment of prefabricated dental implant surgical guide 70 is illustrated. Surgical guide 70 comprises an adjustable removable post 67 with apical post aspect 64 with a bottom end face 102 , and marking agent 104 on it for the purpose of marking and identifying an osteotomy site 46 .
[0070] Referring to FIGS. 10 b and 10 c , use of the prefabricated dental implant surgical guide is illustrated. By pushing or turning coronal post 63 of adjustable removable post 67 so that central post portion 68 moves through central bore 60 , thereby lengthening apical post portion 64 and by using tooth shaped contour 62 as a guide as previously described, osteotomy site 46 in jaw bone 48 can be located and demarcated by pressing end face 102 with marking agent 104 of apical post aspect 64 of adjustable removable post 67 on top of jaw bone 48 leaving a mark denoting the osteotomy site 46 . Osteotomy bur 47 of surgical drill 59 can then be used to initiate osteotomy site preparation. Further preparation, verification and completion of the osteotomy site can then be accomplished as previously described in FIGS. 4 b , 4 c and 4 d.
[0071] Referring now to FIG. 11 a , still another embodiment of prefabricated dental implant surgical guide 72 is illustrated. The multi unit one piece surgical guide 72 comprises fixed apical posts 74 a , 74 b , and 74 c with bottom end faces 109 a , 109 b and 109 c and with marking agents 110 A, 110 b , and 110 c on them for the purpose of marking and identifying an osteotomy sites 46 a , 46 b and 46 c.
[0072] Referring now to FIGS. 11 b and 11 c , use of the prefabricated dental implant surgical guide is illustrated. By holding coronal posts 73 a , 73 b and or 73 c and by using tooth shaped contour 72 a , 72 b and 72 c as a guide as previously described, osteotomy sites 46 a , 46 b and 46 c in jaw bone 48 can be located and demarcated by pressing end faces 109 a , 109 b and 109 c with marking agents 110 a , 110 b and 110 c of fixed apical posts 74 a , 74 b and 74 c on top of jaw bone 48 leaving marks denoting the osteotomy sites 46 a , 46 b and 46 c . Osteotomy bur 47 of surgical drill 59 can then be used to initiate osteotomy site preparations. Further preparation, verification and completion of the osteotomy sites can then be accomplished as previously described in FIGS. 1-4 .
[0073] A method and apparatus for using a prefabricated implant surgical guide during dental implant placement surgery has now been illustrated. It will also be understood that the invention may be embodied in other specific forms without departing from the scope of the invention disclosed and that the examples and embodiments described herein are in all respects illustrative and not restrictive. Those skilled in the art of the present invention will recognize that other embodiments using the concepts described herein are also possible. Further, any reference to claim elements in the singular, for example, using the articles “a,” “an,” or “the” is not to be construed as limiting the element to the singular. | A prefabricated dental implant surgical guide. The implant surgical guide comprises a tooth shaped contour which simulates a natural tooth and the final prosthesis. The tooth shaped contours can be shaped to match any tooth found in the mouth. The system further comprises apical posts which protrude from the apical aspect of the tooth contour of the surgical guide. These apical posts are capable of marking an initial osteotomy site. The apical posts are further able to be placed in to an initial and developing osteotomy site to verify proper implant location, angulation and rotational position prior to implant placement. Significantly the apical post can be attached to the surgical guide and of a fixed length. The apical post can also be adjustable allowing continuous osteotomy site verification and removable allowing an implant surgical drill to pass thru it thereby allowing continuous osteotomy site development and verification. The system further comprises a coronal post aspect to position the surgical guide. The posts can be removed, the tooth contour aspect of the guide hollowed out and then relined and secured to the abutment aspect of an implant thereby functioning as a provisional crown or crowns. The prefabricated dental implant surgical guide can be used to place single implants or multiple side by side implants in a continuous fashion allowing verification of implant location, angulation and rotational position prior to implant placement leading to a more aesthetic, functional and stable prosthesis. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to a hair styling iron with hair curling and straightening capabilities.
2. Description of the Prior Art
Various types of hair styling irons have been widely available and are generally classified into two types, one for hair curling and the other for hair straightening. That is, the prior hair styling irons have been designed specifically to perform either the hair curling or hair straightening. Consequently, the user is required to use different types of the hair styling irons depending upon the desired hair styling, i.e., hair curling and straightening. This is very inconvenient and cost-consuming for the user. There has also been known in the art a hair styling iron having a dual hair styling capabilities, as shown in U.S. Pat. No. 4,739,151. The patent discloses a hair styling iron which provides two different hair clamping sections of different hair contacting surfaces in order to selectively effect styling the hair into different configuration. However, due to the lack of any cylindrical barrel for winding the hair and also to the structural limitation in this patent that the hair is always clamped between two opposing plates, it is not possible to curl the hair as expected by a conventional hair curling iron with a cylindrical barrel, although the hair can be successfully waved or straightened. In this sense, this patent also fails to selectively curl and straighten the hair.
SUMMARY OF THE INVENTION
In view of the inconvenience seen in the prior art hair styling irons, the present invention is contemplated to a hair styling iron which has dual capabilities of curling and straightening the hair. The hair styling iron in accordance with the present invention comprises a barrel incorporating a heater and configured to have a generally circular cross section. A hair clamping tongue is movable relative to the barrel between a clamping position of clamping a strand of hair between the tongue and a peripheral portion of the barrel in order to curl the hair wound around the barrel in cooperation with the heater. The barrel comprises a pair of first and second pipes each having a generally semi-circular cross section with a top rounded outer surface and a bottom outer surface. The first and second pipes are movable relative to each other between a closed position where the outer bottom surfaces of the first and second pipes are kept in closed relation to each other and an open position where the outer bottom surfaces are kept away from each other. At the closed position, a strand of hair can be held between the opposing bottom outer surfaces of the first and second pipes in order to straighten or uncurl the hair in cooperation with the heater. Thus, the hair curling and straightening can be selectively and conveniently effected with a single device.
Accordingly, it is a primary object of the present invention to provide a hair styling iron which is capable of providing hair curling and straightening capabilities for enhanced convenience.
The first and second pipes extends respectively from one of the ends of first and second handles which are pivotally connected at their other ends about a pivot axis so that the first and second pipes are allowed to pivot together with the first and second handles about the pivot axis. The hair clamping tongue is also pivotally supported about the common pivot axis so as to be capable of pivoting together therewith as well as independently therefrom. Thus, when performing hair curling, the hair clamping tongue is made to pivot separately from the first pipe as well as the second pipe for facilitating clamping the hair between the first pipe and the tongue. On the other hand, when performing the hair straightening, the tongue is made to pivot together with the first pipe relative to the second pipe for facilitating to holding the hair between the first and second pipes.
It is therefore another object of the present invention to provide a hair styling iron in which the hair clamping tongue can be made pivotable together with or separately from the first pipe for facilitating hair curling and straightening operations.
In order to further facilitate the handling of the hair clamping tongue and the first pipe in opening and closing relative to the first pipe and the second pipe, respectively, the hair clamping tongue and the first pipe are spring-biased to a release position and an open position, respectively. The hair clamping tongue and the first pipe are capable of being locked in a clamping position or a closed position, respectively by clamp lock means and barrel lock means. Thus, the hair clamping tongue can be kept at its clamping position on the first pipe so as not to be a hindrance to the hair straightening operation by the first and second pipes, while the first and second pipes are kept in the closed position to constitute a barrel for enabling hair curling in cooperation with the hair clamping tongue. With the provision of the lock means, the device can be more conveniently utilized to selectively perform hair curling and straightening operations, which is therefore a further object of the present invention.
Provided at the tip of the first pipe is a water supply means containing a volume of water and means for feeding the water to a heater accommodated within the first pipe. The heater generates steam which is fed outwardly through a number of vents formed in the surface of the first pipe. In order to contain a large volume of water in the water supply means at the tip of the first pipe, the first pipe is configured to have a cross section larger than the second pipe.
It is therefore a still further object of the present invention to provide a hair styling iron which is capable of generating the steam for effectively performing hair curling and straightening.
These and still other objects and advantageous features of the present invention will become more apparent from the following detailed description of the embodiments when taken in conjunction with the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front view of a hair styling iron, shown with a hair clam in its release position ready for curing the hair, in accordance with a first embodiment of the present invention;
FIG. 2 is a vertical section of the hair styling iron FIG. 1 ;
FIGS. 3 and 4 are top and bottom views of the hair styling iron, respectively;
FIG. 5 is an exploded perspective view of a first handle employed in the hair styling iron to carry a first pipe; FIG. 6 is an exploded perspective view illustrating a structure of pivotally coupling the first handle as well as a clamp handle of the clamping tongue to a second handle carrying a second pipe;
FIG. 7 is a sectional view along line 7--7 of FIG. 4 illustrating the above pivot coupling;
FIG. 8 is an exploded perspective view illustrating the above pivot coupling with a pair of springs shown as detached from the second handle;
FIG. 9 is a partial view somewhat schematically illustrating portions of the first handle and the hair clamping tongue on which the two springs act, respectively;
FIG. 10 is a cross-section along line 10--10 of the hair styling iron illustrating a water tank and its associated parts at the tip of the hair styling iron;
FIG. 11 is a front view of the hair styling iron shown in an open position ready for straightening the hair;
FIG. 12 is a front view of the hair styling iron shown in its closed position for effecting the hair straightening;
FIGS. 13 and 14 are perspective views of a hair styling iron, shown in closed and open positions, in accordance with a second embodiment of the present invention.
DETAILED DESCRIPTION OF THE EMBODIMENTS
First Embodiment <FIGS. 1 to 12>
Referring now to FIGS. 1 and 2, there is shown a hair styling iron in accordance with a first embodiment of the present invention. The hair styling iron comprises a pair of first and second pipes 10 and 20 each having a generally semi-circular cross section with a top rounded outer surface and a bottom outer surface. The first and second pipes 10 and 20 extend straight from front ends of first and second handles 30 and 40, respectively. The first and second handles 30 and 40 are pivotally connected at the rear ends thereof so that the first and second pipes are movable between a closed position of FIG. 1 (also shown by solid lines of FIG. 2) and an open position of FIG. 11 (also shown by dotted lines of FIG. 2). At the closed position, the first and second pipes 10 and 20 have their bottom outer surfaces kept in closed relation to each other to define a cylindrical barrel about which a strand of hair is wound. Also in this closed position, the hair is allowed to be held between the first and second pipes 10 and 20 so as to be properly styled therebetween by the effect of heat applied to the contacting surfaces of the first and second pipes 10 and 20. In this embodiment, the outer bottom surfaces of the first and second pipes 10 and 20 are of generally flat configuration, as shown in FIG. 10, in order to straighten the hair between the outer bottom surfaces. It is noted here that the outer bottom surfaces may be suitably rounded or curved at a gradual curvature different from the top rounded surface for desired hair styling.
Also included in the hair styling iron is a hair clamping tongue 50 which extends straight from a front end of a corresponding clamp handle 60. The clamping tongue 50 extends by substantially the same length as the first pipe 10 and is configured to have an arcuately curved cross section in conformity with the top rounded top surface of the first pipe 10 so as to be tightly placed thereupon over the substantially the full length of the first pipe 10. The clamp handle 60 is pivotally supported at its rear end to the first and second handles 30 and 40 so that the hair clamping tongue 50 is movable relative to the top rounded outer surface between a clamping position of clamping therebetween the strand of hair wound about the barrel and a release position which permits the strand of hair to be unwound. Thus, the hair can be curled between the clamping tongue 50 and the barrel in cooperation of the heat applied thereto. The first and second pipes 10 and 20 incorporate first and second heaters 70 and 80, respectively to apply heat to the hairs held between the first and second pipes 10 and 20 for hair straightening as well as the hairs clamped between the first pipe 10 and the clamping tongue 50 for hair curling.
As shown in FIGS. 5 to 7, the first and second handle 30 and 40 are shaped into a semi-cylindrical outer configuration in correspondence to the first and second pipes 10 and 20. The second handle 40 is provided at its rear end with a transversely extending pivot pin 41 which penetrates through a hole 31 in the rear end of the first handle 30 as well as through holes 61 in the rear end of the clamp handle 60 so as to pivotally connect the first handle 30, the second handle 40 and the clamp handle 60 commonly about the pivot pin 41, as shown in FIG. 7, thus allowing the first pipe 10 to move between the closed and open positions as well as allowing the clamp tongue 50 to move between the closed and release positions. A bottom lid 32 is provided to close a bottom opening of the first handle 30. The holes 31 and 61 are formed in corresponding flanges 33 and 63 which extend from the rear ends of the first handle 30 and the clamp handle 60 and received within the rear end of the second handle 40, respectively. As best shown in FIG. 6, the clamp handle 60 has the two flanges 63 between which the flange 33 of the first handle 30 is positioned so that the clamp handle 60 and the first handle 30 are allowed to pivot commonly about the pivot pin 41. The flanges 33 and 63 are respectively formed with shoulders 34 and 64 which are in an opposed relation to a bottom of a recess 42 formed at the rear end of the second handle 40 adjacent the pivot pin 41. As shown in FIGS. 8 and 9, coil springs 35 and 65 are fitted respectively between one of the shoulders 64 of the clamp handle 60 and the bottom of the recess 42 and between the shoulder 34 of the first handle 30 and the bottom of the recess 42 such that the Clamp handle 60 and the first handle 30 are urged respectively together with the clamp tongue 50 and the first pipe 10 into the released position and the open position. Therefore, the clamp tongue 50 is normally kept in the released position, as shown in FIG. 1, in relation to the first and second pipes 10 and 20, while the first pipe 10 is normally kept in the open position, as shown in FIG. 11, in relation to the second pipe 20.
Provided on the bottom of the Second handle 40 is a slider lock 46 with a hook 47 which is engageable with a catch projection 36 on the lid 32 of the first handle 30 for locking the first handle 30 and therefore the first pipe 10 into the closed position relative to the second handle 40, as shown in FIG. 1. Likewise, the clamp handle 60 is provided with a slider lock 66 with a hook 67 which is engageable with a slit 37 in the upper surface of the first handle 30 for locking the clamp handle 60 and therefore the clamp tongue 50 into the clamp position, as shown in FIGS. 11 and 12. Thus, the hair curling operation can be conveniently performed by closing and opening the clamp tongue 50 with the first pipe 10 kept locked to the second pipe 20, as shown in FIGS. 1 and 12. On the other hand a hair straightening operation can be also conveniently performed by closing the first pipe 10 relative to the second pipe 20 with the clamp tongue 50 kept locked to the first pipe 10, as shown in FIGS. 11 and 12.
As shown in FIGS. 2 and 10, the first heater 70 in the first pipe 10 comprises a plate-like heater element 71 encased in a heat tube 72 of good thermal conductivity which is press-fitted within a cylindrical bore 11 of the first pipe 10. A pair of heat-conductive members 73 are disposed between the heater element 71 and the inner wall of the heat tube 72. The heat tube 72 has its entire circumference in contact with the wall of the bore 11, the top rounded outer surface and the bottom outer surface of the first pipe 10 for effectively heating the first pipe 10 uniformly. The heat tube 72 is closed at its front end to define thereto a steam generating surface 74. The second heater 80 comprises a plate-like heater element 81 disposed in the second tube 20 held in contact with the bottom outer surface by a support 81A for intensively heating thereof the bottom outer surface. Detachably attached to the front end of the first pipe 10 is a water tank 90 containing a volume of water and including a water carrying wick 91 extending axially rearward for contact with the steam generating surface 74 in order to supply the water thereto. The tank 90 is axially slidable and is biased forwardly by means of a spring 93 interposed between the wick 91 and the heat generating surface 74 so that the wick 91 is normally kept away from the heat generating surface 74 of the first heater 70. When the tank 90 is pushed inwardly against the bias of the spring 93, the wick 91 comes into contact with the heat generating surface 74 to supply the water thereto, thus generating steam thereato. The resulting steam is fed outwardly of the first pipe 10 through a number of minute vents 12 formed in the top and bottom outer surfaces for enhancing the hair styling of the hairs either clamped between the first pipe 10 and the clamp tongue 50 or held between the first and second pipes 10 and 20. The clamp tongue 50 is formed with a number of minute perforations 51 the steam to escape thererhrough. It is noted in this Connection that, as shown in FIG. 10, the first pipe 10 is configured to have a larger cross section than the second pipe 20 in order to provide a correspondingly larger space for accommodating the water tank and therefore increasing steam generating capacity. Provided at the front end of the second pipe 20 is a dummy cap 95 which resembles the water tank 90 and is likewise made retractable against the bias of a spring 96 held between the rear end of the dummy cap 95 and the heater element 81 of the second heater 80 such that the dummy cap 95 can be pushed in together with the water tank 90 for facilitating the push-in operation of the water tank 90 by the user.
The first and second heaters 80 and 90 are electrically connected through a suitable resistor or resistors to a power cord 100 extending outwardly through the rear end of the second handle 40. A pilot lamp 48 is inserted in a circuit of the heaters and is exposed in the outer surface of the second handle 40 for indication of the energization of the heaters.
Second embodiment <FIGS. 13 and 14>
FIGS. 13 and 14 show a hair styling iron in accordance with a second embodiment of the present invention which is identical in structure and operation to those of the first embodiment except that a hair clamping tongue 50A is pivotally supported at the front end of the like first handle 30A. Like parts are designated by like numerals with a suffix letter "A". In this embodiment, the clamp tongue 50A is biased toward the clamp position on the first pipe 1OA and is caused to move away therefrom into the release position by manipulation of a thumb press 55A at the front end of the first handle 30A. | A hair styling iron for selectively effecting hair straightening or curling includes a generally circular cross-section electrically heated barrel. A tongue is movable relative to the barrel for selectively clamping a strand of hair between the tongue and the peripheral surface of the barrel for curling hair wound therearound. The barrel comprises a first and second pipes each having a generally semi-circular cross section with a top rounded outer surface and a flat bottom outer surface. The pipes are movable relative to each other between a closed position where the flat bottom surfaces are kept in closed relation to each other and an open position where the bottom surfaces are spaced away from each other. In the closed position, a strand of hair can be held between the opposing flat bottom surfaces of the first and second pipes in order to substantially straighten or uncurl the hair. Thus, the hair styling iron can alone provides hair curling and straightening capabilities. | 0 |
FIELD OF THE INVENTION
The present invention relates to horticulture and more particularly, relates to a gardening system and a plant growing system.
BACKGROUND OF THE INVENTION
Container planting is well known and widely practiced by many professional and amateur gardeners. Its uses vary from locations wherein other types of gardening are impossible such as in urban settings including high rise buildings, for decorative and esthetic purposes, and flower boxes.
Container gardening is also widely practiced for optimum space utilization and design such as patio and solarium.
Moreover, there is increased interest in container gardening for commercial purposes.
To date, most container gardening consists of placing a desired amount of soil in a container and then placing the plant therein. There have been numerous proposals in the art for specific types of container structures which disclose various arrangements to permit automatic drainage and/or feeding and/or watering and the like. It is also known in the art to provide for a gardening system which utilizes separate zones, which include inserts for containing the growing medium and soil, with the roots being provided access to air, water and enough space for their optimal development. This system also prevents the spiral root growth pattern that is commonly associated with conventional plant containers. This system, described in U.S. Pat. No. 6,247,269 issued Jun. 19, 2001, has common inventorship with the present application.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an improvement to the system for plant growing described in U.S. Pat. No. 6,247,269.
It is a further object of the present invention to provide a plant growing system wherein plant growth is enhanced by the use of a fungus in a non-soil growing medium.
It is a further object of the present invention to provide a plant growing system wherein root damage is minimized.
It is therefore an object of the present invention to provide an improved container and gardening system which improves plant growth and plant productivity.
According to one aspect of the present invention, there is provided a gardening system comprising a container having a bottom wall and a side wall extending upwardly therefrom, a soil support insert spaced from the bottom wall to define a space between the bottom wall and the soil support insert, at least one wall extending downwardly from the soil support member to define a cavity, a plurality of apertures in the downwardly extending wall, water in the container, an air-space between an upper surface of the water and the soil support member, a non-soil growing medium within the cavity, said non-soil growing medium including mycorrhizal fungi, and a soil on top of the non-soil growing medium.
According to a further aspect of the present invention, there is provided a gardening method comprising the steps of supplying a gardening system comprising a container having a bottom wall and a side wall extending upwardly therefrom, a soil support insert spaced from the bottom wall to define a space between the bottom wall and the soil support insert, at least one wall extending downwardly from the soil support member to define a cavity, a plurality of apertures in the downwardly extending wall, water in the container, an air-space between an upper surface of the water and the soil support member, putting a non-soil growing medium within the cavity, placing a vesicular-arbuscular mycorrhizal inoculum on top of the non-soil growing medium and subsequently putting a soil on top of the mycorrhizal inoculum.
Mycorrhizal fungi are known universal symbionts living in close association with the majority of terrestrial plants. Thus, certain types of mycorrhizal fungi such as ectomycorrhizal fungi (several mushrooms) are associated with the roots of conifer trees. Ericoid mycorrhizal fungi colonize such plants as blueberry, cranberry and rhododendrons. Herbaceous plants as well as numerous deciduous and fruit trees, which make up more than 80% of the flora and include most of the cultivated crops, are living in symbiosis with vesicular-arbuscular mycorrhizal fungi (VAM fungi).
The VAM fungi are obligate symbionts as they cannot survive without living in close association with plants. However, in vitro culture technology is not convenient for large scale production of AM fungal inoculum. During the past decades, it has been demonstrated that VAM fungi can improve plant yield by a better supply of mineral nutrients, increase the production of flowers, protect the roots against phytopathogens, reduce transplantation shock due to a better water supply, increase resistance to drought, promote early vegetable growth, induce a better firmness of plant tissues, which contributes to extend the period of cold storage, increase the survival rate to winter and contribute to stabilize soil particles.
As previously mentioned, it is known from U.S. Pat. No. 6,247,269 to provide a gardening system which utilizes separate zones which include inserts for containing the growing medium and soil with the roots being allowed unlimited access to air and water. The teachings of this patent are hereby incorporated by reference.
In the particular aforementioned U.S. patent, there is taught the use of an insert within an outer container and which insert is designed to support the soil in a spaced relationship from the bottom of the container. The bottom of the container is provided with water while an air space is maintained between a portion of the growing medium and the liquid.
The inserts provide one or more cavities and which cavities extend downwardly into the area with the water. The cavities are filled, at the lower portion thereof, with a non-soil growing medium such as vermiculite while on top of the non-soil medium there may be provided a conventional dirt soil.
The system provides communication means between the exterior of the container and the interior, preferably one for liquid and one for gas. By so doing, air may freely flow in the space between the soil and the water.
In the improved system of the present invention, the ribs defining the slots in the lower portion of the container have an arcuate configuration, the arcuate portion facing towards the interior of the insert. It has been found that by providing such an arrangement, a significant amount of root damage is avoided.
Preferably, the ribs are spaced apart by a distance of between 1.5 and 3 millimeters, to provide slots which intently allow for root growth therethrough. The ribs defining the slots are also formed of a material which is compliant in nature. Thus, the ribs can be slightly deformed by the growing of the roots therethrough while not exerting any excess pressure on the roots. In other words, the rib will at least semi-permanently deform to permit root growth therethrough.
In a particular aspect of the present invention, it has surprisingly been found that the growth of the plants is significantly enhanced by use of mycorrhizal fungi within the non-soil growing medium.
The mycorrhizal fungi is utilized with the inert growing medium which is preferably vermiculite. It can also be mixed with the soil, or placed on top of the non-soil growing medium. Using the system of the present invention, one can enhance the mechanisms of soil ecology as well as achieve root growth improvement. With their extensive filament network, mycorrhizal fungi increase the area of root absorption in the soil much more than that of feeder roots and hairs. This results in increased absorption of relative mild soil nutrients and better plant nutrition, growth and development.
Mycorrhizal fungi prefer soil environment having a good soil aeration, a constant water supply, a stable temperature and low or medium phosphorous content. In the system of the present invention, the air-soil surface is large for the volume of soil and this allows a transfer of air from the soil to the atmosphere. Also, since aeration can occur from the bottom, air can easily move through the soil. Hence, the soil will allow aeration of the roots and of the aerobic mycorrhizal fungi. The system also provides enough carbon dioxide to allow VAM fungi to colonize the root system of most plants.
Mycorrhizal hyphae and spores have much thicker walls than most of the other fungi. Nonetheless, they require adequate amounts of water to prevent their dessication and subsequent death. Using the vermiculite interface provides an ideal environment to foster mycorrhizal growth and development.
The design of the system can also include a jacket around the soil containing inserts to protect the mycorrhizal fungi from the effect of such sudden heating and dessication.
It has also been found that the use of the system of the present invention substantially increases the production of mycorrhizal fungi in the soil medium. Indeed, the system can be used to reproduce the mycorrhizal fungi; after use in the present system, the vermiculite may be stored in a dry place which will trigger mycorrhizal sporulation. These spores and these root sections colonized with the VAM fungi will later give rise to new mycorrhizal growth when environmental conditions are suitable. Thus, the vermiculite may either be reused (with new vermiculite being added) or the vermiculite can be utilized as a mycorrhizal field inoculum for other soil applications. This is also true for the soil or compost substrate in the above layer of the root-forming interface.
BRIEF DESCRIPTION OF THE DRAWINGS
Having thus generally described the invention, reference will be made to the accompanying drawings illustrating an embodiment thereof, in which:
FIG. 1A is a top plan view showing different arrangements of a gardening system according to one embodiment of the present invention;
FIG. 1B is a top plan view showing another embodiment of the present invention;
FIG. 2 is a perspective view of an insert according to one embodiment of the present invention;
FIG. 3 illustrates varying arrangements for the ribs in cross-sectional view as taken along the lines 3 — 3 of FIG. 2 ;
FIGS. 4 to 8 are cross-sectional views illustrating the various stages of plant growth and mycorrhizal fungi colonization utilizing the system of the present invention.
FIG. 9 is a series of graphs illustrating the growth of elite plants using the system of the present invention, both with and without fungi, and a comparison to leeks grown in a normal garden;
FIG. 10 is a side elevational view, partially cut-away, illustrating the growth of a plant in a system according the present invention; and
FIG. 11 is a schematic illustration of the cross-sectional configuration of various types of ribs.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings in greater detail, and by reference characters thereto, there is illustrated in FIG. 1B three different arrangements for a plant growth system according to one embodiment of the present invention.
In the plant growth system which is generally designated by reference numeral 10 , there is provided an outer container 12 which, in the first arrangement, is designed to receive a pair of inserts 14 . Each of inserts 14 are somewhat hemispherical in an overall configuration such that two of the inserts will substantially fill container 12 .
In the second arrangement, there is provided a larger outer container 112 which has a plurality of inserts 14 , there being three such members. Finally, in the third embodiment, there is provided an outer container 212 having four inserts 14 located therein. In another embodiment of the present invention ( FIG. 2 ) there is provided an outer container 112 which has a plurality of inserts 114 that are somewhat larger than inserts 14 , there being three such members. Finally, in the third embodiment, there is provided an outer container 212 having four inserts 214 located therein. The containers may have an aperture 15 .
An alternative arrangement is shown in FIG. 1A wherein the inserts 14 remain the same size while the container may increase in size but hold more of the inserts.
As shown in FIG. 2 , an insert 12 will have an upper rim 16 and a base 18 . The member is designed to sit on legs 20 to keep it spaced from the bottom of a container 12 for reasons which have been previously discussed. The walls (and bottom) are comprised of a plurality of spaced-apart ribs 22 to thereby define elongated slots 24 therebetween. Preferably, each of the slots 24 have a width of between 1.5 to 3 mm.
As shown in FIG. 3 , ribs 22 may have a circular configuration as shown in the upper portion of FIG. 3 thereof or alternatively, they may have only a rounded interior portion as shown in the lower portion of FIG. 3 . In either case, the ribs present a smooth arcuate surface to the roots as they pass therethrough. Also, as previously mentioned, the ribs 22 are preferably formed of a material which is compliant in nature—i.e. it can be slightly deformed to easily permit the passage of roots therethrough without damaging the roots.
Alternatively, the ribs can present a smooth polygonal surface to the roots as they pass therethrough.
Turning to the arrangements shown in FIGS. 4 to 7 , there is illustrated a plant growth system 30 which is similar to that shown in U.S. Pat. No. 6,247,269. Accordingly, only a portion of the container system is illustrated herein.
As shown in FIG. 4 , there is provided a plant growth system 30 which includes an outer container generally designated by reference numeral 28 . Outer container 28 has an upper side wall 32 and a lower side wall 34 which are joined together by merging section 36 . There is also provided a bottom wall 38 .
There is also provided an inner insert 44 of the type illustrated in U.S. Pat. No. 6,247,269.
Inner insert 44 has an upper inner side wall 46 and an upper outer side wall 48 which defines an air space 52 therebetween. Apertures 50 are provided in the merging section between upper inner side wall 46 and upper outer side wall 48 . As may be seen, inner insert 44 seats on both the upper marginal edge of upper side wall 32 and on merging section 36 of outer container 28 .
As described in the aforementioned U.S. patent, there are provided inner cavities defined by inner cavity walls 54 which are formed in a manner similar to that described in the patent and in the embodiment of FIG. 1 herein—i.e. a plurality of ribs defining vertically extending slots as well as some horizontal slots.
As shown in FIG. 4 , the inner insert 44 has a lower portion thereof filled with an inert growing medium such as vermiculite 56 while on top thereof there is supplied a conventional soil 58 . In the bottom of container 28 , there is provided water 60 which is at a level so as to allow for air-space 62 .
The vermiculite 56 is inoculated with mycorrhizal fungi as designated by reference numeral 64 . As shown in FIGS. 5 through 8 , the mycorrhizal fungi spores 64 then infect the root tissue of the plants and aid in the plant being able to access greater nutrients from the soil element (like phosphorous, copper, zinc, etc.). These nutrients are basically insoluble but with the use of the fungi, they become more easily bioavailable. Also, the development of the root system permits the plant to gain access to a larger volume of soil and thereby gain greater access to the nutrition elements.
It has also been shown that the inoculum can also be placed at the interface of the non-soil growing medium and the soil, or close to it, for better results.
As illustrated in FIG. 11 , the ribs may be of various cross-sectional configurations. A typical rib is generally designated by reference numeral 74 and as shown, may have a semi-spherical, or probably hexagonal configuration.
EXAMPLE 1
Seeds were sown both in a gardening system according to the present invention and in a conventional garden soil. In both instances, a control not using mycorrhizal fungi was run as well as one wherein the plants where inoculated with mycorrhizal fungi. In both instances, an organic soil having a compost base was utilized and a liquid plant fertilizer having 20% of marine algae extract was used according to the instructions of the manufacturer.
FIG. 9 is a graph illustrating the results obtained. As will be noted, the non-mycorrhizal fungi controls were similar for both the garden and the system of the present invention. When utilizing the mycorrhizal fungi in the conventional garden soil, there was an improvement in the diameter of the plant as expected. Using the fungi in the container system according to the present invention, there was a substantially greater improvement of plant growth compared to the control and also compared with inoculated plants.
It will be understood that the above described embodiments are for purposes of illustration only and that changes and modifications may be made thereto without departing from the spirit and scope of the invention. | A gardening system wherein there is provided an outer container and a soil support insert placed therein, the soil support insert is spaced with the bottom wall of the container to find a water space and an air space therebetween, the insert having at least one downwardly extending wall which defines a cavity and the downwardly extending wall having a plurality of apertures therein to permit root growth therethrough, a non-soil growing medium within the cavity, the non-soil growing medium including mycorrhizal fungi incorporated therein. The system provides for an enhanced plant growth. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of pending PCT International Patent Application No. PCT/NL/03/00167, filed on Mar. 5, 2003, designating the United States of America, and published, in English, as PCT International Publication No. WO 03/074563 A2 on Sep. 12, 2003, and also claims the benefit, under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Ser. No. 60/362,040, filed on Mar. 6, 2002, the contents of the entirety of both of which are incorporated herein by this reference.
TECHNICAL FIELD
[0002] The invention relates generally to biotechnology and medicine. The invention further relates to the fields of immunology and molecular biology. The invention in particular relates to means and methods for manipulating hypersensitivity responses.
BACKGROUND
[0003] Immunoglobulins (Ig) are important effector molecules of adaptive humoral immune responses. Production of IgE and IgG1 antibodies to innocuous antigens is a reflection of a normal immune response. Binding to Fc receptors, FcεRI or FcγRIII, on mast cells and basophiles, respectively, and subsequent cross-linking of these Fc receptors can trigger hypersensitivity reactions. In patients with allergic syndromes, IgE is thought to play a central role in eliciting immediate hypersensitivity reactions. However, many hypersensitivity diseases do not always correspond with increased serum IgE levels or skin reactivity to common allergens. Studies in epsilon heavy chain gene-targeted mice (IgE-deficient) showed that active anaphylaxis can be induced in the absence of IgE antibodies and was likely due to IgG1. On the other hand, immediate-like hypersensitivity reactions can also be elicited by other antigen-specific factors (1).
[0004] Tetrameric Igs are produced and secreted by plasma cells. However, it is well documented that plasma cells also produce and secrete single Ig light chains (Ig-LC) in excess over Ig heavy chains or gamma chains (2-6). In vivo turnover studies in humans demonstrated that apparently only 60% of synthesized Ig-LC was incorporated into isotypic whole Ig and the remaining fraction was released into serum as free Ig light chain (7). Therefore, Ig-LC can be detected at low levels in normal serum and also in urine and in cerebrospinal fluid. Single Ig light chain and Ig light chain dimers bind antigen specifically. Antigen-binding affinities vary and are generally lower, but also affinities similar to or higher than tetrameric Ig were reported (8-15). It is against current dogma that secreted Ig-LC may play a physiological role, although in some instances, free Ig-LC were found to display antigen-specific proteolytic activity (16, 17). However, in this study we show that Ig-LC can transfer immediate hypersensitivity-like responses in mice. These hypersensitivity-like responses are mast cell-mediated and are not detectable in mast cell-deficient mice. Shortly after antigen exposure of Ig-LC-sensitized animals, mast cell activation and local tissue swelling can be detected. We show herein that Ig-LC can serve as a link in the mechanism by which mast cells regulate a number of immune-mediated diseases.
SUMMARY OF THE INVENTION
[0005] Mast cells are important for the development of acute responses in allergic reactions. Thus far, triggering the high-affinity IgE receptor (FcεRI) and the low-affinity IgG-receptor (FcγRIII) are the only routes known to activate mast cells in an antigen-specific manner. The present invention discloses that Ig-LC can exert their action independent from activation of the FcγRIII or FcεRI receptors. Both receptors signal via the common gamma chain and can trigger hypersensitivity reactions via activation of mast cells. Passive sensitization of animals deficient in the common gamma chain (FcRγ−/−) resulted in similar ear swelling responses after hapten challenge as compared to wild-type (C57BL/6) animals ( FIG. 1 ). This result shows that Ig light chains interact with a receptor that does not need the common gamma chain for signaling and thereby excludes FcεRI and FcγRIII or other gamma chain-associated receptors as effector molecules in Ig-LC-induced hypersensitivity.
[0006] In one aspect, the present invention thus provides an isolated cell comprising an Ig-LC receptor capable of activating a signal transduction pathway in the cell upon binding and cross-linking of an Ig-LC to the receptor, wherein this signal transduction is independent of the presence of a functional gamma chain on the cell. This isolated cell preferably comprises a mast cell or a gamma chain-associated receptor-deficient cell.
[0007] Knowledge of the presence of a gamma chain-independent receptor for Ig-LC opens the route to the identification of the receptor. Many techniques are present in the art to find receptors for ligands. The invention preferably utilizes protein solutions that are enriched for Ig-LC receptors. In one embodiment, the invention, therefore, provides a method for obtaining a protein solution enriched for a receptor for Ig-LC comprising providing a gamma chain-deficient mast cell with Ig-LC and cross-linking the Ig-LC to proteins in its vicinity and purifying Ig-LC and linked proteins from non-linked proteins. This purification can be achieved through many different means. In a preferred embodiment, this is achieved through magnetic beads associated with the Ig-LC. Magnetic beads are coupled to Ig-LC. These beads are then incubated with mast cells or mast cell proteins and after washing the cells, Ig-LC (bait) are chemically cross-linked to cell surface proteins in immediate proximity to the binding site. After lysing the cells, Ig-LC cross-linked cell surface proteins are separated from non-bound proteins using a magnetic device. Proteins are washed and separated using SDS-PAGE. This can be done using gel electrophoresis methods. Proteins can be characterized and identified by sequencing (part of) the proteins from certain positions in the gel. In a preferred embodiment, the receptor comprises a protein with an apparent molecular weight between 37 and 50 kDa and an even more preferred embodiment, the apparent molecular weight is 45 kDa.
[0008] Proteins are further characterized and identified with Maldi-TOF mass spectrometry and/or Edman degradation. Binding of Ig-LC-conjugated magnetic beads coupled to mast cells was visualized in the present invention by light microscopy ( FIGS. 2B-2D ). Binding was specific for light chain, since no binding was detected when beads were conjugated to bovine serum albumin (BSA). The process mentioned above is, of course, very much facilitated by the availability of the results of the genome project. Even very limited information of the sequence can currently be used to at least limit the number of candidate molecules. In many cases, even limited information on the sequence is sufficient to identify a single candidate molecule responsible for the binding to mast cells. Depending on the identified candidates, different methods can be utilized to prove that the molecule is the receptor.
[0009] For example, immunofluorescence microscopy has been used to show that FcRn is present intracellularly, as well as on the outside of the plasma membrane of K562 cells. Flow-cytometric analysis shows that K562 cells are able to bind human kappa Ig-LC. The presence of FcRn on the outside of the cell in combination with the ability to bind Ig-LC supports the proposed role of FcRn as the LC-receptor.
[0010] Yet another receptor present on mast cells of specific interest for binding Ig-LC is CD63, a transmembrane-4 (TM4) membrane protein. This receptor is expressed by, for example, mast cells, granulocytes and leucocytes and cross-linking of this receptor results in mast cell activation and mediator release.
[0011] CD63 is widely expressed on different mammalian cells. In mast cell studies, CD63 has been used as an activation marker, since expression is increased after degranulation. On the other hand, a study in human CD63-transfected rat basophilic cells showed cross-linking of CD63 resulted in mast cell activation and degranulation. Thus far, no ligand for CD63 has been described yet (i.e., orphan receptor).
[0012] Thus, in another aspect, the invention provides a purified and/or isolated and/or recombinant Ig-LC receptor like, for example, a CD63 receptor or an FcRn receptor, or a functional part, derivative and/or analogue thereof, capable of activating an Ig-LC-dependent signal transduction pathway in a cell, wherein activation is, for example, but not limited to, an ion channel, activation being independent of the presence of a functional gamma chain receptor on the cell. A functional part of an Ig-LC receptor is a part comprising the same Ig-LC-binding capabilities. A derivative of the mentioned receptor or part thereof, can be obtained through (conservative) amino acid substitution. A functional part, analogue and/or derivative comprises the same Ig-LC-binding capabilities in kind, not necessarily in amount. The functional part may also be incorporated in a proteinaceous molecule capable of binding to Ig-LC. The molecule may be incorporated in the wall of a mast cell or it may be in a soluble form like, for example, many receptors have a cell-bound form and a soluble form. Therefore, the invention also provides a proteinaceous compound capable of binding to Ig-LC and a mast cell, this compound comprising a FcRn receptor or a functional part thereof. The invention also teaches a proteinaceous compound capable of binding to Ig-LC and a mast cell, this compound comprising a CD63 receptor or a functional part thereof. Once a protein is identified, it is within the power of a person skilled in the art to provide a nucleic acid encoding the protein. Thus, the present invention also provides a nucleic acid encoding an Ig-LC receptor of the invention or a functional part, derivative and/or analogue thereof, capable of activating an Ig-LC-dependent signal transduction pathway in a cell. Expression vectors can be made and these can be introduced into target cells. Thus, these vectors are also part of the invention. For more efficient delivery, such vectors may be packaged into gene delivery vehicles such as, for example, virus or virus-like particles. Such virus or virus-like particles are, therefore, also part of the invention. The artisan is further capable of generating antibodies that are specific for the gamma chain-independent Ig-LC receptor.
[0013] With the knowledge of the gamma chain-independent Ig-LC receptor, it is possible to find compounds that, at least in part, inhibit the signal transduction pathway of the Ig-LC receptor, an example of such a compound is a molecule that competes with the binding of Ig-LC. This can, for instance, be done through molecular modeling or by high-throughput screening. Moreover, knowledge that Ig-LC is capable of binding to the receptor can be used to find competing molecules. Thus, the invention further provides a compound capable of, at least in part, inhibiting a signal transduction pathway of an Ig-LC receptor of the invention. Preferably, the compound comprises a molecule capable of competing with Ig-LC for binding to a gamma chain-independent Ig-LC receptor. Preferably, the compound comprises an antagonist capable of competing with Ig-LC for binding to a gamma chain-independent Ig-LC receptor. Competing molecules can be tested for their capacity to antagonize the action of an Ig-LC. Preferably, this testing comprises the degranulation of mast cells or an Ig-LC-dependent signal transduction pathway in a cell, more preferably independent of the presence of a functional immunoglobulin or gamma chain-associated receptor on the cell.
[0014] In another embodiment, the invention provides a method for determining whether a compound is capable of, at least in part, inhibiting signal transduction of a gamma chain-independent Ig-LC receptor comprising providing a gamma chain receptor-deficient cell comprising the receptor with the compound and determining whether Ig-LC-mediated signal transduction is, at least in part, inhibited in the cell. A suitable antagonist of Ig-LC is an Ig-LC mutated in the receptor binding site such that it is not able to activate the receptor any more. Thus, the invention provides a compound capable of interacting with an Ig-LC receptor capable of preventing the sensitizing of a mast cell. Preferably, this compound comprises an Ig-LC selected for its capacity not to elicit a signal transduction signal.
[0015] An antagonist can be used to prevent or reduce the sensitizing of a mast cell. Thus, the invention also provides a method for preventing or reducing the sensitizing of a mast cell comprising providing the mast cell with an Ig-LC antagonist. Preferably, the antagonist comprises a substance capable of binding to an Ig-LC receptor and incapable of binding an antigen or incapable of activating the receptor after binding an antigen.
[0016] Now that the receptor is found, it is also possible to manipulate the signal transduction pathway that the receptor is part of. This can be done most easily on the level of the receptor itself. It is, for instance, possible to provide libraries of mutated receptors. These libraries can be used to find a mutant that is capable of activating a mast cell, independent of the presence of a bound Ig-LC/antigen complex. Providing activators or antagonists, or even Ig-LC, one can manipulate activation of a mast cell. Thus, the invention also provides the use of an Ig-LC receptor to modulate a mast cell-activated immune response.
[0017] Clinical uses are also within the invention. For instance, an animal suffering or at risk of suffering from a hypersensitivity response can be administered a compound of the invention, thereby reducing the hypersensitivity response or reducing the chance and/or extent with which a hypersensitivity response will appear. In another embodiment, the invention provides a method for reducing a hypersensitivity response in an animal comprising providing the animal with a molecule capable of preventing binding of an Ig-LC to an Ig-LC receptor. The molecule can be a receptor antagonist of the invention. The molecule can also be a molecule capable of binding to an Ig-LC, thereby preventing binding of the bound Ig-LC to a gamma chain-independent receptor or binding of antigen by the receptor-bound Ig-LC. The latter molecule is, for the present invention, called an Ig-LC antagonist or ligand antagonist. The invention further provides an Ig-LC antagonist capable of preventing binding of an Ig-LC to a gamma chain-dependent receptor on mast cells. In one embodiment, a compound capable of, at least in part, inhibiting an Ig-LC signal transduction pathway comprises THP or uromodulin, or a functional part, derivative and/or analogue thereof. In a preferred embodiment, this compound comprises a peptide comprising an amino acid sequence (AHWSGHCCL) (SEQ ID NO:1), or a functional part, derivative, and/or analogue thereof.
[0018] For the present invention, a human is also considered to be an animal. In a preferred embodiment, the animal comprises a mammal. More preferably, the mammal comprises a human.
[0019] The invention further provides a use of a compound capable of, at least in part, inhibiting an Ig-LC signal transduction pathway, preferably an Ig-LC antagonist or a receptor antagonist, in the preparation of a medicament for the treatment of chronic inflammatory and autoimmune diseases and/or immediate and delayed hypersensitivity responses such as contact dermatitis, asthma, psoriasis, inflammatory bowel disease, rheumatoid arthritis, Sjögren, and systemic lupus erythematosus, and/or multiple sclerosis. Preferably, the medicament is formulated and packaged for parenteral and/or oral administration. Preferably, the compound comprises THP or uromoduline, or a functional part, derivative and/or analogue thereof. In a preferred embodiment, the compound comprises a peptide comprising an amino acid sequence (AHWSGHCCL) (SEQ ID NO:1), or a functional part, derivative, and/or analogue thereof.
[0020] The mentioned routes of administration allow the formation of a depot from which a new antagonist is recruited over time, thus allowing for a more prolonged effect of the medicament compared to an intravenous administration. The invention further provides a method of treatment for an animal suffering from, or at risk of suffering from, chronic inflammatory and autoimmune diseases and/or immediate or delayed hypersensitivity-like responses such as asthma, psoriasis, inflammatory bowel disease, rheumatoid arthritis, Sjögren, systemic lupus erythematosus, and/or multiple sclerosis. The method comprises administering to an animal a medicament comprising a compound of the invention such as an Ig-LC antagonist or a gamma chain-independent receptor antagonist and a suitable carrier. In a preferred embodiment, the disease comprises Multiple Sclerosis.
[0021] Free Ig-LC are produced and secreted by B lymphocytes and considerable levels of Ig-LC are present in serum. The present invention demonstrates that Ig-LC confer hypersensitivity in naive animals. Mice passively sensitized with trinitrophenol (TNP)- or oxazolone (Ox)-specific Ig-LC develop a cutaneous swelling response, have elevated plasma histamine and show morphologic signs of mast cell degranulation after challenge with relevant antigen. Induction of hypersensitivity is independent of presence of the common gamma chain, excluding a role for Fc- or other gamma chain-associated receptors. Hapten-specific Ig-LC is produced within 24 hours after topical sensitization with low-molecular weight compounds trinitrophenol chloride(2-chloro1,3,5 trinitrobenzene; picryl chloride (PCl)), 2,4-dinitrofluorobenzene (DNFB) or oxazolone by spleen cells from sensitized mice. Although it is clear that IgE and IgG 1 are central to the induction of immediate hypersensitivity reactions, the present invention shows that Ig-LC are similarly able to transfer hypersensitivity to naive animals. Free Ig-LC are an as yet unappreciated factor in the humoral immune response to antigen exposure and can, upon cross-linking, lead to mast cell-dependent immediate hypersensitivity-like reactions.
DESCRIPTION OF THE FIGURES
[0022] FIG. 1 : Ear swelling induced by cross-linking of Ig light chains is not dependent on Fc-receptors. Common gamma chain knockouts and control mice (C57B1/6) were passively sensitized with TNP-specific Ig light chain or vehicle (PBS). Ears were challenged with picryl chloride (TNP) and ear thickness was measured two hours later.
[0023] FIG. 2A : Quantification of binding of magnetic beads derivatized with albumin (BSA), Ig light chain plus BSA (to improve orientation of Ig light chain). Binding was scored using light microscopy and number of beads attached per cell is shown.
[0024] FIG. 2B : Microscopic visualization of binding Ig light chain-coupled magnetic beads to primary cultured murine bone marrow-derived mast cells (BMMC). BMMC incubated with beads coupled to BSA, showing minor degree of binding.
[0025] FIG. 2C : Ig light chain-derivatized magnetic beads showing clear rosetting of beads around intact cells.
[0026] FIG. 2D : Ig light chain-derivatized magnetic beads (Ig light chain+BSA to correct orientation of the light chains) showing clear rosetting of beads around intact cells.
[0027] FIGS. 3 A- 3 C: Expression of CD63 on COS fibroblast-like cells ( FIG. 3A ), a rat mast cell line RBL-2H3 ( FIG. 3B ) and primary cultured murine mast cells BMMC ( FIG. 3C ). Expression is detected by FACS with an antibody AD1 specific for CD63.
[0028] FIG. 4 : Mast cell dependency of hapten-induced ear swelling in Ig-LC-sensitized mice. Mast cell-deficient (W/W v ) or congenic controls (+/+) were intravenously sensitized with TNP-specific Ig light chain (5 mg). Thirty minutes after sensitization, mice were topically challenged with PCl and ear thickness was monitored at two hours after challenge. Ear swelling in W/W v significantly different from +/+, p<0.05. Local reconstitution of the right ear with bone marrow-derived mast cells in W/W v mice, three weeks prior to the experiment resulted in a complete recovery of the sensitivity to Ig light chain.
[0029] FIG. 5 : Electron micrograph of a mildly degranulated mast cell in the dermis of the ear of a TNP-specific Ig light chain-sensitized mouse at one hour after topical challenge with hapten. Numerous granules remain unaltered, some secretory granules are enlarged, exhibit diminished electron density and release their content (enlargement in b).
[0030] FIGS. 6 A and 6 B: Injection of TNP- or oxazolone-specific Ig light chain resulted in antigen-specific transfer of hapten sensitivity. Mice were intravenously injected with TNP-specific Ig light chain or oxazolone-specific Ig light chain and challenged on the ear with trinitrophenol chloride (PCl) (panel A) or oxazolone (Oxa) (panel B). Controls received vehicle (PBS) and were also topically challenged with both haptens. Ear swelling was measured two hours after challenge.
[0031] FIG. 7 : Mast cells sensitized with Ig light chain recognize antigen in a specific manner. TNP-specific Ig light chain-sensitized cultured mast cells (BMMC) were incubated with TNP- or oxazolone- (OX-) conjugated SRBC; rosetting cells were scored using light microscopy.
[0032] FIG. 8 : Antigen-specific Ig light chain is produced after in vivo skin sensitization with low-molecular weight compounds. Immunoblotting of antigen-binding factors specific for 2-chloro-1,3,5-trinitrobenzene (A), dinitrofluorobenzene (B) and oxazolone (C) with Ig kappa light chain-specific antibody.
[0033] FIG. 9 : Measurement of free kappa Ig light chains in human serum using an Ig kappa light chain-specific ELISA. Samples of six human subjects were analyzed at different dilutions (1000, 2000, and 10,000-fold diluted).
[0034] FIG. 10 : Intravenous administration of different amounts of F991 at 30 minutes before hapten challenge of Ig light chain-sensitized mice results in a dose-dependent inhibition of ear swelling after hapten challenge. Mice were i.v. sensitized with 2 μg TNP-specific Ig light chain at 30 minutes before ear challenge with TNP. Control mice were injected with PBS instead of Ig light chain.
[0035] FIG. 11 : Intraperitoneal administration of F991 (50 μg/animal) at four hours or 24 hours before hapten challenge of Ig light chain-sensitized mice completely inhibits induction of ear swelling after hapten challenge. Mice were i.v. sensitized with 2 μg TNP-specific Ig light chain at 30 minutes before ear challenge with TNP. Control mice were injected with PBS instead of Ig light chain.
[0036] FIG. 12 : Subcutaneous administration of F991 (50 μg/animal) at four hours or 24 hours before hapten challenge of Ig light chain-sensitized mice completely inhibits induction of ear swelling after hapten challenge. Mice were i.v. sensitized with 2 μg TNP-specific Ig light chain at 30 minutes before ear challenge with TNP. Control mice were injected with PBS instead of Ig light chain.
[0037] FIG. 13 : Topical application of F991 as an ointment on the ears results in dose-dependent inhibition of ear swelling after hapten challenge of Ig light chain-sensitized animals. Application of F991 at 100 μg/g cream corresponds with a local dose of 20 μg per animal.
[0038] FIG. 14 : Dorsal application (on back of mice) of F991 in ointment does not result in inhibition of ear swelling after hapten challenge of Ig light chain-sensitized animals.
[0039] FIG. 15 : F991 retains its activity when stored as an ointment at room temperature or at 4° C. for more than three months.
[0040] FIG. 16 : Topical treatment of DNFB-sensitized mice at four hours before hapten challenge results in complete inhibition of the development of contact sensitivity response as determined by ear swelling at two and 24 hours after challenge.
[0041] FIG. 17 : Topical treatment of DNFB-sensitized mice after hapten challenge results in decrease of the development of contact sensitivity response as determined by ear swelling four days after challenge.
[0042] FIG. 18 : Induction of EAE in MOG/pertussis toxin-treated mice is completely suppressed by daily administration of F991 (50 μg/animal i.p.).
[0043] FIG. 19 : Purification of Ig-LC-binding mast cell membrane proteins. Solubilized mast cell membrane fraction was sequentially incubated with albumin (BSA) end Ig-LC-coated beads as described in Example 2. Isolated proteins were fractionated on SDS-PAGE and visualized by silver staining. Arrow points to (glyco)protein of approximately 45 kDa, which is specifically purified with Ig-LC beads; * albumin (present in lanes 1 and 2); ** Ig-LC (present in lane 2).
[0044] FIG. 20 : RT-PCR was used to detect FcRn mRNA in several cell types. PCR was performed with 1 μl and 3 μl of cDNA per 50 μl reaction volume. Human cell line K562 was compared with duplicates of mouse BMMCs and PMCs. A plasmid containing cloned human FcRn cDNA was used as a positive control. The PCR reactions all resulted in DNA fragments that were estimated to have the correct size of 347 bp, as was judged from comparison with the DNA marker bands on the left.
[0045] FIG. 21 : Flow-cytometric analysis of K562 cells labeled with human kappa Ig-LC. Briefly, 10 5 cells were washed once in FACS-buffer and subsequently incubated without any antibody, or in the presence of 1 or 3 μg of fluorescein- (FITC-) labeled kappa Ig-LC monomers. The cells were washed once with FACS buffer (PBS/5% FCS/0.1% sodium azide) and analyzed on a FACS Calibur flow cytometer. The same shift in fluorescent intensity was obtained when FITC-labeled kappa Ig-LC dimers were used instead of the monomers.
[0046] FIG. 22 : Flow-cytometric analysis of human PMNs labeled with human kappa Ig-LC. Briefly, cells were incubated without any stimulus or in the presence of PMA (500 ng/ml, five minutes 37° C.) or fMLP (10 −7 M, ten minutes 37° C.). For every sample, 10 5 cells were washed once in FACS buffer and subsequently incubated without any antibody (no ab) or in the presence of 5 μg of fluorescein (FITC) labeled kappa Ig-LC (LC-FITC). The cells were washed once with FACS buffer (PBS/5% FCS/0.1% sodium azide) and analyzed on a FACS Calibur flow cytometer.
[0047] FIG. 23 : The interaction between soluble hFcRn and biotinylated kappa (κ1, κ2), lambda (λ) and IgG was studied in an ELISA. Binding of different Igs was tested at pH 7.4 (n=2).
[0048] FIG. 24 : Passive cutaneous anaphylaxis induced after local sensitization with Der p 2-specific light chains (filled symbols) followed by systemic challenge with (Der p 2-containing) house dust mite (HDM) extract. Ears were injected with PBS (open symbol) or Der p 2-specific light chains at 20 hours before intravenous injection with HDM extract. Ear thickness was measured 60 minutes after challenge.
[0049] FIG. 25 a: Passive cutaneous anaphylaxis induced after local sensitization with Der p 2-specific light chains (filled symbols) followed by systemic challenge with recombinant Der p 2 protein. Ears were injected with PBS (open symbol) or Der p 2-specific light chains (closed symbols) at 20 hours before intravenous injection with recDer p 2. Ear thickness was measured 60 minutes after challenge.
[0050] FIG. 25 b: Pretreatment with F991 (50 microgram i.p. at four hours before challenge) prevents development of ear swelling in Der p 2-induced passive anaphylaxis. Ears were injected with PBS (open symbol) or Der p 2-specific light chains at 20 hours before challenge by intravenous injection of recombinant Der p 2 protein. Four Hours before challenge, mice received 50 micrograms F991 intraperitoneally. Ear thickness was measured 60 minutes after challenge.
DETAILED DESCRIPTION OF THE INVENTION
[0051] In one aspect, the invention provides evidence for a novel role for free Ig-LC. We show that Ig-LC transfer hapten sensitivity into naive animals and subsequent antigen challenge elicits an immediate hypersensitivity-like response, which appears to be mast cell dependent.
[0052] Mast cells have been implicated in a wide variety of biological responses including immediate hypersensitivity reactions, bacterial sepsis and also in T-cell-dependent reactions such as contact hypersensitivity reactions, experimental autoimmune encephalomyelitis (EAE), or non-allergic asthma. The diseases like contact sensitivity, EAE and non-allergic asthma can be induced by local delayed-type hypersensitivity (DTH) reactions and are independent of IgE or IgG1. Studies in mast cell-deficient animals show that mast cells are crucial in orchestrating a full DTH response. Humoral factors released by B-cells seem important in contact hypersensitivity reactions since hypersensitivity is impaired in B-cell-deficient animals. In ongoing studies, we have found that TNP-specific Ig-LC are capable of rescuing impaired contact hypersensitivity reactions as a result of hapten application in B-cell-deficient mice. In addition, passive sensitization with Ig-LC can give rise to a rapid and profound airway bronchoconstriction in mice after intra-airway antigen challenge, a reaction dependent on mast cell activation. Importantly, Ig-LC are involved in delayed-type hypersensitivity reactions leading to bronchoconstriction, cellular influx in bronchoalveolar lavage, and airway hyper reactivity after active sensitization with low-molecular weight compounds followed by intranasal challenge (manuscript in preparation). It is of interest that the secretion of Ig-LC is augmented under pathological conditions such as multiple sclerosis, Sjögren's disease, systemic lupus erythematosus, and other neurological disorders (18-21). For example, production of Ig-LC in patients with multiple sclerosis is greatly enhanced (20, 22). This production of Ig-LC is associated with recent antigenic stimulation and correlates with severity of the disease. In concord with our hypothesis, it has been demonstrated that mast cells play an important role in the pathogenesis of MS or EAE; substantially reduced disease symptoms are found in mast cell-deficient animals.
EXAMPLES
Example 1
Ig-LC do not Activate Gamma Chain-Associated Receptors
[0053] From our studies, it is clear that mast cells are crucial for the development of acute responses in skin and airways leading to ear swelling and acute bronchoconstriction, respectively. Thus far, triggering the high-affinity IgE receptor (FcεRI) and the low-affinity IgG-receptor (FcγRIII) are the only routes known to activate mast cells in an antigen-specific manner. We investigated whether Ig-LC exerted their action via activation of the FcγRIII or FcεRI receptors. Both receptors signal via the common gamma chain and can trigger hypersensitivity reactions via activation of mast cells. Passive sensitization of animals deficient in the common gamma chain (FcRγ−/−) resulted in similar ear swelling responses after hapten challenge as compared to wild-type (C57BL/6) animals ( FIG. 1 ). This indicates that Ig-LC interacts with a receptor that does not need the common gamma chain for signaling and thereby excludes FcεRI and FcγRIII but also other gamma chain-associated receptors such as PIR-A and -B as effector molecules in Ig-LC-induced hypersensitivity reactions. Preliminary experiments showed that Ig-LC bind to mast cells and recognize antigen in rosetting assays with hapten-conjugated red blood cells. FACS analysis indicated that both IgE and IgG1 do not compete with the binding of Ig-LC to murine bone marrow-derived mast cells, confirming our results in the FcRγ−/− mice. Various attempts to directly activate murine bone marrow-derived mast cells in vitro to release prestored mediators after cross-linking of surface-bound Ig-LC were not successful. Although in some experiments a significant degree of degranulation was found, results were highly variable. The latter may be explained by a possible lack of co-stimulatory factor in vitro, a maturation-dependent expression of cell surface proteins involved in Ig-LC-mediated activation, or the simultaneous presence of inhibitory and activator receptors.
Example 2
Biochemical Isolation and Purification of Ig-LC Receptor
[0054] Chemical cross-linking of ligand to cellular membrane was the method employed to isolate and identify cell surface proteins as putative receptors for various ligands. Magnetic beads were coupled to Ig-LC. These beads were then incubated with murine bone marrow-derived mast cells and after washing the cells, Ig-LC (bait) were chemically cross-linked to cell surface proteins in immediate proximity to the binding site. After lysing the cells, Ig-LC cross-linked cell surface proteins were separated from non-bound proteins using a magnetic device. Proteins were washed and separated using SDS-PAGE (1-D or 2-D), followed by silver staining. Proteins were further characterized and identified with Maldi-TOF mass spectrometry and/or Edman degradation. Binding of Ig-LC-conjugated magnetic beads coupled to mast cells were visualized by light microscopy. Binding was specific for light chain, since no binding was detected when beads were conjugated to bovine serum albumin (BSA) ( FIGS. 2A-2D and 19 ).
Example 3
Expression Cloning of the Ig-LC Receptor
[0055] Expression cloning was used to clone an Ig-LC receptor. A cDNA library from primary cultured murine mast cells (BMMC) was constructed. This cDNA was transfected into mammalian cells. Transfected cells were compared in their binding capacity for Ig-LC using a flow cytometer. Cells binding Ig-LC above background were collected by the FACS sorter. Transfected DNA from these cells were isolated and used for succeeding transfection rounds. After several transfection/sorting rounds, a single Ig-LC receptor-expressing cell population was isolated. The transfected DNA from this population encodes for the putative Ig-LC receptor. A receptor present on mast cells of specific interest for binding Ig-LC is CD 63, a transmembrane-5 (TM5) membrane protein. This receptor is expressed by, for example, mast cells, granulocytes and leucocytes and cross-linking of this receptor results in mast cell activation and mediator release. FACS experiments showed the presence of CD63 on mast cell line RBL-2H3, but not on COS cells ( FIG. 3 ).
[0056] CD63 seems widely expressed on different mammalian cells. In mast cell studies, CD63 has been used as an activation marker, since expression is increased after degranulation. On the other hand, a study in human CD63-transfected rat basophilic cells showed cross-linking of CD63 results in mast cell activation and degranulation. Thus far, no ligand for CD63 has been described yet (i.e., orphan receptor).
[0000] Ig Light Chain Receptor Binding Study:
[0057] In our current studies, we have shown that Ig light chain-mediated hypersensitivity responses can be effectively blocked by a 9-mer peptide (AHWSGHCCL). This peptide binds free light chains and thus prevents binding of the light chain to its receptor. It is, therefore, likely that the prominent binding sequence of this peptide, which is determined by the CCL part of the peptide, is present in the receptor for this ligand. Sequence analysis revealed that a sequence CCL or CCI is conserved in TM4 proteins such as CD63. Importantly, this sequence is present in an extracellular loop of the protein and, therefore, a putative docking site for receptor ligands. CD63 is the most likely candidate of this TM4 family because of its known expression in mast cells and its demonstrated capability to activate mast cells.
Example 4
Role of Mast Cells in Ig-LC Responses
[0058] The involvement of mast cells in eliciting ear swelling responses after topical challenge of Ig-LC-sensitized mice was investigated using mast cell-deficient mice (W/Wv). As shown in FIG. 4 , passive sensitization of mast cell-deficient mice with TNP-specific Ig-LC followed by topical application of TNP did not result in a significant ear swelling at two hours after challenge. As expected, similarly treated control mast cell-sufficient littermates (+/+) showed normal ear swelling responses. To further prove that the absence of mast cells alone was responsible for the completely reduced ear swelling response in the mast cell-deficient mice, we reconstituted these animals with bone marrow-derived mast cells from wild-type animals. Reestablishment of the mast cell population by local injection of bone marrow-derived mast cells restored the ear swelling responses in Ig-LC-sensitized and hapten-challenged animals ( FIG. 4 ).
[0059] Indeed, hapten challenge of Ig-LC-sensitized animals was accompanied with a rapid increase in plasma histamine levels in vivo and direct proof for mast cell activation was obtained after histological and ultrastructural analysis of biopsies of the ears at one hour after topical hapten challenge. Mast cells in tissue sections of mice intravenously sensitized with TNP-specific Ig-LC showed marked signs of degranulation after re-exposure to hapten. Electron microscopy revealed that degranulation was characterized by swelling of intracytoplasmic granules, decrease of electron-density of the granules and extrusion of membrane-free granules from the mast cells ( FIG. 5 ).
Example 5
Specific Recognition of Antigen by Ig-LC
[0060] In general, it is acknowledged that both heavy chains and light chains contribute to binding of antigens by immunoglobulins, which are monomers or multimers of a tetrameric structure consisting of two light chains and two heavy chains. The structure of an Ig-LC can be separated in a constant and variable region. The latter region contains hypervariable domains (CDRs) that are responsible for antigen recognition. The genes encoding these regions undergo rearrangement/mutation to effect affinity maturation and gain specificity for a certain antigen. Similar mechanisms play a role in shaping the antigen recognition by Ig heavy chains.
[0061] In order to prove that free Ig-LC have the capability to recognize and bind to antigen, we have performed the following experiments. First, two Ig-LCs with different antigen specificity were generated by separation of immunoglobulin heavy and light chains from oxazolone- and TNP-specific IgGs. Naive mice were sensitized with the isolated Ig-LC and subsequently topically challenged with TNP or oxazolone. Two hours after challenge, ear thickness was measured. As shown in FIG. 6 , when mice were sensitized with oxazolone-specific Ig-LC, only an increase in ear thickness was measured when the ears were challenged with oxazolone and not after application of picryl chloride, i.e., TNP. Vice versa, when animals were sensitized with TNP-specific Ig-LC, ear swelling was only induced by TNP and not by oxazolone.
[0062] In a second experiment, we investigated if Ig-LC, when bound to mast cells, is able to recognize antigen in a proper way. In in vitro experiments, bone marrow-derived mast cells were sensitized with TNP-specific Ig-LC. Next, sensitized cells were co-incubated with either unlabeled, TNP-labeled or oxazolone-labeled sheep red blood cells (SRBC). Binding (resetting) of the SRBC was scored under a light microscope. As evidenced in FIG. 7 , TNP-specific Ig-LC-sensitized mast cells only show significant binding to TNP-labeled SRBC, but not to unlabeled or with an unrelated hapten (OX)-coupled SRBC. This experiment confirms that Ig-LC are indeed able to specifically recognize antigen.
Example 6
Production of Ig-LC After Contact Sensitization of Mice
[0063] Induction of immediate hypersensitivity by Ig-LC may be physiologically relevant. Ig-LC are produced and secreted upon antigen exposure. To test this hypothesis, spleen and lymph node cells from mice that had been sensitized epicutaneously to PCl, DNFB or oxazolone four days before, were cultured in vitro for one day in the absence of hapten. Hapten-binding proteins from culture supernatant were isolated by hapten-affinity chromatography. Western analysis showed that the hapten-binding factors obtained this way contained Ig kappa light chain ( FIG. 8 ), but no Ig heavy chains were detected (data not shown). Importantly, TNP-binding factor could be isolated from culture supernatant of spleen and lymph node cells isolated from mice as early as one day after topical sensitization with PCl. In this preparation, the presence of Ig-LC was confirmed by Western blot analysis (data not shown). The N-terminal amino acid sequence of this protein showed almost complete homology with mouse Ig kappa light chain.
Example 7
Measurement Ig-LC in Human Serum
[0064] Free Ig-LC can be detected in various human body fluids, e.g., liquor, urine and serum. Using an Ig-LC-specific ELISA, we were able to detect significant levels of Ig-LC in serum ( FIG. 9 ). The detected levels are comparable to those reported earlier by other groups.
Example 8
Effects of F991, an Ig-LC-Binding Peptide
[0065] F991 is developed as an antagonist of Ig light chain. The working hypothesis for this compound is that it binds to Ig light chains and thereby prevents binding of light chains to their putative receptors. F991 is a 9-mer peptide derived from the endogenous protein uromodulin. The potency of F991 to inhibit Ig-LC-induced cutaneous reactions (ear swelling responses) was studied. Our working hypothesis for this compound is that it is an antagonist of Ig-LC and binds to Ig-LC and thereby prevents binding of Ig-LC to their putative receptors. F991 was administered in different dosages, via various administration routes.
[0066] A. Dose-Dependent Inhibition After Intravenous Administration.
[0067] Indicated amounts of F991 per mouse were intravenously injected at 30 minutes before hapten challenge. At that same time point, mice were injected (passively sensitized) with TNP-specific Ig-LC or vehicle (PBS). Two hours after hapten challenge, increase in ear thickness was monitored. FIG. 10 shows a clear dose-dependent inhibition of the ear swelling response by F991. Amounts of 2 μg per mouse (1.9 nmole!!) were sufficient to completely block the Ig-LC-induced ear swelling ( FIG. 10 ).
[0068] B. Other Administration Routes: Intraperitoneal Administration of F991
[0069] Mice were injected with 50 μg of F991 intraperitoneally at four or 24 hours before challenge with hapten. Thirty minutes before challenge, the animals were passively (i.v.) sensitized with TNP-specific Ig-LC and two hours after hapten application onto the ears, ear thickness was measured. As demonstrated in FIG. 11 , i.p. administration of F991, even at 24 hours before hapten challenge, completely prevented the induction of an ear swelling response ( FIG. 11 ).
[0070] C. Subcutaneous Administration of F991
[0071] Protocol (see above) for i.p. administration, except F991, was injected subcutaneously.
[0072] Similar to the i.p. administration of F991 when injected subcutaneously, F991 again completely inhibited Ig-LC-induced ear swelling after hapten challenge ( FIG. 12 ).
Example 9
Epicutaneous Application of F991 (in Ointment)
[0073] A. F991 was prepared as an ointment in Cremor Cetomacrogolis FNA and topically applied on the ear at four hours before hapten challenge. Subsequently, mice were passively sensitized with 2 μg TNP-specific Ig-LC at 30 minutes before and ear thickness was measured two hours after hapten challenge of the ears. As shown in FIG. 13 , topical application of F991 in an ointment resulted in a dose-dependent inhibition of the ear swelling induced after hapten challenge of Ig-LC-sensitized animals ( FIG. 13 ).
[0074] B. We further investigated if local application of F991 as an ointment resulted in systemic inhibition of the Ig-LC-induced effects. Therefore, F991 was applied on the back of the mice instead of at the site of hapten challenge (ear). Mice were again sensitized and challenged as described above. FIG. 14 shows that topical application of F991 does not result in systemic inhibition of the Ig-LC effects. This means that epicutaneous treatment should be done at the site of challenge ( FIG. 14 ).
[0075] C. Stability of F991 in Ointment
[0076] To determine the stability of F991 in ointment, different preparations of F991 in Cremor Cetamacrogolis FNA were tested for their activity after storage for two to three months at room temperature and at 4° C. The different preparations were applied at the ear as described in A (above) and subsequently, ear swelling was monitored after hapten challenge of Ig-LC-sensitized animals. As shown in FIG. 15 , F991 stored under all different conditions retained its activity ( FIG. 15 ).
[0077] D. Next, we investigated if topical treatment with F991 also inhibited the development of contact sensitivity reactions induced after active sensitization. Mice were sensitized with a low-molecular weight compound DNFB on the skin and footpads (on day 0 and 1). Five days after the start of sensitization and four hours before local challenge with hapten, mice were treated with F991 on the ears. Two and 24 hours after hapten challenge, the increase in ear thickness was determined. As shown in FIG. 16 , topical treatment with F991 completely inhibited the ear swelling at both two and 24 hours after challenge. This experiment indicates that topical treatment with F991 may be of therapeutic use in the treatment of contact dermatitis, a disease with similar characteristics ( FIG. 16 ).
[0078] E. Next, we investigated if topical treatment with F991 also inhibited or decreased the development of contact sensitivity reactions induced after active sensitization. Mice were sensitized with a low-molecular weight compound DNFB on the skin and footpads (on day 0 and 1). Five days after the start of sensitization and two hours after local challenge with hapten, mice were treated with F991 on the ears. Ear swelling was measured 22 hours after application of the cream. Subsequently, mice were treated daily with the F991 cream, two hours after measuring of the ear swelling. Control mice were treated with the vehicle cream without F991. Two, 24, 48, 72 and 96 hours after hapten challenge, the increase in ear thickness was determined. As shown in FIG. 17 , topical treatment with F991 diminished the ear swelling at all time-points after two hours after challenge. This experiment indicates that topical treatment with F991 may be of therapeutic use in the treatment of contact dermatitis, a disease with similar characteristics.
Example 10
Ig-LC, Mast Cells and Multiple Sclerosis
[0079] It is well documented that production of Ig-LC in patients with multiple sclerosis is greatly enhanced. Elevated levels of free Ig-LC can be detected in cerebrospinal fluid and urine of MS patients. This production of free Ig-LC is associated with recent antigenic stimulation and correlates with the severity of the disease. In concord with our hypothesis, it has been demonstrated that mast cells play an important role in the pathogenesis of MS; substantially reduced disease symptoms are found in mast cell-deficient animals (23). Further, mast cells are observed in CNS plaques, and histamine and tryptase levels are elevated in the liquor of MS patients, whereas treatment with mast cell stabilizers or antagonists of histamine and serotonin seem to ameliorate MS.
[0080] If light chains were involved in the activation of mast cells in patients with MS, the prediction is that F991 may be of therapeutic interest in the treatment of MS. We tested to see if F991 was able to prevent or reduce development of clinical signs in an established mouse model for MS, i.e., myelin oligodendrocyte glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE). Mice were sensitized with antigenic peptide 35-55 from MOG in complete freund adjuvant. At the day of sensitization and three days later, mice also received an injection with pertussis toxin. In general, ten to twelve days after the start of sensitization, mice developed clinical signs of MS, which can be scored in degree of paralysis (0=no paralysis, 1=tail flaccidity, 2=hind limb weakness, 3=hind limb paralysis, 4=forelimb paralysis or loss of ability to right supine, 5=death). To investigate if F991 is able to prevent development of clinical signs of MS, mice were daily injected with 50 μg F991/animal i.p. starting at day −1 until day 21. As shown in FIG. 18 , treatment with F991 completely prevented the development of clinical signs of paralysis. Control mice developed disease with a mean day of onset of 11.8 and a mean clinical score of 2.3. There was a significant difference in disease burden (mean cumulative EAE score) between the F991-treated group (mean 4.2) and the control group (mean 18.3). Termination of the treatment with F991 at 21 days after sensitization, resulted in the development of some minor clinical symptoms (“silly walk”), but not in a clear manifestation of EAE/MS (data not shown) ( FIG. 18 ).
Example 11
FcRn Receptor Binding to Ig-LC
[0000] 1. Expression of FcRn in Mouse Mast Cells
[0081] A RT-PCR reaction was performed to detect FcRn mRNA in mouse bone marrow-derived mast cells (BMMC) and pulmonary mast cells (PMC).
[0000] Method
[0082] TRIzol reagent (Gibco) was used to isolate total RNA from four-week-old BMMCs and PMCs and cultured K562 erythroleukemia cells. The RNA isolations and subsequent amplification steps from BMMCs and PMCs were performed as duplicates. First strand cDNA was synthesized from 1.6 μg total RNA by using SuperScript reverse transcriptase (Invitrogen) and an oligo dT primer. PCR reactions were done with 1 μl and 3 μl of first strand cDNA per 50 μl reaction volume. The forward and reverse primers for the PCR reactions had the following DNA sequences, respectively: CCTGCTGGGCTGTGAACTGG (SEQ ID NO:2) and GCTCCGGDGGGTAGAAGGAG (SEQ ID NO:3). Using these primers, a DNA fragment of 347 basepairs (bp) was expected to be amplified from both mouse and human sequences. DNA sequences were run on 1.5% agarose gels and visualized by ethidium bromide staining.
[0000] Results
[0083] The main amplified DNA fragment that was obtained after doing the RT-PCR reaction on the RNA isolated from BMMCs, PMCs, K562 cells, and a control plasmid that contained cloned human FcRn cDNA as an insert, had the expected size of approximately 347 bp ( FIG. 20 ). The results indicate that mRNA encoding FcRn is present in PMCs as well as in the BMMCs, although the concentration in BMMCs is a little higher. In K562 cells, even more amplification product was obtained, suggesting that these cells express relatively high levels of FcRn.
[0000] Conclusions
[0084] It should be noted that these experiments are not conclusive about the mRNA expression levels, since no household mRNA level has been determined to ensure that equal amounts of cDNA have been added to each PCR reaction. However, the experiments confirm the presence of FcRn mRNA in mouse BMMCs and PMCs.
[0000] 2. Presence of FcRn on the Outside of Mast Cells
[0085] From literature, it is known that expression of FcRn in cells does not guarantee the presence of the protein on the outside of the cell. The co-expression of β-2-microglobulin is required to transport FcRn to the plasma membrane. The lack of an antibody against mouse FcRn kept us from confirming the presence of FcRn on the outside of the BMMCs.
[0086] Immunofluorescence microscopy has been used to show that FcRn is present intracellularly, as well as on the outside of the plasma membrane of K562 cells. Flow-cytometric analysis shows that K562 cells are able to bind human kappa Ig-LC ( FIG. 21 ). The presence of FcRn on the outside of the cell in combination with the ability to bind Ig-LC is still in agreement with the proposed role of FcRn as the LC-R, although it does not prove this.
[0087] Flow cytometry was also used to show binding of Ig-LC to freshly isolated human neutrophils (PMNs) ( FIG. 22 ). This binding was enhanced after stimulation of PMNs by PMA or fMLP. It is known from literature that most FcRn is present in intracellular vesicles, which fuse with the plasma membrane after stimulation. This finding again matches with the proposed role of FcRn as the LC-R, but does not prove it.
[0000] 3. Interaction Between FcRn and Ig-LC
[0088] An ELISA was used to study a possible interaction between human FcRn (hFcRn) and human κ-Ig-LC.
[0000] Method
[0089] Two different types of human κ-Ig-LCs (κ1 and κ3), a λ-Ig-LC, and a mixture of IgGs were chemically linked to biotin. The Igs were dissolved in PBS at a concentration of 1 mg/ml. The Ig-LCs were incubated in the presence of 426 μg/ml EZ-link Sulfo-NHS-LC-Biotin (Pierce) at room temperature in the dark for 90 minutes. The reaction of the IgGs was performed with 220 μg/ml biotinylation agent for 30 minutes. The labeled Igs were dialyzed against PBS for 12 hours. An ELISA plate was coated with 100 ng/ml recombinant soluble hFcRn (a kind gift of P. Bjorkman) in PBS for 15 hours at 4° C. Blocking of the plate was done with 1% BSA in PBS/0.5% Tween-20 for 60 minutes at room temperature, followed by three washes with washing buffer (PBS containing 0.05% Tween-20). The plate was incubated with various amounts of biotinylated Igs in assay buffer (washing buffer with 0.1% BSA) for 60 minutes at room temperature. After three washes, the plate was incubated with Streptavidin Poly-HRP (100 ng/ml in assay buffer) for 30 minutes, followed by six washes. The plate was assayed with o-phenylenediamine according to the protocol of the manufacturer.
[0000] Results
[0090] Several ELISA experiments showed a significant binding of Ig-LCs and IgG to the hFcRn. An example is shown in FIG. 22 . No binding was seen when the hFcRn was omitted from the coating reaction, suggesting that the interaction is specific (not shown). The amount of signal differs between the Igs, but this is not conclusive since the biotinylation efficiency of each sample has not been determined. However, there are some differences in the shape of the binding curves, with IgG and κ3 reaching a plateau at lower protein concentrations than κ1 and λ. It should be noted that, despite the observed specificity, there were no differences in binding between incubations at pH 7.4 or 6.5 (not shown). This contradicts findings in literature, where several groups independently showed binding of IgG at pH 6.5, but not at pH 7.4.
[0000] Conclusion
[0091] In the described ELISA setup, a significant binding of Ig-LCs to hFcRn was shown. However, further research using another experimental method will be required to confirm and validate this observation.
Example 12
Clinical Safety Study of a Phase 1 Single, Rising Dose, Double-Blind, Placebo-Controlled Study with F991 in Healthy Male Volunteers
[0000] Summary:
[0000] Objectives
[0092] Primary objective: to study the safety and tolerability of F991 at increasing single dose levels in healthy male volunteers
[0093] Secondary objective: to study the pharmacokinetics of F991 in healthy male volunteers
[0094] Tertiary objective: to study the pharmacodynamics of F991 in healthy male volunteers (exploratory)
[0000] Methodology
[0095] Design: This study was a double-blind, placebo-controlled, single rising dose study in two alternating panels of eight healthy male volunteers. In each panel, two volunteers received placebo throughout the study and the other six volunteers received three increasing single doses of F991.
[0000] Procedures and Assessments
[0096] Screening and follow-up: clinical laboratory, full physical examination, ECG; at eligibility screening: medical history, drug screen including alcohol, HBsAg, anti-HCV and anti-HIV 1/2
[0097] Observation period: each period in clinic from −17 hours prior to drug administration up to 24 hours after drug administration
[0098] Blood sampling:
for pharmacokinetics: for total plasma F991:
panel I period 1: pre-dose and at 5, 10, 15, 20, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose panel I period 2 and panel II periods 1 and 2: pre-dose and at 15, 30, 35, 40 and 50 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose panel I period 3: pre-dose and at 15, 30, 45, 50, 55 and 65 minutes and 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose panel II period 3: pre-dose and at 15, 30, 55, 60 and 65 minutes and 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose
for pharmacodynamics: tryptase and Ig-LC (Immunoglobulin Light Chains) pre-dose and one hour and eight hours post-dose
[0105] Safety assessments: vital signs; adverse events (including eyesight); ECG four times each period; clinical laboratory: on admission for each period
[0106] Bioanalysis: by Sponsor
[0000] Volunteers
[0107] 16 healthy male volunteers
[0000] Diagnosis and Main Criteria for Inclusion
[0108] Age: 18-55 yr, inclusive
[0109] Weight: within ±15% deviation from normal range, from 60 to 100 kg, inclusive
[0110] Gender: male
[0000] Study Medication
[0111] Active substance: F991
[0112] Activity: immunomodulating peptide
[0113] Indication: RA, asthma, inflammatory diseases
[0114] Strength: freeze-dried material (8.4 mg) to be reconstituted with 10 mL water/0.9% NaCl: 0.84 mg F991-peptide/mL, 10 mM citrate pH 5, 2.25% mannitol, 0.45% NaCl
[0115] Dosage form: iv infusion
[0116] Placebo: visually matching active substance
[0117] The following treatments were administered, as a single dose in alternating panels, according to the randomization schedule.
[0118] Panel I: period 1: 0.08 mg/kg F991 or placebo iv infusion
period 2: 0.8 mg/kg F991 or placebo iv infusion period 3: 3.2 mg/kg F991 or placebo iv infusion
[0121] Panel II: period 1: 0.32 mg/kg F991 or placebo iv infusion
period 2: 1.6 mg/kg F991 or placebo iv infusion period 3: 6.4 mg/kg F991 or placebo iv infusion
Criteria for Evaluation
[0124] Safety: adverse events, clinical laboratory test results, ECG recordings, vital signs and physical examination
[0125] Pharmacokinetics: pharmacokinetic parameters derived from F991 plasma concentration-time data are: C max , t max , k el , t 1/2 , AUC last , AUC 0-inf , CL and V d
[0126] Pharmacodynamics: pharmacodynamic parameters of tryptase and Ig-LC concentrations
[0000] Statistical Methods
[0127] Safety parameters: descriptive statistics
[0128] Pharmacokinetics parameters: descriptive statistics
[0129] Pharmacodynamic parameters: descriptive statistics
[0000] Results and Conclusions
[0130] No correlation was observed between the dose of F991 and the number, frequency and intensity of AEs. There were no SAEs during the study. All possibly related AEs were of mild intensity, except one, which was a headache of moderate intensity that lasted about 14.5 hours and required treatment with a single dose of 500 mg paracetamol. The most frequently reported AE with a possible relationship to the study drug was headache, however, this occurred mainly in the placebo group. For volunteers on active drug, the most frequently reported AEs were eye disorders. With regard to clinical laboratory data, vital signs, ECG and physical examination, no clinically significant abnormalities were observed. I.V. administration of single rising doses up to 6.4 mg/kg of F991 was safe and well tolerated in healthy male volunteers.
Example 13
The Effect of F91 1 on Allergen Reaction to House Dust Mite in Mice
[0131] Next, we investigated if topical treatment with F991 also inhibited the development of contact sensitivity reactions induced after passive sensitization with house dust mite allergen Der p 2-specific IG-LC. Mice were sensitized with a Der p 2-specific IG-LC in the ear skin. Sixteen hours after sensitization and four hours before systemic challenge with house dust mite extract or recombinant Der p 2, mice were treated with F991 on the ears. Sixty minutes after allergen challenge, the thickness of the ear was determined. As shown in FIGS. 24 and 25 , topical treatment with F991 completely inhibited the ear swelling 60 minutes after challenge. This experiment shows that topical treatment with F991 may be of therapeutic use in the treatment of, for example, cutaneous anaphylaxia and contact dermatitis.
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[0143] 11. Mahana, W., F. Jacquemart, and M. Ermonval. A murine monoclonal multireactive immunoglobulin kappa light chain. Scand. J. Immunol. 39(1):107-10 (1994).
[0144] 12. Ledbetter, J. A., H. P. Fell, L. S. Grosmaire, N. A. Norris, and T. T. Tsu. An immunoglobulin light chain dimer with CD4 antigen specificity. Mol. Immunol. 24(12):1255-61 (1987).
[0145] 13. Schechter, I., and E. Ziv. Binding of 2,4-dinitrophenyl derivatives by the light chain dimer obtained from immunoglobulin A produced by MOPC-315 mouse myeloma. Biochemistry 15(13):2785-90 (1976).
[0146] 14. Painter, R. G., H. J. Sage, and C. Tanford. Contributions of heavy and light chains of rabbit immunoglobulin G to antibody activity. I. Binding studies on isolated heavy and light chains. Biochemistry 11(8):1327-37 (1972).
[0147] 15. Tribbick, G., A. B. Edmundson, T. J. Mason, and H. M. Geysen. Similar binding properties of peptide ligands for a human immunoglobulin and its light chain dimer. Mol. Immunol. 26(7):625-35 (1989).
[0148] 16. Thiagarajan, P., R. Dannenbring, K. Matsuura, A. Tramontano, G. Gololobov, and S. Paul. Monoclonal antibody light chain with prothrombinase activity. Biochemistry 39(21):6459-65 (2000).
[0149] 17. Sun, M., Q. S. Gao, L. Li, and S. Paul. Proteolytic activity of an antibody light chain. J. Immunol. 153(11):5121-6 (1994).
[0150] 18. Fagnart, O. C., C. J. Sindic, and C. Laterre. Free kappa and lambda light chain levels in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. J. Neuroimmunol. 19(1-2):119-32 (1988).
[0151] 19. Moutsopoulos, H. M., A. D. Steinberg, A. S. Fauci, H. C. Lane, and N. M. Papadopoulos. High incidence of free monoclonal lambda light chains in the sera of patients with Sjögren's syndrome. J. Immunol. 130(6):2663-5 (1983).
[0152] 20. Solling, K., J. Solling, and F. K. Romer. Free light chains of immunoglobulins in serum from patients with rheumatoid arthritis, sarcoidosis, chronic infections and pulmonary cancer. Acta. Med. Scand. 209(6):473-7 (1981).
[0153] 21. Lamers, K. J., J. G. de Jong, P. J. Jongen, M. J. Kock-Jansen, M. A. Teunesen, and E. M. Prudon-Rosmulder. Cerebrospinal fluid free kappa light chains versus IgG findings in neurological disorders: qualitative and quantitative measurements. J. Neuroimmunol. 62(1):19-25 (1995).
[0154] 22. Mehta, P. D., S. D. Cook, R. A. Troiano, and P. K. Coyle. Increased free light chains in the urine from patients with multiple sclerosis. Neurology 41(4):540-4 (1991).
[0155] 23. Secor, V. H., W. E. Secor, C. A. Gutekunst, and M. A. Brown. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191(5):813-22 (2000). | Immunoglobulin light chains (Ig-LC) are produced in excess in animals compared to heavy chains. The present invention implicates Ig-LC in hypersensitivity responses and provides ways for manipulating the responses. The invention further provides a common gamma chain-independent receptor on mast cells capable of mediating the mentioned effects of Ig-LC. In response to activation of the pathway of which the found receptor is a part, a mast cell is activated and stimulated to degranulate. | 2 |
TECHNICAL FIELD
[0001] The present invention relates to a homogeneous catalytic system for use in preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin, and more particularly to a Group 4 transition metal catalyst in which a cyclopentadienyl derivative 3,4-positions of which are substituted with alkyls and an electron-donating substituent are crosslinked around the Group 4 transition metal. In addition, the present invention relates to a catalytic system comprising such a transition metal catalyst and a co-catalyst including one or more selected from among aluminoxane and a boron compound and to a method of preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin using the same.
BACKGROUND ART
[0002] Conventional ethylene homopolymers or copolymers with α-olefin have been typically prepared using so-called a Ziegler-Natta catalytic system comprising a titanium or vanadium compound as a main catalyst and an alkylaluminum compound as a co-catalyst. Although the Ziegler-Natta catalytic system is highly active for ethylene polymerization, it has non-uniform active sites, so that the produced polymer has a wide molecular weight distribution, and, in particular, the composition distribution is not uniform in copolymerization of ethylene and α-olefin.
[0003] Recently, there has been developed a metallocene catalytic system composed of a metallocene compound of Group 4 transition metal of the periodic table, such as titanium, zirconium, hafnium, etc., and a co-catalyst such as methylaluminoxane. Because the metallocene catalytic system is a homogeneous catalyst having single active sites, it enables the preparation of polyethylene having a narrower molecular weight distribution and a more uniform composition distribution, compared to when using the conventional Ziegler-Natta catalytic system. For example, EP Patent Application Publication Nos. 320,762 and 3,726,325, Japanese Patent Laid-open Publication No. Sho. 63-092621, and Japanese Patent Laid-open Publication Nos. Hei. 02-84405 and 03-2347 disclose a metallocene compound such as Cp 2 TiCl 2 , Cp 2 ZrCl 2 , Cp 2 ZrMeCl, Cp 2 ZrMe 2 , ethylene(IndH 4 ) 2 ZrCl 2 , etc., which is activated with a methylaluminoxane co-catalyst, so that ethylene is highly actively polymerized, thereby preparing polyethylene having a molecular weight distribution (Mw/Mn) of 1.5˜2.0. However, this catalytic system makes it difficult to obtain a high-molecular-weight polymer. In particular, when this is applied to solution polymerization at a high temperature of at least 140° C., polymerization activity is drastically decreased and β-dehydrogenation is predominantly carried out, and thus such a catalytic system is known to be unsuitable to prepare a high-molecular-weight polymer having a weight average molecular weight (Mw) of 100,000 or more.
[0004] U.S. Pat. No. 5,084,534 by Exxon discloses the preparation of a copolymer having a narrow molecular weight distribution of 1.8˜3.0 and a uniform composition distribution by polymerizing ethylene alone or ethylene with 1-hexene or 1-octene at 150˜200° C. using a (n-BuCp) 2 ZrCl 2 catalyst and a methylaluminoxane co-catalyst. In addition, EP Patent Nos. 0416815 and 0420436, by Dow, disclose a catalyst the structure of which is geometrically controlled by connecting an amide group in the form of a ring to a cyclopentadiene ligand, and which exhibits high catalytic activity upon polymerizing ethylene alone or ethylene with α-olefin under slurry polymerization or solution polymerization conditions and also increases high reactivity with comonomers, thereby enabling the preparation of a high-molecular-weight polymer having a uniform composition distribution. As in the metallocene catalyst, however, the above catalyst is drastically deteriorated in terms of catalytic stability and comonomer incorporations in proportion to an increase in the temperature under high-temperature solution polymerization conditions of at least 140° C., and economic benefits negate attributed to high material cost, making it difficult to industrially use it.
SUMMARY OF THE INVENTION
[0005] Culminating in the present invention, intensive and thorough research was carried out by the present inventors aiming to solve the problems encountered in the related art, which resulted in the finding that a geometrically constrained catalyst in which a cyclopentadienyl derivative 3,4-positions of which are substituted with alkyls and an electron-donating substituent are crosslinked around a Group 4 transition metal is remarkably advanced in terms of comonomer incorporations, making it suitable to prepare an ethylene homopolymer or an elastic copolymer of ethylene and α-olefin, having high molecular weight and high activity using solution polymerization at a high temperature of at least 140° C.
[0006] Therefore, an object of the present invention is to provide a catalyst having single active sites, which may exhibit superior thermal stability and is advanced in terms of comonomer incorporations, and a high-temperature solution polymerization method which enables an ethylene homopolymer or a copolymer of ethylene and α-olefin, having various properties, to be easily prepared from an industrial point of view using such a catalyst.
[0007] In one aspect to accomplish the above object, the present invention provides a transition metal compound represented by Chemical Formula 1 below, in which a cyclopentadiene derivative 3,4-positions of which are substituted with alkyls an electron-donating substituent are crosslinked around a Group 4 transition metal of the periodic table as a central metal. In addition, the present invention provides a catalyst composition comprising the above transition metal compound and a co-catalyst selected from among an aluminum compound, a boron compound and mixtures thereof, and a method of preparing an ethylene homopolymer or a copolymer of ethylene with α-olefin using the same.
[0000]
[0008] [In Chemical Formula 1, M is a Group 4 transition metal of the periodic table;
[0009] R 1 and R 2 are a (C1-C7) alkyl group;
[0010] D is —O—, —S—, —N(R 5 )— or —P(R 6 )—, in which R 5 and R 6 are independently a hydrogen atom, a (C1-C20) alkyl group, a (C3-C20) cycloalkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkylcarbonyl group, or a (C3-C20) cycloalkylcarbonyl group;
[0011] R 3 and R 4 are independently a hydrogen atom, a (C1-C20) alkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkoxy group, or a (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group;
[0012] X is independently a halogen atom, a (C1-C20) alkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkoxy group, a (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted amino group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted amide group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted phosphine group, or a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted phosphido group, in which the case where X is a cyclopentadienyl derivative is excluded;
[0013] the alkyl group of R 1 and R 2 , the alkyl group, aryl group, arylalkyl group and alkoxy group of R 3 and R 4 , the alkyl group, cycloalkyl group, aryl group, arylalkyl group, alkylcarbonyl group and cycloalkylcarbonyl group of R 5 and R 6 , the alkyl group, aryl group, arylalkyl group and alkoxy group of X may be further substituted with one or more selected from among a (C1-C20) alkyl group, a (C3-C20) cycloalkyl group, a (C6-C30) aryl group, and a (C6-C30) aryl(C1-C20) alkyl group; and
[0014] n is an integer of 1˜4].
[0015] In another aspect, the present invention provides a transition metal catalyst composition for preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin, comprising the above transition metal compound and a co-catalyst selected from among an aluminum compound, a boron compound and mixtures thereof, and an ethylene homopolymer or a copolymer of ethylene and α-olefin using the transition metal compound or the catalyst composition.
[0016] Below, the present invention is described in more detail. Specifically, M is preferably titanium, zirconium or hafnium. Also, R 1 and R 2 which are independently located at 3,4-positions of cyclopentadienyl able to form η 5 -bond with M are a (C1-C7) alkyl group, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, or a n-pentyl group, and particularly useful is a methyl group.
[0017] Also, R 5 and R 6 are independently a hydrogen atom, a (C1-C20) alkyl group, a (C3-C20) cycloalkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkylcarbonyl group or a (C3-C20) cycloalkylcarbonyl group, and more specifically a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a sec-butyl group, a tert-butyl group, a cyclohexyl group, a dicyclohexylmethyl group, an adamantyl group, a phenyl group, a phenylmethyl group, a methylcarbonyl group, an ethylcarbonyl group, a n-propylcarbonyl group, an isopropylcarbonyl group, a tert-butylcarbonyl group or an adamantylcarbonyl group. Particularly useful is a tert-butyl group.
[0018] Also, R 3 and R 4 bound with Si are independently a hydrogen atom, a (C1-C20) alkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkoxy group, or a (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group, and examples of the (C1-C20) alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, an amyl group, a n-hexyl group, a n-octyl group, a n-decyl group, a n-dodecyl group, a n-pentadecyl group or a n-eicosyl group, and particularly useful is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group or an amyl group; examples of the (C6-C30) aryl group or the (C6-C30) aryl(C1-C20) alkyl group include a benzyl group, a (2-methylphenyl)methyl group, a (3-methylphenyl)methyl group, a (4-methylphenyl)methyl group, a (2,3-dimethylphenyl)methyl group, a (2,4-dimethylphenyl)methyl group, a (2,5-dimethylphenyl)methyl group, a (2,6-dimethylphenyl)methyl group, a (3,4-dimethylphenyl)methyl group, a (4,6-dimethylphenyl)methyl group, a (2,3,4-trimethylphenyl)methyl group, a (2,3,5-trimethylphenyl)methyl group, a (2,3,6-trimethylphenyl)methyl group, a (3,4,5-trimethylphenyl)methyl group, a (2,4,6-trimethylphenyl)methyl group, a (2,3,4,5-tetramethylphenyl)methyl group, a (2,3,4,6-tetramethylphenyl)methyl group, a (2,3,5,6-tetramethylphenyl)methyl group, a (pentamethylphenyl)methyl group, an (ethylphenyl)methyl group, a (n-propylphenyl)methyl group, an (isopropylphenyl)methyl group, a (n-butylphenyl)methyl group, a (sec-butylphenyl)methyl group, a (tert-butylphenyl)methyl group, a (n-pentylphenyl)methyl group, a (neopentylphenyl)methyl group, a (n-hexylphenyl)methyl group, a (n-octylphenyl)methyl group, a (n-decylphenyl)methyl group, a (n-dodecylphenyl)methyl group, a (n-tetradecylphenyl)methyl group, a naphthylmethyl group or an anthracenylmethyl group, and particularly useful is benzyl; examples of the (C1-C20) alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, a neopentoxy group, a n-hexoxy group, a n-octoxy group, a n-dodecoxy group, a n-pentadecoxy group, or a n-eicosoxy group, and particularly useful is a methoxy group, an ethoxy group, an isopropoxy group or a tert-butoxy group; and examples of the (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group include a trimethylsiloxy group, a triethylsiloxy group, a tri-n-propylsiloxy group, a triisopropylsiloxy group, a tri-n-butylsiloxy group, a tri-sec-butylsiloxy group, a tri-tert-butylsiloxy group, a tri-isobutylsiloxy group, a tert-butyldimethylsiloxy group, a tri-n-pentylsiloxy group, a tri-n-hexylsiloxy group or a tricyclohexylsiloxy group, and particularly useful is a trimethylsiloxy group or a tert-butyldimethylsiloxy group.
[0019] X is independently a halogen atom, a (C1-C20) alkyl group, a (C6-C30) aryl group, a (C6-C30) aryl(C1-C20) alkyl group, a (C1-C20) alkoxy group, a (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted amino group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted amide group, a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted phosphine group, or a (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or tri(C1-C20) alkylsilyl substituted phosphido group, wherein the case where X is a cyclopentadienyl derivative is excluded. Examples of the halogen atom include fluorine, chlorine, bromine or iodine; examples of the (C1-C20) alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, an amyl group, a n-hexyl group, a n-octyl group, a n-decyl group, a n-dodecyl group, a n-pentadecyl group or a n-eicosyl group, and particularly useful is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group or an amyl group; examples of the (C6-C30) aryl(C1-C20) alkyl group include a benzyl group, a (2-methylphenyl)methyl group, a (3-methylphenyl)methyl group, a (4-methylphenyl)methyl group, a (2,3-dimethylphenyl)methyl group, a (2,4-dimethylphenyl)methyl group, a (2,5-dimethylphenyl)methyl group, a (2,6-dimethylphenyl)methyl group, a (3,4-dimethylphenyl)methyl group, a (4,6-dimethylphenyl)methyl group, a (2,3,4-trimethylphenyl)methyl group, a (2,3,5-trimethylphenyl)methyl group, a (2,3,6-trimethylphenyl)methyl group, a (3,4,5-trimethylphenyl)methyl group, a (2,4,6-trimethylphenyl)methyl group, a (2,3,4,5-tetramethylphenyl)methyl group, a (2,3,4,6-tetramethylphenyl)methyl group, a (2,3,5,6-tetramethylphenyl)methyl group, a (pentamethylphenyl)methyl group, an (ethylphenyl)methyl group, a (n-propylphenyl)methyl group, an (isopropylphenyl)methyl group, a (n-butylphenyl)methyl group, a (sec-butylphenyl)methyl group, a (tert-butylphenyl)methyl group, a (n-pentylphenyl)methyl group, a (neopentylphenyl)methyl group, a (n-hexylphenyl)methyl group, a (n-octylphenyl)methyl group, a (n-decylphenyl)methyl group, a (n-decylphenyl)methyl group, a (n-tetradecylphenyl)methyl group, a naphthylmethyl group or an anthracenylmethyl group, and particularly useful is a benzyl group; examples of the (C1-C20) alkoxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, a neopentoxy group, a n-hexoxy group, a n-octoxy group, a n-dodecoxy group, a n-pentadecoxy group, or a n-eicosoxy group, and particularly useful is a methoxy group, an ethoxy group, an isopropoxy group or a tert-butoxy group; examples of the (C1-C20) alkyl or (C3-C20) cycloalkyl substituted siloxy group include a trimethylsiloxy group, a triethylsiloxy group, a tri-n-propylsiloxy group, a triisopropylsiloxy group, a tri-n-butylsiloxy group, a tri-sec-butylsiloxy group, a tri-tert-butylsiloxy group, a tri-isobutylsiloxy group, a tert-butyldimethylsiloxy group, a tri-n-pentylsiloxy group, a tri-n-hexylsiloxy group or a tricyclohexylsiloxy group, and particularly useful is a trimethylsiloxy group or a tert-butyldimethylsiloxy group; examples of the (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or (C1-C20) alkylsilyl substituted amino group include a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, a di-n-butylamino group, a di-sec-butylamino group, a di-tert-butylamino group, a diisobutylamino group, a tert-butylisopropylamino group, a di-n-hexylamino group, a di-n-octylamino group, a di-n-decylamino group, a diphenylamino group, a dibenzylamino group, a methylethylamino group, a methylphenylamino group, a benzylhexylamino group, a bistrimethylsilylamino group or a bi-tert-butyldimethylsilylamino group, and particularly useful is a dimethylamino group or a diethylamino group; examples of the (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or (C1-C20) alkylsilyl substituted amide group include a dibenzylamide group, a methylethylamide group, a methylphenylamide group or a benzylhexylamide group, and particularly useful is a diphenylamide group; examples of the (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or (C1-C20) alkylsilyl substituted phosphine group include a dimethylphosphine group, a diethylphosphine group, a di-n-propylphosphine group, a diisopropylphosphine group, a di-n-butylphosphine group, a di-sec-butylphosphine group, a di-tert-butylphosphine group, a diisobutylphosphine group, a tert-butylisopropylphosphine group, a di-n-hexylphosphine group, a di-n-octylphosphine group, a di-n-decylphosphine group, a diphenylphosphine group, a dibenzylphosphine group, a methylethylphosphine group, a methylphenylphosphine group, a benzylhexylphosphine group, a bistrimethylsilylphosphine group or a bis-tert-butyldimethylsilylphosphine group; and examples of the (C1-C20) alkyl, (C6-C30) aryl, (C6-C30) aryl(C1-C20) alkyl or (C1-C20) alkylsilyl substituted phosphido group include a dibenzylphosphido group, a methylethylphosphido group, a methylphenylphosphido group, a benzylhexylphosphido group or a bistrimethylsilylphosphido group.
[0020] Also, n is an integer of 1˜4 selected by the oxidation number of transition metal, and preferably an integer of 1 or 2.
[0021] The present invention provides an ethylene homopolymer or a copolymer of ethylene and α-olefin, prepared using the transition metal compound as a catalyst.
[0022] On the other hand, in order to use the transition metal compound of Chemical Formula 1 as a catalyst component active for olefin polymerization, while the ligand X of the transition metal compound according to the present invention is extracted and the central metal thereof is cationized, a boron compound, an aluminum compound or a mixture thereof, corresponding to a counter ion having weak bondability, namely, an anion, is utilized as a co-catalyst. As such, the aluminum compound which is responsible for removing a small amount of polar material such as water acting as catalytic poison may function as an alkylating agent in the case where the ligand X is halogen.
[0023] Useful as the co-catalyst in the present invention, the boron compound may be selected from among compounds of Chemical Formulas 2, 3 and 4 below as disclosed in U.S. Pat. No. 5,198,401.
[0000] B(R 7 ) 3 [Chemical Formula 2]
[0000] [R 8 ] + [B(R 7 ) 4 ] − [Chemical Formula 3]
[0000] [(R 9 ) q ZH] + [B(R 7 ) 4 ] − [Chemical Formula 4]
[0024] [In Chemical Formulas 2 to 4, B is a boron atom; R 7 is a phenyl group, in which the phenyl group may be further substituted with three to five substituents selected from among a fluorine atom, a fluorine-substituted or unsubstituted (C1-C20) alkyl group, and a fluorine-substituted or unsubstituted (C1-C20) alkoxy group; R 8 is a (C5-C7) cycloalkyl radical, a (C1-C20) alkyl(C6-C20) aryl radical or a (C6-C30) aryl(C1-C20) alkyl radical, for example, a triphenylmethyl radical; Z is a nitrogen atom or a phosphorus atom; R 9 is a (C1-C20) alkyl radical or an anilinium radical substituted with two (C1-C4) alkyl groups along with a nitrogen atom; and q is an integer of 2 or 3.]
[0025] Preferred examples of the boron-based co-catalyst include one or more selected from among tris(pentafluorophenyl)borane, tris(2,3,5,6-tetrafluorophenyl)borane, tris(2,3,4,5-tetrafluorophenyl)borane, tris(3,4,5-trifluorophenyl)borane, tris(2,3,4-trifluorophenyl)borane, phenylbis(pentafluorophenyl)borane, tetrakis(pentafluorophenyl)borate, tetrakis(2,3,5,6-tetrafluorophenyl)borate, tetrakis(2,3,4,5-tetrafluorophenyl)borate, tetrakis(3,4,5-trifluorophenyl)borate, tetrakis(2,2,4-trifluorophenyl)borate, phenylbis(pentafluorophenyl)borate and tetrakis(3,5-bistrifluoromethylphenyl)borate, and specific combination examples thereof include ferrocenium tetrakis(pentafluorophenyl)borate, 1,1′-dimethylferrocenium tetrakis(pentafluorophenyl)borate, tetrakis(pentafluorophenyl)borate, triphenylmethyl tetrakis(pentafluorophenyl)borate, triphenylmethyl tetrakis(3,5-bistrifluoromethylphenyl)borate, triethylammonium tetrakis(pentafluorophenyl)borate, tripropylammonium tetrakis(pentafluorophenyl)borate, tri(n-butyl) ammonium tetrakis(pentafluorophenyl)borate, tri(n-butyl) ammonium tetrakis(3,5-bistrifluoromethylphenyl)borate, N,N-dimethylanilinium tetrakis(pentafluorophenyl)borate, N,N-diethylanilinium tetrakis(pentafluorophenyl)borate, N,N-2,4,6-pentamethylanilinium tetrakis(pentafluorophenyl)borate, N,N-dimethylanilinium tetrakis(3,5-bistrifluoromethylphenyl)borate, diisopropylammonium tetrakis(pentafluorophenyl)borate, dicyclohexylammonium tetrakis(pentafluorophenyl)borate, triphenylphosphonium tetrakis(pentafluorophenyl)borate, tri(methylphenyl)phosphonium tetrakis(pentafluorophenyl)borate or tri(dimethylphenyl)phosphonium tetrakis(pentafluorophenyl)borate, and particularly useful is N,N-dimethylanilinium tetrakis(pentafluorophenyl)borate, triphenylmethyl tetrakis(pentafluorophenyl)borate or tris(pentafluoro)borane.
[0026] The aluminum compound used in the present invention may include an aluminoxane compound of Chemical Formula 5 or 6 below, an organic aluminum compound of Chemical Formula 7 below, or an organic aluminum hydrocarbyl oxide compound of Chemical Formula 8 or 9 below.
[0000] (—Al(R 10 )—O—) m [Chemical Formula 5]
[0000] (R 10 ) 2 Al—(—O(R 10 )—) p —(R 10 ) 2 [Chemical Formula 6]
[0000] (R 11 ) r Al(E) 3-r [Chemical Formula 7]
[0000] (R 12 ) 2 AlOR 13 [Chemical Formula 8]
[0000] R 12 Al(OR 13 ) 2 [Chemical Formula 9]
[0027] [In Chemical Formulas 5 to 9, R 10 is a linear or non-linear (C1-C20) alkyl group, and preferably is a methyl group or an isobutyl group; m and p are independently an integer of 5˜20; R 11 and R 12 are independently a (C1-C20) alkyl group; E is a hydrogen atom or a halogen atom; r is an integer of 1˜3; and R 13 is a (C1-C20) alkyl group or a (C6-C30) aryl group.]
[0028] Useful as the co-catalyst, the aluminum compound is one or more selected from aluminoxane and organic aluminum, and the aluminoxane compound may include methylaluminoxane, modified methylaluminoxane or tetraisobutylaluminoxane; and the organic aluminum compound is selected from among trialkylaluminum, dialkylaluminum chloride, alkylaluminum dichloride, and dialkylaluminum hydride. Specific examples of the organic aluminum compound include trialkylaluminum, including trimethylaluminum, triethylaluminum, tripropylaluminum, triisobutylaluminum and trihexylaluminum; dialkylaluminum chloride, including dimethylaluminum chloride, diethylaluminum chloride, dipropylaluminum chloride, diisobutylaluminum chloride, and dihexylaluminum chloride; alkylaluminum dichloride, including methylaluminum dichloride, ethylaluminum dichloride, propylaluminum dichloride, isobutylaluminum dichloride and hexylaluminum dichloride; and dialkylaluminum hydride, including dimethylaluminum hydride, diethylaluminum hydride, dipropylaluminum hydride, diisobutylaluminum hydride and dihexylaluminum hydride, and preferably useful is trialkylaluminum, and more preferably is triethylaluminum or triisobutylaluminum, in which the molar ratio of central transition metal (M) to aluminum atom (Al) is 1:50˜5,000.
[0029] As the ratio of transition metal compound to co-catalyst, the molar ratio of central transition metal (M) to boron atom (B) to aluminum atom (Al) is 1:0.1˜100:10˜1,000, and more preferably 1:0.5˜5:25˜500. The preparation of an ethylene homopolymer or a copolymer of ethylene and α-olefin is possible within the above range, and the range of the ratio may vary depending on the purity of reaction.
[0030] In another aspect, the present invention provides an ethylene homopolymer or a copolymer of ethylene and α-olefin, prepared using the transition metal compound as the catalyst composition, and the preparation method is performed in a solution phase by brining the transition metal compound, the co-catalyst, and ethylene or α-olefin comonomer into contact with each other in the presence of an appropriate solvent. As such, the transition metal compound and the co-catalyst component may be separately added into a reactor or respective components may be pre-mixed and then introduced into a reactor.
[0031] The organic solvent used in the preparation method is preferably a (C3-C20)hydrocarbon, and specific examples thereof include butane, isobutane, pentane, hexane, heptane, octane, isooctane, nonane, decane, dodecane, cyclohexane, methylcyclohexane, benzene, toluene and xylene.
[0032] Specifically, upon preparation of the ethylene homopolymer, an ethylene monomer is used alone, and the pressure of ethylene suitable for the present invention is 1˜1000 atm, and preferably 10˜150 atm. When the pressure falls in the above range, a reactor made of a thin material may be used and there is no need for an additional compression process, thus generating economic benefits and increasing the yield of polymer. The polymerization temperature is 60˜300° C., and preferably 80˜250° C. If the polymerization temperature is 80° C. or higher, low-density polymers may be prepared thanks to advanced comonomer incorporations. In contrast, if the polymerization temperature is 250° C. or lower, the conversion from ethylene into polymer may increase, thus obtaining high-density polymers.
[0033] Also in the method of preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin using the transition metal catalyst composition, the comonomer which is polymerized with ethylene may include α-olefin of (C3-C18)hydrocarbon, and is preferably selected from among propylene, 1-butene, 1-pentene, 4-methyl-1-pentene, 1-hexene, 1-heptene, 1-octene, 1-decene, 1-undecene, 1-dodecene, 1-tetradecene, 1-hexadecene, 1-octadecene, and 1-itocene. More preferably, 1-butene, 1-hexene, 1-octene, or 1-decene may be copolymerized with ethylene. In this case, the preferred ethylene pressure and polymerization temperature are the same as in the preparation of high-density polyethylene, and the ethylene copolymer prepared using the method according to the present invention has an ethylene content of 50 wt % or more, preferably 60 wt % or more, and more preferably 60˜99 wt %. As mentioned above, when using α-olefin of (C4-C10) hydrocarbon as the comonomer, the resultant linear low-density polyethylene (LLDPE) has a density of 0.850˜0.950 g/cc, and preferably the preparation of an olefinic copolymer having a density of 0.860˜0.940 g/cc is possible.
[0034] In order to regulate the molecular weight upon preparation of the ethylene homopolymer or copolymer according to the present invention, hydrogen may be used as a molecular weight regulating agent, so that a weight average molecular weight (Mw) is 80,000˜500,000, and a molecular weight distribution (Mw/Mn) which is the ratio of weight average molecular weight/number average molecular weight is 1.5˜4.1.
[0035] The catalyst composition according to the present invention is present in a uniform form in the polymerization reactor, and thus is preferably applied to solution polymerization that is carried out at a temperature not lower than the melting point of the corresponding polymer. However, as disclosed in U.S. Pat. No. 4,752,597, a heterogeneous catalytic system resulting from supporting the above transition metal compound and a co-catalyst on a porous metal oxide support may be employed in slurry polymerization or gas polymerization.
[0036] According to the present invention, a transition metal compound or a catalyst composition including the transition metal compound can be easily produced at high yield using a simple process by reducing the number of alkyls except for a specific portion of cyclopentadiene, thus generating economic benefits. Furthermore, the catalyst has high thermal stability and thus maintains high catalytic activity upon olefin polymerization under high-temperature solution polymerization conditions and also enables the preparation of a high-molecular-weight polymer at high yield. Also, because the catalyst is advanced in terms of comonomer incorporations, its industrial availability is higher compared to conventionally known metallocene and non-metallocene based catalysts having single active sites.
[0037] Thus, the transition metal catalyst composition and the preparation method according to the present invention can be efficiently utilized for preparing copolymers of ethylene and α-olefin, having various properties and elastic moduli.
DETAILED DESCRIPTION OF THE INVENTION
[0038] A better understanding of the present invention may be obtained via the following examples that are set forth to illustrate, but are not to be construed as limiting, the present invention.
[0039] Unless otherwise stated, all ligands and catalyst synthesis tests were performed using standard Schlenk or glove box techniques in a nitrogen atmosphere, and the organic solvent used in the reaction was refluxed in the presence of sodium metal and benzophenone to remove water, and then distilled just before use. The 1 H-NMR analysis of the synthesized ligand and catalyst was performed at room temperature using a Bruker 500 MHz spectrometer.
[0040] As a polymerization solvent, cyclohexane was sequentially passed through Q-5 catalyst (available from BASF), silica gel, and activated alumina of the reactor, and bubbled with high-purity nitrogen, thus sufficiently removing water, oxygen and other catalyst poisoning materials, and then used.
[0041] The resultant polymer was analyzed via the following methods.
[0042] 1. Melt Flow Index (MI)
[0043] Measurement was performed according to ASTM D 2839.
[0044] 2. Density
[0045] According to ASTM D 1505, measurement was performed using a density gradient tube.
[0046] 3. Analysis of Melting Point (Tm)
[0047] Measurement was performed under 2 nd heating conditions at a rate of 10° C./min in a nitrogen atmosphere using Dupont DSC2910.
[0048] 4. Molecular weight and molecular weight distribution
[0049] Measurement was performed in the presence of 1,2,3-trichlorobenzene solvent at a rate of 1.0 mL/min at 135° C. using PL210 GPC equipped with PL Mixed-BX2+preCol, and the molecular weight was corrected using a PL polystyrene standard material.
[0050] 5. α-Olefin Content of Copolymer (wt %)
[0051] Measurement was performed in 13 C-NMR mode at 120° C. in the presence of a solvent mixture comprising 1,2,4-trichlorobenzene/C6D 6 (7/3 weight ratio) at 125 MHz using a Bruker DRX500 nuclear magnetic resonance spectrometer.
(Reference: Randal, J. C. JMS - Rev. Macromol. Chem. Phys. 1980, C29, 201)
Preparative Example 1
Synthesis of (dichloro)(tert-butylamido)(3,4-dimethylcyclopentadienyl)(dimethylsilane)titanium (IV)
(1) Synthesis of Crotonic Acid Isopropyl Ester
[0053] Crotonic acid (193.7 g, 2.25 mol) was dissolved in 2-propanol (860 mL, 11.25 mol) in a 2 L flask and then well stirred, after which sulfuric acid (24 mL, 0.45 mol) was slowly added in droplets to the mixture and refluxed and stirred for 48 hours or longer. The stirred mixture was cooled to room temperature, after which the obtained mixture was washed with distilled water (1000 mL), and the organic layer was separated, neutralized and subjected to atmospheric distillation (80° C.), thus obtaining 220 g (1.71 mol, yield 76.3%) of crotonic acid isopropyl ester.
[0054] 1 H-NMR(C6D 6 ) δ=1.01˜1.06 (d, 6H), 1.26˜1.37 (q, 3H), 5.01˜5.08 (m, 1H), 5.70˜5.79 (m, 1H), 6.82˜6.93 (m, 1H) ppm
(2) Synthesis of 3,4-dimethyl-2-cyclopentenone
[0055] 1 L of polyphosphoric acid was added into a 2 L flask, purged with nitrogen, and then refluxed and stirred at 100° C., after which crotonic acid isopropyl ester (76.9 g, 0.6 mol) was slowly added in droplets thereto, and the mixture was stirred for 3 hours and thus turned into dark brown. The mixture thus obtained was mixed with ice water (500 mL) and then neutralized with sodium carbonate, after which the organic layer was extracted with ethylether and then subjected to vacuum distillation (105° C., 40 torr), thus obtaining 56 g (0.51 mol, yield 84.7%) of 3,4-dimethyl-2-cyclopentenone as a colorless transparent liquid.
[0056] 1 H-NMR (CDCl 3 ) δ=1.05˜1.09 (d, 3H), 1.83˜1.87 (q, 1H), 1.98 (s, 3H), 2.45˜2.51 (q, 1H), 2.67˜2.70 (m, 1H), 5.73 (s, 1H) ppm
(3) Synthesis of tert-butyl-1-(3,4-dimethylcyclopentadienyl)-1,1-dimethylsilaneamine
[0057] In a nitrogen atmosphere, lithium aluminum hydride (6.07 g, 0.16 mol) was dissolved in diethylether (250 mL), and 3,4-dimethyl-2-cyclopentenone (33.95 g, 0.31 mol) was slowly added in droplets thereto at 0° C. Refluxing for 30 minutes and cooling to 0° C. via room temperature were performed, after which distilled water (15 mL) was slowly added in droplets thereto and thus unreacted lithium aluminum hydride was removed. The reaction mixture was slowly added to dilute sulfuric acid and the organic layer was extracted with diethylether and then subjected to vacuum distillation, thus obtaining 21.2 g of 2,3-dimethylcyclopentadiene as a yellow liquid. This solution was transferred into a flask and dissolved in pentane (200 mL), after which n-butyl lithium (141 mL, 0.225 mol, 1.6 M) was added in droplets thereto at −78° C. The temperature was increased to room temperature and the reaction was then carried out for 12 hours, thus obtaining 10.5 g (yield 46.9%) of 1,2-dimethylcyclopentadienyl lithium as off-white powder. 5.45 g (54.5 mmol) of the powder was placed in a flask containing diethylether (80 mL), and dichlorodimethylsilane (6.8 mL, 54.5 mmol) was then added in droplets thereto at −78° C. Subsequently, the temperature was increased to room temperature and the reaction was carried out for 12 hours or longer. Diethylether was removed using vacuum distillation, and the resultant product was washed with pentane, thus obtaining 6.35 g (yield 62.4%) of dimethylsilyl-3,4-dimethylcyclopentadienyl chloride as a yellow liquid. This liquid was transferred into a flask without purification and then dissolved in tetrahydrofuran (90 mL), after which lithium-tert-butylamine (2.69 g, 34.0 mmol) was slowly added in droplets thereto at −78° C. The reaction was carried out at room temperature for 12 hours or longer and the solvent was then completely removed using vacuum drying, after which the resultant product was extracted with purified pentane, thus obtaining, as a yellow liquid, 6.15 g (27.5 mmol, yield 80.9%) of tert-butyl-1-(3,4-dimethylcyclopentadienyl)-1,1-dimethylsilaneamine.
[0058] 1 H NMR(C6D 6 ): δ=0.00 (s, 6H), 0.28 (s, 3H), 1.05 (s, 3H), 1.07 (s, 9H), 1.09 (s, 3H), 1.85 (s, 2H), 1.94 (s, 2H), 1.98 (s, 6H), 2.89 (t, 1H), 3.17 (t, 1H), 6.16 (s, 2H), 6.31˜6.70 (m, 1H) ppm
(4) Synthesis of (dichloro)(tert-butylamido)(3,4-dimethylcyclopentadienyl)(dimethylsilane)titanium (IV)
[0059] tert-Butyl-1-(3,4-dimethylcyclopentadienyl)-1,1-dimethylsilaneamine (6.15 g, 27.5 mmol) was placed in a flask and dissolved in diethylether (100 mL) in a nitrogen atmosphere, after which n-butyl lithium (22.0 mL) was slowly added in droplets thereto at −78° C. The temperature was gradually increased to room temperature and the reaction was carried out for 12 hours or longer. The solvent was completely removed using vacuum drying and the resultant product was washed with pentane, thus obtaining as off-white powder 5.24 g (yield 81.0%) of lithium (tert-butylamido)(3,4-dimethylcyclopentadienyl)dimethylsilane. 3.00 g (12.8 mmol) of the powder and tetrachlorobis(tetrahydrofuran)titanium (IV) (4.26 g, 12.8 mmol) were placed together in a flask and toluene (50 mL) was added thereto so that the reaction was carried out at 80° C. for 24 hours or longer. The temperature was decreased to room temperature and filtration was conducted thus removing lithium chloride, and solvent was removed using vacuum drying, after which the resultant product was extracted with pentane and recrystallized, thus obtaining as a yellow solid 1.73 g (yield 39.9%) of (dichloro)(tert-butylamido)(3,4-dimethylcyclopentadienyl) (dimethylsilane) titanium (IV).
[0060] 1 H NMR(C6D 6 ): δ=0.26 (s, 6H), 1.40 (s, 9H), 2.04 (s, 6H), 5.91 (s, 2H) ppm; 13 C NMR (C6D 6 ): δ=0.97, 13.41, 33.18, 105.91, 123.05, 127.84, 128.22, 133.45 ppm.
Preparative Example 2
Synthesis of (dichloro)(tert-butylamido)(3,4-dimethylcyclopentadienyl)(dimethylsilane)zirconium (IV)
[0061] Lithium(tert-butylamido)3,4-dimethylcyclopentadienyldimethylsilane (0.9 g, 3.83 mmol) and zirconium (IV) chloride (0.891 g, 3.83 mmol) were placed together in a flask and toluene (20 mL) was added thereto so that the reaction was carried out at 80° C. for 24 hours or longer. The temperature was decreased to room temperature and filtration was conducted thus removing lithium chloride and solvent was removed using vacuum drying, after which the resultant product was extracted with pentane and recrystallized, thus obtaining as a pale brown solid 0.89 g (yield 60.5%) of (dichloro) (tert-butylamido)(3,4-dimethylcyclopentadienyl)(dimethylsilane)zirconium (IV).
[0062] 1 H NMR(C6D 6 ): δ=0.30 (s, 6H), 1.31 (s, 9H), 2.00 (s, 6H), 5.90 (s, 2H) ppm; 13 C NMR (C6D 6 ): δ=0.07, 14.36, 32.65, 107.74, 126.86, 126.91, 128.82, 139.34 ppm.
Comparative Preparative Example 1
Synthesis of (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)titanium (IV)
(1) Synthesis of (tert-butylamino)(2,3,4,5-tetramethylcyclopenta-2,4-dienyl)dimethylsilane
[0063] 2,3,4,5-tetramethylcyclopenta-2,4-diene (3.67 g, 30 mmol) was added into a flask containing tetrahydrofuran (100 mL), n-butyl lithium (12 mL) was added in droplets thereto at 0° C., and the reaction temperature was gradually increased to room temperature so that the reaction was carried out for 8 hours. This solution was cooled to −78° C., dichloromethylsilane (3.87 g, 30 mmol) was slowly added in droplets thereto, and then the reaction was carried out for 12 hours. After the reaction, the volatile material was removed, and the resultant product was extracted with hexane (100 mL), after which the volatile material was removed, thereby obtaining as pale yellow oil 5.5 g of (chloro) (dimethyl) (2,3,4,5-tetramethylcyclopentadienyl)silane. The (chloro)(dimethyl)(2,3,4,5-tetramethylcyclopentadienyl)silane thus obtained was dissolved in tetrahydrofuran (100 mL) without additional purification, after which lithium tert-butylamide (2.02 g) was added in droplets thereto at 0° C. and the reaction was carried out at room temperature for 2 hours. After the reaction, the volatile material was removed, and the resultant product was extracted with hexane (100 mL), thus obtaining as pale yellow oil 6.09 g (yield 81%) of (tert-butylamino)(2,3,4,5-tetramethylcyclopenta-2,4-dienyl)dimethylsilane.
[0064] 1 H-NMR(C6D 6 ) δ=0.11 (s, 6H), 1.11 (s, 9H), 1.86 (s, 6H), 2.00 (s, 6H) 2.78 (s, 1H) ppm
(2) Synthesis of (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)titanium (IV)
[0065] (tert-Butylamino)(2,3,4,5-tetramethylcyclopenta-2,4-dienyl)dimethylsilane (6.09 g 24.2 mmol) was dissolved in diethylether (100 mL), and n-butyl lithium (9.7 mL) was added in droplets thereto at −78° C., after which the reaction temperature was gradually increased to room temperature and the reaction was carried out for 12 hours. After the reaction, the volatile material was removed, and the resultant product was extracted with hexane (100 mL) thus obtaining 6.25 g of an orange-colored solid. The solid thus obtained was dissolved in toluene (100 mL), and tetrachlorotitanium (IV) (4.50 g 23.7 mmol) was added in droplets thereto at −78° C., after which the reaction temperature was increased to room temperature and the reaction was carried out for 7 hours. After completion of the reaction, the volatile material was removed, and the resultant product was extracted with purified pentane (100 mL) and recrystallized at −35° C., filtered and then vacuum dried, thus obtaining as an orange-colored solid 0.87 g(yield 10%) of (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)titanium (IV).
[0066] 1 H-NMR(C6D 6 ) δ=0.43 (s, 6H), 1.43 (s, 9H), 2.00 (s, 6H), 2.01 (s, 6H) ppm
Comparative Preparative Example 2
Synthesis of (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)zirconium (IV)
[0067] 1.3 g (yield 13.3%) of (dichloro) (tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)zirconium (IV) was synthesized in the same manner as in Comparative Preparative Example 1, with the exception that 5.52 g (23.7 mmol) of tetrachlorozirconium (IV) was used.
[0068] 1 H-NMR(C6D 6 ) δ=0.40 (s, 6H), 1.40 (s, 9H), 1.97 (s, 6H), 2.00 (s, 6H) ppm.
Example 1
[0069] Ethylene and 1-octene was copolymerized via the following procedures using a batch type polymerization device. Specifically, 1170 mL of cyclohexane and 30 mL of 1-octene were added into a 2000 mL stainless steel reactor sufficiently dried and purged with nitrogen, after which 22.1 mL of modified methylaluminoxane-7 (available from Akzo Nobel, modified MAO-7, 7 wt % Al Isopar solution) 54.2 mM toluene solution was fed into the reactor. The temperature of the reactor was increased to 80° C., after which 0.4 mL of the (dichloro)(tert-butylamido)(3,4-dimethylcyclopentadienyl)(dimethylsilane)titanium (IV) (5.0 mM toluene solution) synthesized in Preparative Example 1 and 2.0 mL of triphenylmethylinium tetrakis pentafluorophenylborate (99%, Boulder Scientific) 10 mM toluene solution were sequentially added thereto, and the inner pressure of the reactor was adjusted up to 30 kg/cm 2 with ethylene, after which polymerization was carried out.
[0070] During the reaction time of 5 minutes, the temperature arrived at 162.2° C. in maximum. After 5 minutes, 100 mL of ethanol containing 10 vol % hydrochloric acid aqueous solution was added thereto, thus terminating the polymerization, after which stirring was performed using 1.5 L of ethanol for 1 hour, followed by filtering and separating the reaction product. The recovered reaction product was dried in a vacuum oven at 60° C. for 8 hours, yielding 62.8 g of a polymer. The polymer had a melting point of 117.48° C., a melt index of 0.016, and a density of 0.9124 g/cc, and upon analysis using gel chromatography, a weight average molecular weight (Mw) of 202,000 g/mol, a molecular weight distribution (Mw/Mn) of 4.05, and a 1-octene content of 7.68 wt %.
Example 2
[0071] Ethylene and 1-octene were copolymerized in the same manner as in Example 1, with the exception that the reaction temperature was increased up to 140° C. before adding the catalyst. During the reaction time of 5 minutes, the temperature arrived at 180.9° C. in maximum, and 48.04 g of a polymer was finally obtained. The polymer had a melting point of 119.02° C., a melt index of 1.5, a density of 0.9152 g/cc, and upon analysis using gel chromatography, a Mw of 109,100 g/mol, a Mw/Mn of 2.33, and a 1-octene content of 4.98 wt %.
Example 3
[0072] Ethylene and 1-octene were copolymerized in the same manner as in Example 1, with the exception that 0.4 mL of the (dichloro)(tert-butylamido) (3,4-dimethylcyclopentadienyl)(dimethylsilane)zirconium (IV) (5.0 mM toluene solution) synthesized in Preparative Example 2 was added and the reaction time was set to 10 minutes. During the reaction time of 10 minutes, the temperature arrived at 98.2° C. in maximum, and 4.62 g of a polymer was finally obtained. The polymer had a melting point of 133.28° C., a melt index of 0.165, a density of 0.9370 g/cc, and upon analysis using gel chromatography, a Mw of 211,600 g/mol, a Mw/Mn of 3.13, and a 1-octene content of 0.82 wt %.
Comparative Example 1
[0073] Ethylene and 1-octene were copolymerized in the same manner as in Example 1, with the exception that the (dichloro) (tert-butylamido) (2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)titanium (IV) synthesized in Comparative Preparative Example 1 was added. During the reaction time of 5 minutes, the temperature arrived at 163.0° C. in maximum, and 66.68 g of a polymer was finally obtained. The polymer had a melting point of 116.35° C., a melt index of 0.004, a density of 0.9420 g/cc, and upon analysis using gel chromatography, a Mw of 247,800 g/mol, a Mw/Mn of 7.30, and a 1-octene content of 6.55 wt %.
Comparative Example 2
[0074] Ethylene and 1-octene were copolymerized in the same manner as in Example 1, with the exception that the reaction temperature was increased up to 140° C. before adding the catalyst, and the (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)titanium (IV) synthesized in Comparative Preparative Example 1 was added. During the reaction time of 5 minutes, the temperature arrived at 184.4° C. in maximum, and 40.03 g of a polymer was finally obtained. The polymer had a melting point of 116.21° C., a melt index of 0.56, a density of 0.9218 g/cc, and upon analysis using gel chromatography, a Mw of 106,000 g/mol, a Mw/Mn of 4.31, and a 1-octene content of 6.34 wt %.
Comparative Example 3
[0075] Ethylene and 1-octene were copolymerized in the same manner as in Example 1, with the exception that 0.4 mL of the (dichloro)(tert-butylamido)(2,3,4,5-tetramethylcyclopentadienyl)(dimethylsilane)zirconium (IV) (5.0 mM toluene solution) synthesized in Comparative Preparative Example 2 was added and the reaction time was set to 10 minutes. During the reaction time of 10 minutes, the temperature arrived at 102.1° C. in maximum, and 16.49 g of a polymer was finally obtained. The polymer had a melting point of 125.93° C., a melt index of 0.087, a density of 0.9405 g/cc, and upon analysis using gel chromatography, a Mw of 426,800 g/mol, a Mw/Mn of 3.31, and a 1-octene content of 2.2 wt %.
[0076] As is apparent from the above examples, in the polymerization of ethylene alone and in combination with 1-octene under the above polymerization conditions, the polymers could be produced at higher yield, and olefin copolymers having higher 1-octene contents were obtained under the same conditions, compared to the comparative examples. In particular, low-density copolymers could be successfully prepared from ethylene and 1-octene.
[0077] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions, and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims. | Provided is a homogeneous catalytic system for use in preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin, and more particularly a Group 4 transition metal compound in which a cyclopentadienyl derivative 3,4-positions of which are substituted with alkyls and an electron-donating substituent are crosslinked around a Group 4 transition metal. Also provided is a method of preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin, having high molecular weight, under high-temperature solution polymerization conditions using the catalytic system including such a transition metal compound and a co-catalyst composed of an aluminum compound, a boron compound or a mixture thereof. The catalyst according to present invention has high thermal stability and enables the incorporation of α-olefin, and is thus effective in preparing an ethylene homopolymer or a copolymer of ethylene and α-olefin, having various properties, in industrial polymerization processes. | 2 |
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional patent application Ser. No. 60/443,525, filed on Jan. 28, 2003, and entitled “NOVEL BONE GRAFT COMPOSITE”, the contents of which are hereby incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention disclosed herein generally relates to a novel bone graft composite. The invention also relates to therapeutic applications using such bone graft composite.
BACKGROUND OF THE INVENTION
[0003] Benign bone tumors such as giant cell tumor (GCT), unicameral bone cyst (UBC) an aneurismal bone cyst (ABC) are characterized by bone destruction that is mediated by osteoclasts. The consequences of benign bone tumors include bone destruction and pathologic fractures. Most of bone tumors occur near the joint and pathologic fractures can further destroy the joints. Affected patients often require joint replacement surgeries. These bone tumors often are recurring and the typical example is GCT that also recurs in 30% to 40% of the cases. Other examples include UBC and ABC that occur in growing children. Recurrence is greater than 30% to 50% after a single treatment such as injection of bone marrow or bone grafting. UBC and ABC cause recurrent fractures, deformity and growth disturbances.
[0004] Most of the currently available treatments consist of mechanical removal of a tumor, bone grafting using allografts and internal fixation to restore the structural integrity of bone. Bone grafts are often dissolved by reactivation of tumor cells and lose the goal of structural restoration. The drawbacks associated with surgical treatment include postoperative morbidity, and recurrence and resorption (or loss) of bone grafts. The recurrent lesions are characterized by resorption of the transplanted bone.
[0005] Understanding the fundamental pathophysiology of bone destruction is the first step in designing novel therapeutic strategies. In the past, bone destruction was thought to be the consequence of destructive effects of tumor cells. It has been suggested that tumor cells attract and activate monocytes, which in turn fuse to form osteoclasts.
[0006] Mediation of osteoclast activation involves specific gene activation such as receptor activator of nuclear factor κβ ligand, (RANKL). RANKL stimulates the formation of multinucleated osteoclasts from monocytic precursors. Bone tumor cells attract immune cells and express RANKL to destroy the bone. Osteoclasts, which can melt the bone, are abundant in primary and metastatic bone tumors. After discovery of major signaling molecules such as osteoprotegerin (OPG; Osteoclastogenesis Inhibiting Factor) or receptor activator of nuclear factor kappa κβ: (RANKL; OPG ligand; TRANCE; Osteoclastogenesis Factor), molecular mechanisms by which bone is destroyed has been better elucidated.
[0007] Bisphosphonates have a history of successful clinical use for the treatment and prevention of pathological bone destruction of various origins, such as osteolytic bone diseases due to malignancy, Paget's disease, osteogenesis imperfecta, hypercalcemia caused by malignancy, and tumor metastases in bone including multiple myeloma. There are a number of bisphosphonates currently available that have been approved for such clinical use. Such bisphosphonates include but are not limited to Alendronate, Etidronate, Pamidronate, Zolendronate, Risedronate and Tiludronate. The mode of delivery of such bisphosphonate may be oral or intravenous. Limited absorption from the gastrointestinal tract and fast appearance of bisphosphonate following intravenous administration are all characteristics of known bisphosphonates. Bisphosphonates are rapidly cleared from plasma. The half-life in bone however, is very long, partially as long as the half-life of the bone in which they are replaced.
[0008] Bisphosphonates are analogues of the physiologically occurring inorganic pyrophosphates. Selective action of the bisphosphonate on bone is based on the binding of the bisphosphonate moiety to the bone mineral. However, the molecular mode of action remains unclear and may differ from compound to compound. At the tissue level, all bisphosphonates inhibit bone destruction and lead to an increase in bone mineral density by decreasing bone resorption and bone turnover. At the cellular level, the ultimate target of bisphosphonate action is the osteoclast. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. Recent studies show that bisphosphonates can be classified into at least 2 groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen containing bisphosphonates (such as zolendronate, pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The P—C—P bond of the bisphosphonates is completely resistant to enzymatic hydrolysis (Fleisch H., Bisphosphonates in Bone Disease, Academic Press, 2002, Ch. 22, pp. 30-33).
[0009] The present invention makes use of the effect of the bisphosphonates in inhibiting the activity of osteoclasts and preventing bone resorption in the design of a novel bone graft composite. Such bone graft composite finds applicability in treating or decreasing tumor recurrence, decreasing osteoclast activity and formation, elimination of osteoclasts and restoration of bone loss.
SUMMARY OF THE INVENTION
[0010] The present invention provides for bone graft composite comprising a bisphosphonate, a bone graft and a carrier material. In a preferred embodiment, such bisphosphonate is Pamidronate.
[0011] The present invention also provides for a method of treating a patient suffering from bone destruction by inserting a bone graft composite at the site of such bone destruction.
[0012] Additional aspects of the present invention will be apparent in view of the description that follows.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 is a diagram illustrating the therapeutic rationale using the bone graft composite of the invention.
[0014] FIG. 2 is a diagram showing that Pamidronate induces apoptosis of giant cell tumors in a dose dependent manner. The control picture shows plumpy, polyhedral cytoplasm. Addition of 100 and 200 μM of Pamidronate induces cell death. Annexin V staining indicates apoptosis of tumor cells.
[0015] FIG. 3 is a diagram showing an apoptosis (*) and necrosis assay using Annexin V and propium iodide. The apoptotic population increases with a higher dose of Pamidronate.
[0016] FIG. 4 shows the effect of the bone graft composite of the invention on the giant cell tumor and unicameral bone cyst.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The definitions below serve to provide a clear and consistent understanding of the specification and claims, including the scope to be given such terms.
[0018] By the term “bone” is intended for the purposes of the present invention, bone recovered from any source including animal and human, for example, human bone recovered for the production of allografts, and animal bone recovered for the production of xenografts, such allografts and xenografts suitable for implantation into a human.
[0019] By the term “bisphosphonate” is intended for the purposes of the present invention to include without limitation a bisphosphonate such as Pamidronate, Alendronate, Etidronate, Zolendronate, Risendronate and Tiludronate.
[0020] By the term “bone graft material” is intended for the purposes of the present invention to include hydroxyapatite, tricalcium phosphate, synthetic material such as autogenous bone graft, gel foam, bone cement or any other calcium containing material.
[0021] By the term “carrier material” is intended for the purposes of the present invention to include bone chips or any other calcium containing material.
[0022] A therapeutic rationale has been developed using bisphosphonate in a bone graft composite. In one embodiment, the bone graft composite includes a bisphosphonate in a carrier material and a bone graft material. In another embodiment, the bone graft composite includes a bisphosphonate and a bone graft material. The bone graft composite can be formed by mixing with a bisphosphonate solution bone graft material. A carrier material may also be included and mixed in. When the carrier material is not included, the bone graft material serves the dual purpose of bone graft and carrier materials. As shown in FIG. 1 , prior to implantation of the bone graft composite, a surgical procedure is performed to remove the tumor cells from the anatomic site of tumor. The choice of surgical procedure is dictated by the site of primary pathology and by the physical size of the bone graft composite. Following removal of the tumor cell, the bone graft composite is implanted. The bone graft composite prevents recurrence by inducing apoptosis of osteoclasts and tumor cells. In addition, the composite provides protection with bisphosphonate against bone graft resorption and tumor recurrence.
[0023] To study the effect of bisphosphonate, the inventor has identified tumor stromal cells derived monocyte chemotactic factor (SDF-1) in the giant cell tumor of bone as a model to provide insight into the molecular interaction between tumor cells and host immune system that generate osteoclasts. These tumor cells undergo apoptosis in response to an antiresorptive agent in vitro. The cells were grown from the giant cell tumors. The giant cell tumor is comprised of neoplastic stromal cells, monocytes and osteoclast-like multinucleated cells. The neoplastic stromal cells express RANKL, which stimulates monocytes to form multinucleated giant cells. This is generally observed after several passages of cell lines, suggesting autocrine effect of neoplastic cell-monocyte interaction. In order to identify monocyte-attracting factors, RNAs from the tumor tissue and cell lines were hybridized with stromal cell derived factor (SDF-1). The tumor expressed SDF-1 that may mediate the molecular interaction between neoplastic tumor cells and monocytes. Specific therapeutic regimens can be designed to block the osteoclastogenesis from monocytes, to inhibit osteoclasts and to inhibit or decrease monocyte chemoattractive factors.
[0024] Several factors have an effect on the selection of a bisphosphonate. These factors include the level of osteoclasts inhibition by the particular bisphosphonate both in vitro and in vivo. Other factors include the tolerance of such bisphosphonate by the bone tissue, and the tolerance of such bisphosphonate by a patient.
[0025] For the purpose of demonstrating the effect of bisphosphonate, in vitro assays were performed using Pamidornate. Pamidronate is well tolerated by patients with metastatic bone cancers and osteoporosis. FIG. 2 shows the shrunken and irregular morphology of tumor cells after treatment with Pamidronate, and shows that Pamidronate at concentrations of 50 μm, 100 μm and 200 μm induces apoptosis of tumor cells of giant cells in a dose-dependent manner. FIG. 3 shows apoptosis and necrosis assay using Annexin V and propium iodide. The apoptotic population increases with a higher dose of Pamidronate. FIG. 4 shows the effect of the bone graft composite of the invention in the giant cell tumor and unicameral bone cyst in vitro. The tumor cells are shown to regress when brought into contact with the bone graft composite of the invention. It will be appreciated by one skilled in the art that the results in FIGS. 2, 3 and 4 are in no way limited to a particular bisphosphonate.
[0026] The present bone graft composite is useful for implantation in patients suffering from defects caused by pathological bone destruction of various origins such as osteolytic bone disease. Those of ordinary skill in the art to which the present invention pertains can readily select and employ a particular bone graft composite without undue experimentation. Factors to be considered in such selection and employment include: the type and size of graft bone, its anatomic site of fusion, and the age of the patient. Graft selection and surgical techniques are factors that can be readily selected, optimized and employed by those of ordinary skill in the art without undue experimentation and are discussed in various references (e.g. Campanaci, M., Baldini, N., Boriani, S., Sudanese, A., Giant Cell Tumors of Bone, J. Bone Joint Surg. (Am), 1987, 69-106-114).
[0027] While the foregoing invention has been described in some detail for purposes of clarity and understanding, it will be appreciated by one skilled in the art, from a reading of the disclosure, that various changes in form and detail can be made without departing from the true scope of the invention in the appended claims. | A bone graft composite comprising a bisphosphonate is provided which is suitable for treating bone destruction. The bisphosphonate provides bone graft protection. | 0 |
This application is a non-provisional application for patent entitled to a filing date and claiming the benefit of earlier-filed Provisional Application for Patent No. 61/046,907, filed on Apr. 22, 2008 under 37 CFR 1.53 (c).
FIELD OF THE INVENTION
This invention relates to a method and kit for assembling marine propulsion systems and securing them to a marine vessel. Particularly, this invention relates to the assembling of marine propulsion systems that are comprised of certain types of outboard sterndrive units connected to certain types of inboard engines by means of transom assemblies that are also used to attach the propulsion systems to the vessels. More particularly, the invention relates to a method and kit for assembling Mercruiser Alpha-One-type sterndrive units and Outboard Marine Corporation (“OMC”) Cobra-type inboard engines and attaching them to a marine vessel by means of transom assemblies. Specifically, the invention relates to a novel technique for adapting Mercruiser Alpha-One-type sterndrive units to OMC Cobra-type inboard engines and transom assemblies using commercially available parts and minimal special hardware. The invention is also further applicable to the assembling of other marine propulsion systems that are comprised of similar combinations of other outboard sterndrive units attached to other similar inboard engines by means of transom assemblies.
BACKGROUND OF THE INVENTION
Inboard-outboard marine propulsion systems, sometimes also referred to as “marine engine packages”, or “I/O propulsion systems”, are well-known in the marine vessel industry. These systems usually consist of an inboard component that includes an internal combustion engine and related hardware, an outboard component often enclosed in a casing with conventional hardware, and a transom assembly that serves the purpose of connecting the inboard component to the outboard component and securing the propulsion system to the vessel. The inboard component and the outboard component are connected to each other by a series of bolts, nuts, pins and other hardware that allow the transmission of power from the inboard component to the outdrive. Additional hardware is provided to secure the propulsion system to the transom of the vessel. Among these inboard-outboard marine propulsion systems, those manufactured by Outboard Marine Corporation (“OMC”) have been used for years in the industry due to their durability and reliability, and many boats and other marine vessels are equipped with these types of systems. OMC inboard-outboard marine propulsion systems are no longer manufactured by OMC, even though their inboard engine components continue to be available as used parts and aftermarket equipment. In addition, inboard engine components of the type made by Volvo Penta and similar manufacturers continue to be available, new, used and as aftermarket equipment. Hardware to secure propulsion systems to the transom of boats and other marine vessels exist which usually consist of various arrangements of support plates, gimbal rings, bell housings, gimbal housings and other such parts. For example, U.S. Pat. Nos. 4,872,531 and 5,238,433 disclose the use of such types of hardware arrangements in conjunction with marine sterndrive units and inboard engines of watercraft inboard-outboard propulsion systems. The hardware arrangements described in these patents, however, have their limitations and are not suitable for adapting Mercruiser Alpha-One-type sterndrive units to OMC Cobra-type inboard engines and transom assemblies using commercially available parts and minimal special hardware.
It is apparent that a need exists for a technique whereby Mercruiser Alpha-One-type sterndrive units may be adapted to OMC Cobra-type inboard engines and transom assemblies using commercially available parts and minimal special hardware. The present invention is directed toward providing such a technique.
It is an object of the present invention to provide a method and a kit for the proper and safe assembling of inboard-outboard marine propulsion systems. It is a specific object of the present invention to provide a method and a kit for assembling Mercruiser Alpha-One-type sterndrive units and OMC Cobra-type inboard engines and attaching them to a marine vessel by means of transom assemblies. It is also an object of the present invention to provide a method and a conversion kit for adapting Mercruiser Alpha-One-type sterndrive units to OMC Cobra-type inboard engines and transom assemblies using commercially available parts and minimal special hardware. Another object of this invention is to provide a commercially practicable method and system for the proper and safe assembling of inboard-outboard marine propulsion systems while utilizing conventional components in a novel fashion in a safe and cost-effective manner. These and other objects of the invention will be apparent to those skilled in the art from the description that follows.
SUMMARY OF THE INVENTION
The method and the system of this invention center around the innovative concept of providing a modified transom assembly design, as well as a method for its use and installation. The invention allows the use of Mercruiser Alpha-One-type sterndrive units on marine vessels originally equipped with OMC Cobra-type inboard engines and does not require the replacement of the OMC transom assembly. Conventional hardware is used in assembling the propulsion system Is and securing it to the vessel. The modified transom assembly system of the invention is sometimes referred to as the “Mercruiser® Alpha®-One Conversion Kit” or, simply, as the “Mercruiser® Conversion Kit”. Mercruiser and Alpha are believed to be registered marks of the Brunswick Corporation. The invention is also further applicable to the assembling of other marine propulsion systems that are comprised of equivalent combinations of other similar sterndrive units attached to other similar inboard engines by means of transom assemblies.
The modified transom assembly design of the invention involves the following components:
(a) An inner transom plate comprised of an inner transom support plate (made of aluminum or some other strong and corrosion-resistant metal or material), equipped with means for connecting an inboard engine on one side and means for attaching a gimbal housing on its other side. The means for connecting an inboard engine on one side include two or more inner transom plate through holes drilled on protruding members of the support plate and companion inner transom plate threaded bolts and nuts, or similar suitable hardware. The means for attaching the gimbal housing to the other side of the support plate are preferably six through holes adapted to receive threaded studs, or similar suitable hardware.
(b) A gimbal housing comprised of a gimbal housing casting with means for attaching the inner transom plate to its back (mounting) surface and means for connecting to its opposite surface a gimbal ring and the bellows from the bell housing. The means for attaching the inner transom plate to its back surface preferably include six gimbal housing threaded studs and matching nuts. The means for connecting a gimbal ring to its opposite surface preferably comprise symmetrically-located upper and lower gimbal housing through holes adapted to receive retaining pins (“gimbal housing swivel pins”). The means for connecting the bell housing bellows to its opposite surface include at least one pipe-shaped casting, flanged at one end (the “gimbal housing flanged casting”), and adapted to receive a gimbal bearing inside it, and the bell housing bellows on its outside. A clamp and an optional seal are used to secure the parts in place.
(c) A gimbal ring comprised of a gimbal ring casting made of aluminum (or some other strong and corrosion-resistant metal or material), having a substantially oval overall shape, and provided with a gimbal ring support base at the bottom and several symmetrically-located openings, or “through holes”. A first pair of gimbal ring through holes on the side brackets of the casting is adapted to receive two machine-made hinge pins that allow the bell housing to oscillate up and down. A second pair of gimbal ring through holes are provided on the side brackets, below the first pair and located near the support base of the gimbal ring. This second pair of through holes serves to receive the hydraulic cylinder trim pin described below. A third pair of gimbal ring through holes on the casting support base and the casting top bracket, respectively, align themselves with the upper and lower through holes of the gimbal housing so that gimbal housing swivel pins may be placed in the through holes to secure the gimbal ring to the gimbal housing. The gimbal ring is also provided with two or more spacers, made of strong plastic or similar material, that are attachable to the inner portion of the “ears” of the gimbal ring. The gimbal ring may also include a steering arm or similar means for steering the marine vessel.
(d) Two trim cylinders and trim pins. The trim cylinders are hydraulic cylinders. The first trim pin penetrates the gimbal ring through holes located near the support base of the gimbal ring and is used to secure two ends of the trim cylinders to the gimbal ring. The second trim pin, on a parallel plane with the first trim pin, is connected to the other ends of the trim cylinders and serves to secure the other ends to the sterndrive. Suitable hardware should also be included.
(e) A bell housing that comprises a bell housing casting (made of aluminum or some other strong and corrosion-resistant metal or material), sized and shaped to fit inside the gimbal ring and provided with symmetrically-located bell housing through holes that align themselves with through holes in the gimbal ring and allow the bell housing to be secured to the gimbal ring by means of hinge pins. The bell housing also includes the custom-made bell housing u-joint bellows, the bell housing flanges, the bell housing clamps, the bell housing first water hose, the bell housing second water hose, and a bell housing adaptor nipple.
The method of the invention may be conveniently described with reference to a particularly preferred embodiment and application, that is, the mating of a Mercruiser Alpha-One-type sterndrive to an OMC Cobra-type inboard engine. It should be understood, however, that the method has applications in the proper assembling of other equivalent combinations of similar sterndrive units attached to other inboard engines by means of transom assemblies. In this preferred embodiment, the method of the invention comprises: (a) mating the inner diameter of the gimbal housing end of the Mercruiser Alpha-One-type sterndrive unit's u-joint rubber bellows to the gimbal housing flange of OMC Cobra-type engine's transom assembly by means of a u-joint bellows clamp; (b) attaching the bell housing of the Mercruiser Alpha-One-type sterndrive unit to the OMC Cobra-type engine's transom assembly's gimbal ring by means of two custom-made hinge pins that are specifically threaded to match the bell housing threaded holes on the Mercruiser Alpha-One-type sterndrive unit, said two custom-made hinge pins also having smooth bearing surfaces that match the inner diameters of the gimbal ring through holes; (c) attaching the Mercruiser Alpha-One-type sterndrive unit's seawater pump output hose (bell housing first water hose) to the seawater pump output hose (bell housing second water hose) of the OMC Cobra-type engine's transom assembly by means of a bell housing adaptor nipple that increases the effective diameter (ID) of the Mercruiser Alpha-type sterndrive unit's seawater pump output hose (bell housing first water hose) to match the effective diameter (ID) of the seawater pump output hose (bell housing second water hose) of the OMC Cobra-type engine's transom assembly; and (d) modifying (cut or filed to fit) the Mercruiser Alpha-One-type sterndrive unit's stops, as needed, to limit the amount of negative trim, and/or to trim down the bow of the marine vessel and optimize the ability to raise and lower the bow of the vessel. Bushings made of fiber or some other suitable material may be inserted and pressed into the gimbal ring through holes in order to minimize wear on the OMC Cobra-type engine's transom assembly's gimbal ring. The modified transom assembly may also be provided with two or more spacer guides, made of strong plastic or similar material, that are attachable to the inner portion of the “ears” of the gimbal ring.
BRIEF DESCRIPTION OF THE DRAWINGS
A clear understanding of the key features of the invention summarized above may be had by reference to the appended drawings. Accordingly:
FIG. 1 a and FIG. 1 b illustrate the modified transom assembly of the invention showing all of its components. FIG. 1 a shows the inner transom plate, the gimbal housing and the gimbal ring components of the invention with their related hardware; and FIG. 1 b shows the bell housing component of the invention and its related hardware.
FIG. 2 is a diagram of the gimbal ring component and the spacer guides of the modified transom assembly of the invention.
FIG. 3 is a diagram of the bell housing component of the modified transom assembly of the invention, showing the custom-made bell housing u-joint bellows and the bell housing adaptor nipple.
FIG. 4 is a diagram of one of the machine-made gimbal ring hinge pins of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The various components of the modified transom assembly of the invention are shown in FIG. 1 a and FIG. 1 b . Accordingly, referring to FIG. 1 a and FIG. 1 b , inner transom plate 101 is comprised of inner transom support plate 102 , which is a casting made of aluminum or some other strong and corrosion-resistant metal or material and equipped with means for connecting an inboard engine on one side and means for attaching a gimbal housing on its other side. The inner transom plate is normally placed inside the vessel. (So that its various parts are easily discernible, the inner transom plate is shown, in FIG. 1 a , oriented 180 degrees from the direction in which it normally faces the gimbal housing.) The means for connecting an inboard engine on one side include two or more inner transom plate through holes 105 drilled on protruding members 106 of support plate 102 and companion inner transom plate threaded bolts and nuts (not shown). The means for attaching the gimbal housing to the other side of support plate 102 are preferably six through holes 103 adapted to receive threaded studs or similar suitable hardware 104 .
Gimbal housing 107 is comprised of gimbal housing casting 108 , which is a casting made of aluminum or some other strong and corrosion-resistant metal or material and equipped with means for attaching inner transom plate 101 to its back (mounting) surface and with means for connecting to its opposite surface a gimbal ring and the bellows from the bell housing. The gimbal housing is normally placed outside the vessel. The means for attaching inner transom plate 101 to the back surface of gimbal housing casting 108 preferably include six or more gimbal housing threaded holes (not shown) and matching studs 115 , as well related hardware 104 . The means for connecting a gimbal ring to the opposite surface of gimbal housing casting 108 comprise symmetrically-located upper and lower gimbal housing through holes 109 adapted to receive upper and lower gimbal housing swivel pins 110 , which are retaining pins. Removable casting 111 is used to conveniently retain lower gimbal housing swivel pin 110 in place. The upper gimbal housing through hole 109 can alternatively receive built-in swivel pin 126 as described below. The means for connecting the bell housing bellows to the opposite surface of the gimbal housing casting 108 include at least one gimbal housing flanged casting 117 , which is a pipe-shaped casting, flanged at one end and adapted to receive the gimbal bearing 112 inside and the bell housing bellows on the outside. The gimbal housing flanged casting is sometimes referred to in this Specification as the “gimbal housing flange”. A clamp (not shown) and an optional seal 113 are used to secure the parts in place. Gimbal housing water tube 114 , described below, is also part of the gimbal housing.
Gimbal ring 118 is comprised of gimbal ring casting 119 , which is a casting made of aluminum or some other strong and corrosion-resistant metal or material, having a substantially oval overall shape and provided with gimbal ring support base 120 at the bottom and several symmetrically-located openings, or “through holes”. The gimbal ring allows the sterndrive to swing left and right. As shown in FIG. 1 a , gimbal ring support base 120 includes two symmetrically-spaced ear-shaped portions that are sometimes referred to as the “ears” of the gimbal ring. A first pair of gimbal ring through holes 121 on the side brackets of the casting is adapted to receive two machine-made hinge pins 122 and (optional) companion hinge pin bushings 123 that allow the bell housing to oscillate up and down. A second pair of gimbal ring through holes 124 are provided on the side brackets, below the first pair and located near the support base of the gimbal ring. This second pair of through holes serves to receive the hydraulic cylinder trim pin described below. A third pair of gimbal ring through holes 125 on the casting support base and the casting top bracket, respectively, align themselves with the upper and lower gimbal housing through holes 109 so that gimbal housing swivel pins 110 may be placed in the through holes to secure the gimbal ring to the gimbal housing. In a preferred embodiment, built-in swivel pin 126 is used instead of a regular swivel pin 110 to secure the upper portion of the gimbal ring to the gimbal housing. The gimbal ring is also provided with two or more spacer guides, made of strong plastic or similar material, that are attachable to the inner portion of the “ears” of the gimbal ring. The gimbal ring may also include a steering arm or similar means for steering the marine vessel. In the illustration shown in FIG. 1 a , steering lever 127 and lever retaining bolt 128 are used for that purpose.
The transom assembly also includes two trim cylinders and two trim pins. The two trim cylinders 129 are twin hydraulic cylinders shaped and sized to be mated to the trim pins. The first trim pin 130 is shaped and sized to penetrate and fit snuggly into second pair of gimbal ring through holes 124 , located near the support base of the gimbal ring, and to mate to one end of the two trim cylinders. Suitable hardware 131 , in the form of bushings, washers, clips, caps and the like, is used to connect the cylinders to the trim pins. The first trim pin 130 is used to secure two ends of trim cylinders 129 to the gimbal ring. The second trim pin 132 , on a parallel plane with first trim pin 130 , is connected to the other ends of trim cylinders 129 by suitable hardware 131 and serves to secure the other ends of trim cylinders 129 to the sterndrive.
The transom assembly also comprises a modified bell housing 133 that comprises a bell housing casting 134 , which is a casting made of aluminum or some other strong and corrosion-resistant metal or material, and sized and shaped to fit inside the gimbal ring. Bell housing casting 134 is provided with symmetrically-located and threaded bell housing holes 137 that align with first pair of gimbal ring through holes 121 in the gimbal ring and allow the bell housing to be secured to the gimbal ring by means of machine-made hinge pins 122 and optional companion hinge pin bushings 123 so that the bell housing is able to oscillate up and down.
The bell housing 133 , FIG. 1 b , also includes the bell housing u-joint bellows 138 , preferably made of rubber or rubber-like material, the bell housing flanges (not shown), which are similar to the flange of gimbal housing flanged casting 117 ), the bell housing gasket 136 , the bell housing clamps 145 , the bell housing first water hose 143 , the bell housing second water hose 144 , and the bell housing adaptor nipple 146 . The bell housing attaches to the gimbal housing and allows the sterndrive to move up and down. Studs 135 and gasket 136 are used to attach the sterndrive (not shown) to bell housing casting 134 . Bell housing u-joint bellows sleeve 139 is used to secure one end of bell housing u-joint bellows 138 to a flange located in bell housing 133 ; gimbal housing u-joint bellows clamp 140 is used to secure the other end of bell housing u-joint bellows 138 to gimbal housing flange 117 . The bell housing u-joint bellows surround and protect a segment of the stemdrive shaft, usually the segment that comprises the u-joints of the shaft. Other bellows, such as bell housing exhaust bellows 141 , and bell housing exhaust bellows clamps (worm gear clamps) 142 may be used, optionally, as exhaust conduits or engine exhaust tubes. Additional bellows and suitable flanges and clamps may also be used to shroud and protect cables and other mechanical parts.
The bell housing 133 further includes bell housing first water hose 143 , bell housing second water hose 144 , and bell housing adaptor nipple 146 , as well as suitable clamps 145 . Bell housing first water hose 143 is a hose made of rubber or rubber-like material, having a length of anywhere between about 3 and 8 inches, an inside diameter of approximately ¾ inch and an outside diameter of approximately 1 1/8 inch. Bell housing first water hose 143 is connectable on one end to the bell housing water inlet (not shown) and on its other end to bell housing adaptor nipple 146 . Bell housing second water hose 144 is a hose made of rubber or rubber-like material, having a length of anywhere between about 3 and 8 inches, an inside diameter of approximately 1 inch and an outside diameter of approximately 1 5/16 inch. Bell housing second water hose 144 is connectable on one end to bell housing adaptor nipple 146 and on its other end to gimbal housing water tube 114 . Suitable clamps 145 are used to make these connections. The gimbal housing water tube 114 is a molded plastic tube having a length of anywhere between about 6 and 12 inches, a variable-size inside diameter and an outside diameter of approximately 1 inch. Gimbal housing water tube 114 is attached to gimbal housing casting 108 by means of suitable hardware 116 . The gimbal housing water tube is used to transfer water from the bell housing second water hose to the engine for engine cooling purposes. The bell housing first water hose is connected to the bell housing water inlet by means of a water inlet nipple (not shown). The bell housing water inlet is a cavity that receives seawater withdrawn from the sea by means of a cavity in the sterndrive. The bell housing water inlet is preferably cylindrical and runs the depth of the bell housing. The bell housing water inlet may be threaded at its backside (facing the gimbal housing) to best secure it to the water inlet nipple (if the water inlet nipple is also threaded). The water inlet nipple may also be glued, pressed or, if convenient, bolted to the bell housing, or it may even be part of the bell housing casting. Preferably, the water inlet nipple is made of plastic and pressed and glued to the bell housing casting on one end.
Bell housing first water hose 143 and bell housing second water hose 144 are connected to each other by means of bell housing adaptor nipple 146 . Bell housing adaptor nipple 146 is a 2 1/8 -inch-long unthreaded pipe-shaped conduit provided with an opening at each end. The first opening is substantially round and has an outside diameter (“OD”) of approximately ¾ inch and an inside diameter (“ID”) of approximately ½ inch. The second opening is substantially round and has an outside diameter of approximately 1 inch and an inside diameter of approximately ¾ inch. Worm gear clamps or similar clamping devices are used on both ends of bell housing adaptor nipple 146 in order to secure first water hose 143 and second water hose 144 to it. Bell housing adaptor nipple 146 is preferably made of a strong plastic. The adaptor nipple may also be made of stainless steel, brass or some other metal.
The gimbal ring component and the spacer guides of the modified transom assembly design of the invention are illustrated in FIG. 2 , where gimbal ring 201 is shown with first pair of gimbal ring through holes 202 drilled through gimbal ring side brackets 203 , second pair of gimbal ring through holes 204 , drilled through the lower portions of side brackets 203 , and third pair of gimbal ring through holes 205 drilled through the upper and lower supporting brackets 206 and 207 , respectively. Built-in swivel pin 208 fits in upper through hole 205 and functions as a swivel pin to secure the upper portion of the gimbal ring to the gimbal housing. The first pair of gimbal ring through holes 202 is not threaded; the holes are aligned with each other on the same plane; and each of their inner diameters is adapted to receive the smooth-bearing outer surface of the custom-made hinge pin, depicted in FIG. 4 , below. The second pair of through holes 204 serves to receive the hydraulic cylinder trim pin, as already described. The third pair of gimbal ring through holes 205 on the casting support base and the casting top bracket, respectively, align themselves with the upper and lower gimbal housing through holes so that gimbal housing swivel pins may be placed in the through holes to secure the gimbal ring to the gimbal housing. Spacer guides 209 may be round, square, triangular or of any other convenient shape. They may also mimic the shape of the “ears” of the gimbal ring as shown in FIG. 2 . The spacer guides should be made of strong plastic or similar minimum-wear material and have a minimum thickness of approximately ½ inch and a maximum thickness of approximately ¾ inch. They may be bolted, glued or otherwise attached to the “ears” of the gimbal ring or, alternatively, they may be bolted, glued or otherwise attached to the sides of the sterndrive. In one preferred embodiment the spacer guides are ½-inch-thick round plastic ring-shaped pads 210 , capable of being bolted to the sides of the sterndrive.
FIG. 3 is a diagram of two elements of the bell housing component of the modified transom assembly of the invention, showing the custom-made bell housing u-joint bellows 301 and the bell housing adaptor nipple 306 . As illustrated in FIG. 3 , custom-made accordion-shaped rubber bellows 301 are ridged on their outer surface and on their inner surface, except for the ends; their length is 5 1/4 inches, and their outside diameter (OD), including the ridges, is 5½ inches. Their inside diameter (ID) is 3 7/8 inches, except for the portion that comprises the gimbal housing end, which has an ID of 4 inches. Bell housing end 302 of rubber bellows 301 is sized to retain that end of the bellows and secure it to a flange (not shown) located in the bell housing. Thus, its length is approximately ½ inch, its inside diameter (ID) is 3 7/8 inches, its major outside diameter, including the ridge, is 4 3/8 inches, and its minor outside diameter is 4 1/8 inches. Bell housing u-joint bellows sleeve 303 fits snuggly inside bell housing end 302 of rubber bellows 301 and is sized accordingly. Making and sizing the bell housing end 302 of rubber bellows 301 in this fashion, together with bellows sleeve 303 , allows the assembler to connect the modified bell housing component of the invention to a Mercruiser Alpha-One-type sterndrive unit. Gimbal housing end 304 is sized to retain that end of the bellows and secure it to the gimbal housing flange casting (flange 117 in FIG. 1 a ). Thus, the length of gimbal housing end 304 is approximately ½ inch, its inside diameter (ID) is 4 inches, its major outside diameter, including the ridge, is 4 3/8 inches, and its minor outside diameter is 4 1/4 inches. Bell housing u-joint bellows clamp 305 , used to conveniently secure gimbal housing end 304 of rubber bellows 301 to the gimbal housing flange, fits outside gimbal housing end 304 and is sized accordingly. Making and sizing the gimbal housing end 304 of rubber bellows 301 in this fashion, together with bellows clamp 305 , allows the assembler to connect the modified bell housing component of the invention to an OMC Cobra-type inboard engine. Overall, gimbal housing end 304 has smaller outside and inside diameters than bell housing end 302 . Neither end is ridged on its inside surface.
Bell housing adaptor nipple 306 is used to connect the bell housing first water hose to the bell housing second water hose. Preferably, bell housing adaptor nipple 306 is a 2 1/8 -inch-long unthreaded pipe-shaped conduit provided with an opening at each end. The first portion 307 of adaptor nipple 306 is about 1 inch long and substantially round. This portion 307 , shown in FIG. 3 as the upper portion of the nipple, has an outside diameter (“OD”) of approximately ¾ inch and an inside diameter (“ID”) of approximately ½ inch. The second portion 308 is also substantially round, has an outside diameter of approximately 1 inch and an inside diameter of approximately ¾ inch. Portion 307 fits snuggly into one end of the first water hose, while portion 308 fits snuggly into one end of the second water hose. Worm gear clamps or similar clamping devices are used on both ends of bell housing adaptor nipple 306 in order to secure to it the first water hose and the second water hose. Bell housing adaptor nipple 306 may be made of stainless steel, brass or some other metal. Preferably, the adaptor nipple is made of a strong plastic.
As already described, the bell housing casting is provided with symmetrically-located and threaded bell housing holes that align with a first pair of gimbal ring through holes in the gimbal ring and allow the bell housing to be secured to the gimbal ring by means of two machine-made hinge pins, as well as optional companion hinge pin bushings, so that the bell housing is able to oscillate up and down. Each pin is machined to custom specifications. The kind of machine-made hinge pin used for this purpose is shown in FIG. 4 as hinge pin 401 , having a first portion 402 comprising a ¾-inch-long solid cylinder, threaded on the outside to 18 threads-per-inch of length, and having a ⅝-inch outside diameter. Hinge pin 401 also has a second portion 403 comprising a ¾-inch-long solid cylinder, having a 1-inch outside diameter. The second portion 403 of pin 401 is not threaded. A socket indentation 404 , shaped and sized to fit an Allen wrench, is provided at the base of second portion 403 for ease of installation. The machined custom-made hinge pins are made of stainless steel or other similarly strong and corrosion-resistant metal. The outside surface of first portion 402 of hinge pin 401 is threaded, as specified above, in order to match and fit inside the symmetrically-located and threaded bell housing holes (shown as holes 137 in FIG. 1 b ), while the outside surface of second portion 403 of hinge pin 401 is not threaded, but is machined to fit in smoothly in gimbal ring through holes on the side brackets of the gimbal ring casting (shown as through holes 121 in FIG. 1 a ). Making and using the two machined custom-made hinge pins in this fashion allows the assembler to properly secure the modified transom system's bell housing to the gimbal ring so that the bell housing may oscillate up and down and the propulsion system is able to operate properly.
The modified transom assembly of the invention may be used in conjunction with the method of the invention in order to assemble Mercruiser Alpha-One-type sterndrive units and OMC Cobra-type engines, and attach them to marine vessels. Accordingly, in reference to FIG. 1 a and FIG. 1 b , the method of the invention comprises: (a) mating the inner diameter of the gimbal housing end of the Mercruiser Alpha-One-type sterndrive unit's u-joint rubber bellows 138 to gimbal housing flange 117 of OMC Cobra-type engine's transom assembly by means of u-joint bellows clamp 140 ; (b) attaching the bell housing 133 of the Mercruiser Alpha-One-type sterndrive unit to the OMC Cobra-type engine's transom assembly's gimbal ring 118 by means of two machine-made hinge pins 122 , threaded to match the bell housing threaded holes 137 on said Mercruiser Alpha-One-type sterndrive unit, said two hinge pins 122 having smooth bearing surfaces matching the inner diameters of gimbal ring through holes 121 ; (c) attaching the Mercruiser Alpha-One-type sterndrive unit's seawater pump output hose (bell housing first water hose 143 ) to the seawater pump output hose (bell housing second water hose 144 ) of the OMC Cobra-type engine's transom assembly by means of bell housing adaptor nipple 146 , which increases the effective diameter (ID) of the Mercruiser Alpha-type sterndrive unit's seawater pump output hose (bell housing first water hose 143 ) to match the effective diameter (ID) of the seawater pump output hose (bell housing second water hose 144 ) of the OMC Cobra-type engine's transom assembly; and (d) modifying (cut, shaved or filed to fit) the Mercruiser Alpha-One-type sterndrive unit's stops, as needed, to limit the amount of negative trim, and/or to trim down the bow of the marine vessel and optimize the ability to raise and lower the bow of the vessel. The sterndrive stops are protrusions located on the upper portion of the housing of the sterndrive and designed to limit the degree of negative trim of the vessel. Optionally, fiber bushings 123 may be inserted and pressed into through holes 121 to minimize wear on the OMC Cobra-type engine's transom assembly's gimbal ring.
It will be understood that the appended figures depict preferred embodiments of the present invention and, therefore, are not to be considered as limiting its scope with regard to other embodiments which the invention is capable of contemplating. While the invention has been described in terms of particular embodiments and applications, in both summarized and detailed forms, it is not intended that these descriptions in any way limit its scope to any such embodiments and applications, and it will be understood that various substitutions, changes and variations in the described embodiments, applications and details of the method and system illustrated herein and of their operation can be made by those skilled in the art without departing from the spirit of this invention. | A method and a conversion kit are provided for assembling marine propulsion systems such as those comprised of a Mercruiser Alpha One® type sterndrive unit, an OMC Cobra® type inboard engine and a transom assembly, and attaching the propulsion systems to marine vessels. The method and the kit use commercially available parts and minimal special hardware. The technique involves a modified transom assembly comprised of an inner transom plate, a gimbal housing, a gimbal ring equipped with machined custom-made hinge pins, two trim cylinders with corresponding trim pins, and a bell housing with specially designed bellows and adaptor nipple. The invention is also applicable to the assembling of other marine propulsion systems that are comprised of equivalent combinations of similar sterndrive units attached to other similar inboard engines by means of transom assemblies. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to PCT/IB2012/000021 filed Jan. 10, 2012, which claims priority to European Application 11150905.5 filed Jan. 13, 2011, both of which are hereby incorporated in their entireties.
BACKGROUND
The present disclosure relates to a method for drying a wet CO 2 rich gas stream from an oxy-combustion process, in particular to a drying method with an adsorption process using a desiccant (adsorbent) and regenerating this adsorbent.
A wet CO2 rich gas stream from an oxy-combustion process has to be treated in order to remove H2O during or after a first compression step. The moisture of the wet CO2 rich gas stream has to be limited due to the need to avoid the formation of solid hydrates or a corrosive, free water phase during the downstream separation or injection process. For such a drying step or process, at least one vessel containing at least one desiccant for adsorbing the moisture from the wet CO2 rich gas stream passing the desiccant in one direction is typically used. For desiccant regeneration the flow through the desiccant bed is provided in the reverse direction. Typical installations foresee two dryers, where one is in operation whilst the other is in standby, respectively in regeneration mode.
Document WO 2009/071816 A2 discloses a method for drying a gas rich in carbon dioxide at high pressure, in which the gas rich in carbon dioxide is cleaned in an adsorption drying unit, comprising at least two bottles of adsorbent operating in a cycle in which one bottle is supplied with gas rich in carbon dioxide for drying whilst another bottle is pressurized and regenerated by means of a flow of dry gas produced by the drying unit, the drying unit producing at least one dry gas rich in carbon dioxide on the first pressurisation of at least one bottle, during which a pressurised gas other than a product from the drying unit is provided to the bottle.
It can be seen as disadvantageous from this known method that the produced dry gas rich in carbon dioxide is used as regeneration gas and after regeneration the gas is discharged to the atmosphere. This causes a disadvantageous loss of CO2. On the other hand recycling of the CO2 leads to disadvantageous increased power demand for compression.
SUMMARY
The above drawbacks and deficiencies are overcome or alleviated by a method for drying a wet CO2 rich gas stream from an oxy-combustion process, the method comprising: compressing the wet CO2 rich gas stream to a drying process operating pressure, cooling the wet CO2 rich gas stream in at least one cooler, alternately drying the wet CO2 rich gas stream in at least one dryer which contains at least one desiccant bed and regenerating the desiccant bed by conducting a heated regenerating gas through the dryer in opposite direction to the flow direction of the wet CO2 rich gas stream, separating the dried CO2 rich gas stream in a purification process to a purified CO2 gas stream and a waste gas stream rich in nitrogen and oxygen, whereby the waste gas stream rich in nitrogen and oxygen is used as regenerating gas, and subsequently to the regeneration the dryer is purged at least once by a pressurized CO2 rich gas stream conducted from the compressor, and whereby the dryer is charged up to the drying process operating pressure with a pressurized CO2 rich gas stream conducted from the compressor before each drying process. Other advantageous embodiments of the invention can be seen from the appended claims.
The present method provides a method for drying a wet CO 2 rich gas stream from an oxy-combustion process having low CO 2 losses and an energetically high efficiency. More specifically, the method for drying a wet CO2 rich gas stream from an oxy-combustion process offers the following advantages:
Less CO2 losses since a gas stream with low CO2 content is taken for the regeneration of the desiccant in the dryer,
The energetic consumption during the drying and regeneration process is reduced.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the invention will become apparent from the following description of embodiments of the invention given by way of non-limiting examples only, and with reference to the accompanying drawings, in which:
FIG. 1 is a schematic diagram of a method for drying a wet CO 2 rich gas stream from an oxy-combustion process according to a first embodiment,
FIG. 2 is a schematic diagram of a method for drying a wet CO 2 rich gas stream from an oxy-combustion process according to a second embodiment.
DETAILED DESCRIPTION
A wet CO2 rich gas stream from an oxy combustion process has to be treated in order to remove H2O during or after a first compression step. The moisture of the wet CO2 rich gas stream has to be limited due to the need to avoid the formation of solid hydrates or a corrosive, free water phase during the downstream separation or injection process of the CO2 purification process.
According to FIG. 1 the wet CO2 rich gas stream 1 , which gas stream can also be designated as a flue gas stream coming in hot condition from an oxy-combustion process is conducted via line 11 to a compressor 2 and the gas is compressed therein to a drying process operating pressure which lies preferably between 10 to 60 bar. The compressor 2 usually possesses multiple compression stages and therefore it is also possible to install the drying unit 6 . 1 , 6 . 2 at an intermediate compression stage. Most preferably the pressure as drying process operating pressure is selected in the range of 25 to 55 bar. Thus, it is possible to minimize the water load to the drying process by a condensation step between the compression stage discharge 2 and the dryer 6 . 1 , 6 . 2 . In the embodiment of the invention shown in FIG. 1 the hot gas stream 1 downstream of the compressor 2 is conducted (via line 11 ) and cooled in at least one cooler, preferably in two coolers 3 . 1 and 3 . 2 . Further and preferably, a flue gas treatment device 4 located downstream of the cooler 3 . 1 for removing of Hg, SOx, dust and the like as well as preferably a vapour liquid separator 5 located downstream of the cooler 3 . 2 to separate condensed moisture from the gas stream and a liquid outlet via a line 13 leading to a waste water treatment (not shown) are arranged. The provision of the flue gas treatment device 4 is extending the lifetime of the desiccant 7 . 1 , 7 . 2 located in the dryer 6 . 1 , 6 . 2 while the provision of the vapour liquid separator 5 will help to reduce the size of the dryer 6 . 1 , 6 . 2 .
Downstream of the cooler 3 . 1 , 3 . 2 preferably two dryers 6 . 1 , 6 . 2 are arranged for drying the wet CO2 rich gas stream 1 . Each dryer contains at least one fixed bed of desiccant 7 . 1 , 7 . 2 for adsorbing the moisture of the wet CO2 rich gas stream 1 . According to the invention each dryer 6 . 1 , 6 . 2 works alternately in a drying mode and in a regenerating mode. In the drying mode the wet CO2 rich gas stream 1 is dried by the desiccant 7 . 1 , 7 . 2 and in the regenerating mode the desiccant 7 . 1 , 7 . 2 is regenerated by a regeneration gas stream 9 . According to FIG. 1 dryer 6 . 2 is in drying mode and dryer 6 . 1 is in regeneration mode or in stand-by mode. Therefore, if two or more dryers 6 . 1 , 6 . 2 are used then the dryers are arranged preferably in parallel to use them as described before. The valves 20 . 1 , 20 . 2 and 17 . 1 , 17 . 2 will be opened and/or closed accordingly.
Another preferable embodiment of the invention provides an arrangement having two dryers 6 . 1 , 6 . 2 in series operation (not shown in the figures) with provisions to change the sequence in which the dryers 6 . 1 , 6 . 2 are passed by the CO2 rich gas stream 1 to prevent water breakthrough into the downstream system. In such arrangements the dryer 6 . 1 , 6 . 2 being passed first by the CO2 rich gas stream 1 is then also reaching its adsorption capacity first. This dryer 6 . 1 , 6 . 2 will be taken out of operation by bypassing it, then being regenerated and put back into operation with the changed sequence, that does mean the regenerated dryer 6 . 1 , 6 . 2 is being passed by the CO2 rich gas stream 1 as second.
Downstream of the dryers 6 . 1 , 6 . 2 the dried CO2 rich gas stream (dried flue gas stream) 8 underlies a purification process (not shown) where the dried CO2 rich gas stream 8 is separated to an almost pure CO2 gas stream and a waste gas stream containing high amounts of nitrogen and oxygen.
According to the invention the waste gas containing nitrogen and oxygen is used as regeneration gas 9 and conducted via a line 12 to the dryer 6 . 1 , 6 . 2 in the opposite flow direction compared to the flow direction of the wet CO2 rich gas stream 1 and during the regenerating mode of the dryers 6 . 1 , 6 . 2 for desorbing the moisture of the desiccant 7 . 1 , 7 . 2 . Before the regeneration gas stream 9 is brought to the dryers 6 . 1 , 6 . 2 it is heated up to a temperature of preferable more than 160° C. and less than 300° C. by a heater 10 . The regeneration gas stream 9 uses a lower pressure than the wet CO2 rich gas stream 1 during the drying mode. The regeneration process has a periodic recurrence, but the cycle time depends on the desiccant 7 . 1 , 7 . 2 (adsorbent) and the moisture content of the wet CO2 rich gas stream 1 .
According to the invention the dryer 6 . 1 , 6 . 2 is purged or cleaned at least once by a CO2 rich gas stream after the regeneration of the desiccant 7 . 1 , 7 . 2 and which purging gas stream is taken from the outlet of compressor 2 . Purging of the dryer 6 . 1 , 6 . 2 is done by partly pressurization with the CO2 rich gas stream followed by depressurization of the dryer 6 . 1 , 6 . 2 to atmosphere or back into the upstream process or drying process respectively. The purging has to be done to reduce the content of inert gases like nitrogen entrained by the regeneration gas stream 9 into the dryer 6 . 1 , 6 . 2 . According to FIG. 1 the CO2 rich gas stream is taken preferably directly from the outlet of compressor 2 (upstream of the coolers 3 . 1 , 3 . 2 ) via line 14 . According to another preferred embodiment and shown in FIG. 2 the CO2 rich gas stream for purging the dryer 6 . 1 , 6 . 2 is taken downstream of the cooler 3 . 1 , 3 . 2 via line 15 and heated in the heater 10 up to at least 80° C. before the CO2 rich gas stream is brought for purging to the dryer 6 . 1 , 6 . 2 . By heating up the CO2 rich gas stream to the before-said temperature solid CO2 formation caused by expansion of the gas into the dryer vessel, having the pressure of the regeneration gas, is avoided.
In order to take back the dryer 6 . 1 , 6 . 2 in operation and according to the invention the pressure in the dryer 6 . 1 , 6 . 2 will be increased up to the drying process operating pressure with a CO2 rich gas stream after the regeneration process and/or purging process. According to FIG. 1 the CO2 rich gas stream for increasing the pressure in the dryer 6 . 1 , 6 . 2 is taken preferably directly from the outlet of compressor 2 (upstream of the coolers 3 . 1 , 3 . 2 ) via line 14 . According to another preferred embodiment and shown in FIG. 2 the CO2 rich gas stream for increasing the pressure in the dryer 6 . 1 , 6 . 2 is taken downstream of the cooler 3 . 1 , 3 . 2 via line 15 and heated in the heater 10 before the CO2 rich gas stream is brought to the dryer 6 . 1 , 6 . 2 . Therefore, a hot CO2 rich gas stream (either heated by the compressor 2 or by heater 10 ) is used for charging the dryer 6 . 1 , 6 . 2 .
By charging the dryer 6 . 1 , 6 . 2 before the drying process according to the invention pressure surges during the switchover between the regeneration process and the drying process will be prevented because pressure surges can lead to damages like compacting/crushing of the dryer bed (desiccant bed) or bed lifting, in case of upward pressurizing flow, as well as a possible shut down of the compressor 2 or disturbances in the process. Therefore, at least one valve 16 . 1 , 16 . 2 in the inlet and at least one valve 17 . 1 , 17 . 2 in the outlet piping (or directly attached on the dryer 6 . 1 , 6 . 2 ) is provided to decrease and/or increase the pressure in the dryer 6 . 1 , 6 . 2 . A common method to decrease the pressure or to relief the dryer 6 . 1 , 6 . 2 respectively is, that the contained gas will be send via a valve 18 . 1 , 18 . 2 to the atmosphere. This also is done with the charged regeneration gas. This operation will be done if the normal feed and product line is blocked.
By using a hot CO2 rich gas stream according to the invention for charging the dryer 6 . 1 , 6 . 2 instead of using a dried but cold CO2 stream from a dryer 6 . 1 , 6 . 2 thermal stresses in the used material of the dryer 6 . 1 , 6 . 2 and in the desiccant 7 . 1 , 7 . 2 are prevented. By using the hot gas stream according to the invention low temperatures with dry ice formation (in worst case) after the adiabatic expansion into the dryer 6 . 1 , 6 . 2 can be prevented because the expanded hot gas stream has also a lower but not too cold temperature. The temperature of the hot CO2 rich gas stream depends from the compression relation of the compressor 2 and lies preferably between 80-140° C. Otherwise, when the CO2 rich gas stream is heated in the heater 10 then it is heated up preferably to at least 80° C. before the CO2 rich gas stream is brought for charging to the dryer 6 . 1 , 6 . 2 .
For the first pressurization or charging of the dryer 6 . 1 , 6 . 2 after erection of the system no special installations have to be foreseen. This is preferably achieved by ensuring that all desiccants beds 7 . 1 , 7 . 2 of all dryer 6 . 1 , 6 . 2 necessary for adsorption operation are open to the compressor 2 at compressor start-up, that does mean that the appropriate valves are open.
According to the operating mode (drying, regeneration, purging, charging or stand-by) of the dryer 6 . 1 , 6 . 2 the valves 16 . 1 , 16 . 2 , 17 . 1 , 17 . 2 , 18 . 1 , 18 . 2 , 19 . 1 , 19 . 2 , 20 . 1 , 20 . 2 , 21 and 22 are either opened or closed. For example, during the drying process valves 20 . 2 and 17 . 2 of dryer 6 . 2 (or valves 20 . 1 and 17 . 1 of dryer 6 . 1 ) are open, all other valves of dryer 6 . 2 are closed. During the regeneration process valves 21 (exists only according the example of FIGS. 2 ), 19 . 2 and 18 . 2 of dryer 6 . 2 (or valves 19 . 1 and 18 . 1 of dryer 6 . 1 ) are opened, all other valves of dryer 6 . 2 are closed (including valve 22 which exists only according the example of FIG. 2 ). During the purging process valves 22 (exists only according the example of FIGS. 2 ) and 16 . 2 of dryer 6 . 2 (or valve 16 . 1 of dryer 6 . 1 ) are opened and closed after a certain pressure level, preferably 10 to 15 bar is reached. Then the valve 18 . 2 (or valve 18 . 1 of dryer 6 . 1 ) is opened to depressurize the system once again. This sequence can be repeated in case that impurity levels are still too high. Otherwise, charging of the dryer 6 . 1 , 6 . 2 can be initiated by opening of valves 22 (exists only according the example of FIGS. 2 ) and 16 . 2 of dryer 6 . 2 (or valve 16 . 1 of dryer 6 . 1 ), all other valves of dryer 6 . 2 are closed (including valve 21 which exists only according the example of FIG. 2 ). When the pressure level in the dryer 6 . 1 , 6 . 2 has reached the drying process operating pressure level the line 11 . 2 with its process valves 20 . 2 and 17 . 2 of dryer 6 . 2 (or line 11 . 1 with its valves 20 . 1 and 17 . 1 of dryer 6 . 1 ) can be opened to put the respective dryer back into adsorption operation, that does mean drying operation.
The drying and regenerating process according the invention provides a best solution with respect to energetic consumption and also low CO2 losses.
While the invention has been described with reference to various exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. | A method for drying a wet CO 2 rich gas stream from an oxy-combustion process that includes: compressing the wet CO 2 rich gas stream to a drying process operating pressure, cooling the wet CO 2 rich gas stream in at least one cooler, alternately drying the wet CO 2 rich gas stream in at least one dryer which contains at least one desiccant bed and regenerating the desiccant bed by conducting a heated regenerating gas through the dryer in opposite direction to the flow direction of the wet CO 2 rich gas stream, separating the dried CO 2 rich gas stream in a purification process to a purified CO 2 gas stream and a waste gas stream rich in nitrogen and oxygen, whereby the waste gas stream rich in nitrogen and oxygen is used as regenerating gas, and subsequently to the regeneration the dryer is purged at least once by a pressurized CO 2 rich gas stream conducted from the compressor, and whereby the dryer is charged up to the drying process operating pressure with a pressurized CO 2 rich gas stream conducted from the compressor before each drying process. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of my prior design patent application Ser. No. 29/067,232, filed Feb. 28, 1997, now U.S. Pat. No. D 393,899.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to toilet seat lifting devices and more particularly pertains to a new sanitary toilet seat apparatus for permitting a user to raise and lower a toilet seat without having to touch the toilet seat directly.
2. Description of the Prior Art
The use of toilet seat lifting devices is known in the prior art. More specifically, toilet seat lifting devices heretofore devised and utilized are known to consist basically of familiar, expected and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which have been developed for the fulfillment of countless objectives and requirements.
Known prior art toilet seat lifting devices include U.S. Pat. No. 5,437,063; U.S. Pat. No. 5,020,165; U.S. Pat. No. 4,910,810; U.S. Pat. No. Des. 351,550; U.S. Pat. No. 5,394,570; and U.S. Pat. No. 5,435,017.
While these devices fulfill their respective, particular objectives and requirements, the aforementioned patents do not disclose a new sanitary toilet seat apparatus. The inventive device includes a toilet seat which is pivotally couplable to a toilet. At least one counterweight member is coupled to the back end of the toilet seat. A handle member is pivotally coupled to the counterweight member such that the upper end of the handle member upwardly extends from the counterweight member.
In these respects, the sanitary toilet seat apparatus according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in so doing provides an apparatus primarily developed for the purpose of permitting a user to raise and lower a toilet seat without having to touch the toilet seat directly.
SUMMARY OF THE INVENTION
In view of the foregoing disadvantages inherent in the known types of toilet seat lifting devices now present in the prior art, the present invention provides a new sanitary toilet seat apparatus construction wherein the same can be utilized for permitting a user to raise and lower a toilet seat without having to touch the toilet seat directly.
The general purpose of the present invention, which will be described subsequently in greater detail, is to provide a new sanitary toilet seat apparatus and method which has many of the advantages of the toilet seat lifting devices mentioned heretofore and many novel features that result in a new sanitary toilet seat apparatus which is not anticipated, rendered obvious, suggested, or even implied by any of the prior art toilet seat lifting devices, either alone or in any combination thereof.
To attain this, the present invention generally comprises a toilet seat which is pivotally couplable to a toilet. At least one counterweight member is coupled to the back end of the toilet seat. A handle member is pivotally coupled to the counterweight member such that the upper end of the handle member upwardly extends from the counterweight member.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are additional features of the invention that will be described hereinafter and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
Further, the purpose of the foregoing abstract is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way.
It is therefore an object of the present invention to provide a new sanitary toilet seat apparatus and method which has many of the advantages of the toilet seat lifting devices mentioned heretofore and many novel features that result in a new sanitary toilet seat apparatus which is not anticipated, rendered obvious, suggested, or even implied by any of the prior art toilet seat lifting devices, either alone or in any combination thereof.
It is another object of the present invention to provide a new sanitary toilet seat apparatus which may be easily and efficiently manufactured and marketed.
It is a further object of the present invention to provide a new sanitary toilet seat apparatus which is of a durable and reliable construction.
An even further object of the present invention is to provide a new sanitary toilet seat apparatus which is susceptible of a low cost of manufacture with regard to both materials and labor, and which accordingly is then susceptible of low prices of sale to the consuming public, thereby making such sanitary toilet seat apparatus economically available to the buying public.
Still yet another object of the present invention is to provide a new sanitary toilet seat apparatus which provides in the apparatuses and methods of the prior art some of the advantages thereof, while simultaneously overcoming some of the disadvantages normally associated therewith.
Still another object of the present invention is to provide a new sanitary toilet seat apparatus for permitting a user to raise and lower a toilet seat without having to touch the toilet seat directly.
Yet another object of the present invention is to provide a new sanitary toilet seat apparatus which includes a toilet seat which is pivotally couplable to a toilet. At least one counterweight member is coupled to the back end of the toilet seat. A handle member is pivotally coupled to the counterweight member such that the upper end of the handle member upwardly extends from the counterweight member.
Still yet another object of the present invention is to provide a new sanitary toilet seat apparatus that allows easy raising and lowering of the toilet seat.
These together with other objects of the invention, along with the various features of novelty which characterize the invention, are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be made to the accompanying drawings and descriptive matter in which there are illustrated preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood and objects other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:
FIG. 1 is a schematic top view of a new sanitary toilet seat apparatus according to the present invention.
FIG. 2 is a schematic bottom view of the present invention.
FIG. 3 is a schematic first side view of the present invention.
FIG. 4 is a schematic second side view of the present invention.
FIG. 5 is a schematic back view of the present invention.
FIG. 6 is a schematic front view of the present invention.
FIG. 7 is a schematic side view of the present invention illustrating the pivoting of the seat.
FIG. 8 is a schematic perspective view of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference now to the drawings, and in particular to FIGS. 1 through 8 thereof, a new sanitary toilet seat apparatus embodying the principles and concepts of the present invention and is generally designated by the reference numeral 10 will be described.
As best illustrated in FIGS. 1 through 8, the sanitary toilet seat apparatus 10 generally comprises a toilet seat 12 which is pivotally couplable to a toilet. At least one counterweight member is coupled to the back end 16 of the toilet seat 12. A handle member 30 is pivotally coupled to the counterweight member such that the upper end 31 of the handle member 30 upwardly extends from the counterweight member.
In closer detail, the toilet seat 12 has top and bottom faces 13,14, front and back ends 15,16 and a pair of sides 17,18. As illustrated in FIGS. 7 and 8, the back end 16 of the toilet seat 12 is pivotally couplable with mounting brackets 19 to a toilet 11 such that the toilet seat 12 is pivotable between a lowered position and a raised position with respect to the toilet bowl of the toilet.
A pair of counterweight members 20,21 are coupled to the back end 16 of the toilet seat 12 and extend outwards away from the pivot axis of the pivot coupling between the back of the toilet seat and the toilet. Preferably, one of the counterweight members 20 is positioned towards one side 17 of the toilet seat 12 while the other counterweight member 21 is positioned adjacent the other side 18 of the toilet seat 12. The counterweight members 20,21 are designed for providing a counterweight for aiding raising and lowering of the toilet seat 12. In the preferred embodiment, each of the counterweight members 20,21 has a pair of spaced apart side portions 22,23 outwardly extending from the back end 16 of the toilet seat 12. Ideally, the side portions 22,23 of each of the counterweight members 20,21 are generally triangular with each having a top edge 24, a front edge 25 and a generally arcuate back edge 26. In this ideal embodiment, the top edges 24 of the side portions 22,23 face in a direction generally parallel to the direction the top face 13 of the toilet seat 12 faces and the front edges 25 of the side portions 22,23 face towards the direction which the front end 15 of the toilet faces. Each counterweight member has a removable pivot pin 27 extending between the side portions 22,23 of the counterweight member. Preferably, the pivot pin 27 is positioned adjacent the back edges 26 of the side portions 22,23 of the counterweight member towards the top edges 24 of the side portions 22,23 of the counterweight member.
The elongate handle member 30 has opposite upper and lower ends 31,32, and a longitudinal axis extending between the upper and lower ends 31,32 of the handle member 30. The handle member 30 may be pivotally coupled to either of the counterweight members depending on the preference of the user. In particular, the handle member 30 is interposed between the side portions 22,23 of the particular counterweight member 20 it is pivotally coupled to. The handle member 30 has a pivot bore extending therethrough. The pivot bore of the handle member 30 is preferably positioned between the upper and lower ends 31,32 of the handle member 30 and is generally perpendicular to the longitudinal axis of the handle member 30. The pivot pin 27 of the one counterweight member 20 is extended through the pivot bore of the handle member 30 such that the handle member 30 is pivotally coupled to that counterweight member so that the upper end 31 of the handle member 30 extends upwardly from the counterweight member and the lower end 32 of the handle member 30 downwardly depends from the counterweight member.
Preferably, the lower end 32 of the handle member 30 has a secondary counterweight portion 33. The secondary counterweight portion 33 is designed for aiding the maintaining of the longitudinal axis of the handle member 30 in a vertical plane when the toilet seat 12 is pivoted between the raised and lowered positions so that the upper end of the handle member is easily reached by a user.
In use, a user uses the upper end of the handle member to both raise and lower the toilet seat from the toilet bowl. When pivoting the toilet seat from the lowered position towards the raised position, the user pushes downwards on the handle. Conversely, when pivoting the toilet seat from the raised position towards the lowered position, the user pulls upwards on the handle member.
As to a further discussion of the manner of usage and operation of the present invention, the same should be apparent from the above description. Accordingly, no further discussion relating to the manner of usage and operation will be provided.
With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention.
Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. | A new sanitary toilet seat apparatus for permitting a user to raise and lower a toilet seat without having to touch the toilet seat directly. The inventive device includes a toilet seat which is pivotally couplable to a toilet. At least one counterweight member is coupled to the back end of the toilet seat. A handle member is pivotally coupled to the counterweight member such that the upper end of the handle member upwardly extends from the counterweight member. | 0 |
FIELD OF THE INVENTION
[0001] The present invention relates to a desulfurizer for catalytic conversion and absorption of carbonyl sulfide contained in a gas and a desulfurizer for catalytic conversion and absorption of carbon disulfide in a gas and preparation methods thereof, belonging to desulfurization technical field.
BACKGROUND OF THE INVENTION
[0002] It is well known organic sulfur widely exists in a feed gas produced by a chemical method using coal, gas and oil as raw materials, and its presence will cause poisoning deactivation of a catalyst in the subsequent processes. More and more studies and researches have been carried out for developing new technologies, such as preparation technologies of a feed gas using a low-grade coal and a coke-oven gas, coal-gas poly-generation technologies, and low-temperature steam transformation technologies.
[0003] Carbonyl sulfide is neutral or slightly acidic, and has a stable chemical property, so it is difficult to be removed completely by using a conventional desulphurization method. There are two removal methods of carbonyl sulfide in industry, i.e. dry desulfurization and wet desulphurization. Fine desulfurization is difficult to be realized by the wet desulphurization as restricted by factors such as chemical equilibrium, so carbonyl sulfide is generally removed by the dry desulfurization method wherein the carbonyl sulfide is converted into hydrogen sulfide by hydrogenolysis or hydrolysis in order for removal. Dry desulfurization generally comprises two methods, i.e. hydrolysis method and hydrogenolysis method. There are two kinds of catalysts for carbonyl sulfide hydrolysis at home and abroad. The first one is a simple conversion type hydrolysis catalyst which only has conversion effect on the carbonyl sulfide and has to be used in combination with a desulfurizer such as zinc oxide and activated carbon. The second one is conversion-adsorption type hydrolysis catalyst which not only has a conversion effect on an organic sulfur such as carbonyl sulfide, but also has an absorption effect on hydrogen sulfide converted from the organic sulfur, so it can be used alone for removal of trace sulfur. In recent years, a conversion-adsorption type bifunctional desulfurizer has drawn a great attention. For example, Chinese patent application CN1069673A discloses a catalyst for organic sulfur hydrolysis at room temperature, comprising potassium carbonate in an amount of 2-25 wt % and a spherical γ-Al 2 O 3 . When this desulfurizer is used at room temperature, the conversion rate of carbonyl sulfide reaches up to 95%, and it is capable of converting the carbonyl sulfide while absorbing hydrogen sulfide. Although the above desulfurizer for carbonyl sulfide conversion can reach a higher conversion rate at room temperature, the disadvantage is that it is just applicable to treat carbonyl sulfide with a lower concentration, such as no more than 30 mgS/m 3 , but is not applicable to treat carbonyl sulfide with a high concentration. Therefore, the problem to be solved in the prior art is how to develop a desulfurizer that can realize efficient conversion and absorption of a high-concentration carbonyl sulfide. In a chemical feed gas, CS 2 generally exists in an amount of approximately 10% of the amount of COS. CS 2 is a polar molecule and its hydrolytic process is as below:
[0000] CS 2 +H 2 O→COS+H 2 S (1)
[0000] COS+H 2 O→CO 2 +H 2 S (2)
[0000] CS 2 +CO 2 →2COS (3)
[0004] In the above process, CS 2 is converted into COS. The hydrolysis conversion rate of CS 2 is subjected to influences of carbonic oxide and hydrogen sulfide atmospheres, and it is difficult to realize a complete removal of CS 2 . In the prior art, Chinese patent application CN10112123A discloses a catalyst for carbon disulfide hydrolysis under moderate temperature, comprising a spherical γ-Al 2 O 3 as a carrier, alkali metal oxide K 2 O as a promoter, and zirconium dioxide ZrO 2 and a rare-earth metal oxide La 2 O 3 as a modifier, and prepared by an incipient-wetness impregnation method comprising impregnating the promoter and modifier followed by calcinations. The obtained catalyst has a better performance against carbon deposition and side reactions not contributing to the conversion.
[0005] Although the above catalyst has a high efficiency for treatment of CS 2 under certain conditions, it is only applicable to treat CS 2 with a concentration range of 200-500 mgS/m 3 , but not applicable to treat CS 2 with a high concentration. Therefore, the problem to be solved in the prior art is how to develop a desulfurizer which can achieve efficient conversion and absorption of a high-concentration CS 2 .
SUMMARY OF THE INVENTION
[0006] In order to solve the problem that the hydrolysis catalyst for carbonyl sulfide in the prior art is inapplicable under conditions where the carbonyl sulfide has a high-concentration, the present invention provides a desulfurizer for conversion and absorption of carbonyl sulfide with a wide-range concentration, and also provides a method for preparing the desulfurizer.
[0007] In another aspect, in order to solve the problem that the hydrolysis catalyst of CS 2 in the prior art is inapplicable under conditions where CS 2 has a high concentration, the present invention provides a desulfurizer for conversion and absorption of CS 2 with a wide-range concentration, and also provides a method for preparing the desulfurizer.
[0008] In one aspect, the present invention provides a desulfurizer for conversion and absorption of high-concentration carbonyl sulfide, comprising:
magnetic iron oxide red Fe 21.333 O 32 in an amount of 50-75 parts by weight; K 2 O in an amount of 5-10 parts by weight; anatase-type TiO 2 in an amount of 5-35 parts by weight; and a binder in an amount of 5-10 parts by weight. In accordance with one embodiment, the binder is selected from a group consisting of bentonite, kaolin clay, attapulgite, Yang Gan soil and any combination thereof.
[0013] In another aspect, the present invention provides a method for preparing the desulfurizer, comprising:
(1) mixing and reacting a FeSO 4 solution with an alkaline substance solution or solid by controlling the alkali ratio of the alkaline substance solution or solid and the FeSO 4 solution to 1-1.1 to form a first mixture, filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 ; or mixing and kneading a FeSO 4 solid with an alkaline substance solid by controlling the alkali ratio of the alkaline substance solid and the FeSO 4 solid to 1-1.1 to form a first mixture, followed by washing with water and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 ; and (2) mixing 50-75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5-35 parts by weight of anatase type TiO 2 , 5-10 parts by weight of K 2 O and 5-10 parts by weight of a binder to form a second mixture, followed by roll molding at room temperature and drying the second mixture to produce the desulfurizer.
[0017] In accordance with one embodiment, the filter cake in the step (1) is calcined at 350° C. for 2-5 hours.
[0018] In accordance with one embodiment, the alkaline substance is selected from the group consisting of hydroxides of Group IA, Na 2 CO 3 , (NH 4 ) 2 CO 3 , K 2 CO 3 , NaHCO 3 , NH 4 HCO 3 , KHCO 3 and any combination thereof.
[0019] In accordance with one embodiment, the anatase type TiO 2 and K 2 O in Step (2) are prepared by mixing and calcining 6.1-42.7 parts by weight of metatitanic acid and 7.3-14.7 parts by weight of K 2 CO 3 at a temperature of 500-700° C.
[0020] In accordance with one embodiment, the metatitanic acid is prepared by a method comprising
preparing a ferrous sulfate solution by dissolving a ferrous sulfate solid in water, wherein the ferrous sulfate solid is a by-product from titanium dioxide production by a sulfuric acid method, heating the ferrous sulfate solution up to 40-100° C., adjusting a pH value of the ferrous sulfate solution to 1-2 by adding an acid, and reacting the ferrous sulfate solution with a flocculating agent to yield a precipitate, followed by filtering the precipitate to obtain the metatitanic acid.
[0025] In accordance with one embodiment, the ferrous sulfate solution has a FeSO 4 concentration of 1-2.5 mol/L.
[0026] In accordance with one embodiment, the acid added for adjusting the pH value is selected from the group consisting of nitric acid, hydrochloric acid, sulfuric acid and any combination thereof.
[0027] In accordance with one embodiment, the step (1) of the method for preparing the desulfurizer for conversion and absorption of high-concentration carbonyl sulfide of the present invention comprises: mixing and reacting a FeSO 4 solution with an alkaline substance solution or solid by controlling the alkali ratio of the alkaline substance solution or solid and the FeSO 4 solution to 1-1.1 to form a first mixture, filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 . By mixing the FeSO 4 solution with the alkaline substance solution or solid, they will react to produce a precipitate. In a preferred embodiment, the precipitate is filtered to obtain a filter cake, then the filter cake is washed with water prior to calcinations. Alternatively, the above reactions can be realized through solid phase reactions by mixing and kneading a FeSO 4 solid with an alkaline substance solid by controlling the alkali ratio of the alkaline substance solid and the FeSO 4 solid to 1-1.1 to form a first mixture, followed by washing with water and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 .
[0028] In accordance with one embodiment, the step (2) comprises mixing 50-75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5-35 parts by weight of anatase type TiO 2 , 5-10 parts by weight of K 2 O and 5-10 parts by weight of a binder to form a second mixture, followed by roll molding at room temperature and drying the second mixture to produce the desulfurizer.
[0029] In a preferred embodiment, the anatase type TiO 2 and K 2 O in the step (2) are prepared by mixing and calcining 6.1-42.7 parts by weight of metatitanic acid (TiO(OH) 2 ) and 7.3-14.7 parts by weight of K 2 CO 3 at a temperature of 500-700° C. The inventors found that the desulfurizer, prepared using the mixture of the anatase-type TiO 2 and K 2 O obtained by calcining the metatitanic acid and K 2 CO 3 together, has an unexpectedly excellent sulfur capacity.
[0030] In another aspect, the present invention provides a desulfurizer for catalytic conversion and absorption of carbon disulfide, comprising
magnetic iron oxide red Fe 21.333 O 32 in an amount of 50-75 parts by weight; anatase-type TiO 2 in an amount of 5-15 parts by weight; K 2 O in an amount of 2-8 parts by weight; γ-Al 2 O 3 in an amount of 5-20 parts by weight; and a binder in an amount of 5-10 parts by weight.
[0036] In accordance with one embodiment, the binder is selected from the group consisting of bentonite, kaolin clay, attapulgite, Yang Gan soil and any combination thereof. In another aspect, the present invention provides a method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide, comprising
(1) mixing and reacting a FeSO 4 solution with an alkaline substance solution or solid by controlling the alkali ratio of the alkaline substance solution or solid and the FeSO 4 solution to 1-1.1 to form a first mixture, filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 ; or mixing and kneading a FeSO 4 solid with an alkaline substance solid by controlling the alkali ratio of the alkaline substance solid and the FeSO 4 solid to 1-1.1 to form a first mixture, followed by washing with water and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 ; and (2) mixing 50-75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5-15 parts by weight of anatase-type TiO 2 , 2-8 parts by weight of K 2 O, 5-20 parts by weight of γ-Al 2 O 3 and 5-10 parts by weight of a binder to form a second mixture, followed by roll molding at room temperature and drying the second mixture to produce the desulfurizer.
[0040] In accordance with one embodiment, the filter cake in the step (1) is calcined at 350° C. for 2-5 hours.
[0041] In accordance with one embodiment, the alkaline substance is selected from the group consisting of hydroxides of Group IA, Na 2 CO 3 , (NH 4 ) 2 CO 3 , K 2 CO 3 , NaHCO 3 , NH 4 HCO 3 , KHCO 3 and any combination thereof.
[0042] In accordance with one embodiment, the anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in step (2) are prepared by mixing and calcining 6.1-18.4 parts by weight of metatitanic acid, 2.9-11.7 parts by weight of K 2 CO 3 and 5.9-23.5 parts by weight of pseudo-boehmite at a temperature of 500-700° C.
[0043] In accordance with one embodiment, the metatitanic acid is prepared by a method comprising
preparing a ferrous sulfate solution by dissolving a ferrous sulfate solid in water, wherein the ferrous sulfate solid is a by-product from titanium dioxide production by a sulfuric acid method, heating the ferrous sulfate solution up to 40-100° C., adjusting a pH value of the ferrous sulfate solution to 1-2 by adding an acid, and reacting the ferrous sulfate solution with a flocculating agent to yield a precipitate, followed by filtering the precipitate to obtain the metatitanic acid.
[0048] In accordance with one embodiment, the ferrous sulfate solution has a FeSO 4 concentration of 1-2.5 mol/L.
[0049] In accordance with one embodiment, the acid added for adjusting the pH value is selected from the group consisting of nitric acid, hydrochloric acid, sulfuric acid and any combination thereof.
[0050] In accordance with one embodiment, the step (1) of the method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide comprises mixing and reacting a FeSO 4 solution with an alkaline substance solution or solid by controlling the alkali ratio of the alkaline substance solution or solid and the FeSO 4 solution to 1-1.1 to form a first mixture, filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 . In this manner, by mixing the FeSO 4 solution with the alkaline substance solution or solid, they will react to produce a precipitate. In an preferred embodiment, the precipitate is filtered to obtain a filter cake, then the filter cake is washed with water prior to calcinations.
[0051] Alternatively, the above reactions can be realized through solid phase reactions by mixing and kneading a FeSO 4 solid with an alkaline substance solid by controlling the alkali ratio of the alkaline substance solid and the FeSO 4 solid to 1-1.1 to form a first mixture, followed by washing with water and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 250-400° C. to yield the magnetic iron oxide red Fe 21.333 O 32 .
[0052] In accordance with one embodiment, the step (2) comprises mixing 50-75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5-15 parts by weight of anatase-type TiO 2 , 2-8 parts by weight of K 2 O, 5-20 parts by weight of γ-Al 2 O 3 and 5-10 parts by weight of a binder to form a second mixture, followed by roll molding at room temperature and drying the second mixture to produce the desulfurizer. In a preferred embodiment, the anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in step (2) are prepared by mixing and calcining 6.1-18.4 parts by weight of metatitanic acid TiO(OH) 2 , 2.9-11.7 parts by weight of K 2 CO 3 and 5.9-23.5 parts by weight of pseudo-boehmite (i.e. boehmite) at a temperature of 500-700° C. The inventors found that the desulfurizer, prepared using the mixture of the anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 obtained by calcining the metatitanic acid, K 2 CO 3 and pseudo-boehmite together, has an unexpectedly excellent sulfur capacity.
[0053] The present invention has the following advantages:
[0054] (1) The desulfurizer for conversion and absorption of high-concentration carbonyl sulfide comprises magnetic iron oxide red Fe 21.333 O 32 , anatase-type TiO 2 , alkali metal oxide K 2 O and a binder, which ensures that the desulfurizer can achieve conversion and absorption of carbonyl sulfide contained in a gas under moderate temperature, can treat carbonyl sulfide with a wide range of concentration to achieve complete removal of high-concentration carbonyl sulfide, and has a high sulfur capacity when applied at low temperature and moderate temperature. In the present invention, the anatase-type TiO 2 , alkali metal oxide K 2 O and magnetic iron oxide red Fe 21.333 O 32 in specific contents can work synergetically to impart optimized alkaline activity centers to the desulfurizer, so the desulfurizer has excellent conversion and absorption rate even if used in a condition where the carbonyl sulfide has a high-concentration.
[0055] (2) Among the components of the desulfurizer for conversion and absorption of high-concentration carbonyl sulfide, the anatase-type TiO 2 is prepared using ferrous sulfate recycled as a by-product from titanium dioxide production by a sulfuric acid method. The titanium dioxide production by a sulfuric acid method comprises decomposing ilmenite (FeTiO 3 ) with sulfuric acid to form titanium and iron sulfates which then dissolves in the reaction solution. Subsequently iron ions crystallizes as ferrous sulfate solid (FeSO 4 .7H 2 O) which can be separated from the titaniferous solution as a principal by-product. The obtained ferrous sulfate solid contains Ti in an approximate amount of 5%. So far, the ferrous sulfate solid as by-product has not got effectively recycled for further utilization. The present invention employs this by-product and recycles the Ti ion contained therein to prepare metatitanic acid, thus effectively reducing the cost for producing the desulfurizer.
[0056] (3) The desulfurizer for catalytic conversion and absorption of carbon disulfide comprises magnetic iron oxide red Fe 21.333 O 32 , anatase-type TiO 2 , alkali metal oxide K 2 O and γ-Al 2 O 3 and a binder, which ensures that the desulfurizer can achieve conversion and absorption of CS 2 contained in a gas under moderate temperature, can treat CS 2 with a wide range of concentration to achieve complete removal of high-concentration CS 2 , and has a high sulfur capacity when applied at moderate temperature. In the present invention, the anatase-type TiO 2 , alkali metal oxide K 2 O and γ-Al 2 O 3 and magnetic iron oxide red Fe 21.333 O 32 in specific contents can work synergetically to impart optimized alkaline activity centers to the desulfurizer, so the desulfurizer has excellent conversion and absorption efficiency even if used in a condition where the CS 2 has a high concentration.
[0057] (4) Among the components of the desulfurizer for catalytic conversion and absorption of carbon disulfide, the anatase-type TiO 2 is prepared using ferrous sulfate recycled as a by-product from titanium dioxide production by a sulfuric acid method. The titanium dioxide production by a sulfuric acid method comprises decomposing ilmenite (FeTiO 3 ) with sulfuric acid to form titanium and iron sulfates which then dissolves in the reaction solution. Subsequently iron ions crystallizes as ferrous sulfate solid (FeSO 4 .7H 2 O) which can be separated from the titaniferous solution as a principal by-product. The obtained ferrous sulfate solid contains Ti in an approximate amount of 5%. So far, the ferrous sulfate solid as by-product has not got effectively recycled for further utilization. The present invention employs this by-product and recycles the Ti ion contained therein to prepare metatitanic acid, thus effectively reducing the cost for producing the desulfurizer.
BRIEF DESCRIPTION OF DRAWINGS
[0058] FIG. 1 shows the XRD pattern of the magnetic iron oxide red Fe 21.333 O 32 prepared in the present invention.
DESCRIPTION OF EMBODIMENTS
Example 1
The Preparation of Metatitanic Acid
[0059] Addling 5 kg of ferrous sulfate solid which is a by-product from titanium dioxide production by a sulfuric acid method into a reactor, dissolving the ferrous sulfate solid with 6 L of water to form a ferrous sulfate solution, heating the ferrous sulfate solution at 60° C. for 30 min, adjusting a pH value of the ferrous sulfate solution to 1 by adding an acid, and reacting the ferrous sulfate solution with polyacrylamide as a flocculating agent to yield a precipitate, followed by filtering the precipitate while hot to obtain a metatitanic acid solid A, and finally drying the metatitanic acid solid A at 110° C. for 1 h.
[0060] Adding 1.67 kg of ferrous sulfate solid which is a by-product from titanium dioxide production by a sulfuric acid method into a reactor, dissolving the ferrous sulfate solid with 6 L of water to form a ferrous sulfate solution, heating the ferrous sulfate solution at 100° C. for 30 min, adjusting a pH value of the ferrous sulfate solution to 2 by adding an acid, and reacting the ferrous sulfate solution with a flocculating agent polyacrylamide to yield a precipitate, followed by filtering the precipitate while hot to obtain a metatitanic acid solid B, and finally drying the metatitanic acid solid B at 110° C. for 1 h.
Example 2
The Preparation of Anatase Type TiO 2 and K 2 O
[0061] Mixing the metatitanic acid A prepared by example 1 and K 2 CO 3 and calcining at a temperature of 500° C. to obtain the anatase type TiO 2 and K 2 O.
Example 3
[0062] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 50 parts by weight, anatase-type TiO 2 in an amount of 5 parts by weight, K 2 O in an amount of 5 parts by weight, and bentonite in an amount of 5 parts by weight.
[0063] The method for preparing the desulfurizer for catalytic conversion and absorption of carbonyl sulfide comprises:
[0064] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 6 L of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; then filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 ; and
[0065] (2) mixing 50 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5 parts by weight of anatase-type TiO 2 , 5 parts by weight of K 2 O, and 5 parts by weight of bentonite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0066] The anatase-type TiO 2 and K 2 O in the present example are prepared by the example 2.
Example 4
[0067] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 75 parts by weight; anatase-type TiO 2 in an amount of 35 parts by weight; K 2 O in an amount of 10 parts by weight; and Yang Gan soil in an amount of 10 parts by weight.
[0068] The method for preparing the desulfurizer for catalytic conversion and absorption of carbonyl sulfide comprises:
[0069] (1) mixing 500 g of FeSO 4 .7H 2 O solid with 333 g of NaHCO 3 solid by controlling the alkali ratio of NaHCO 3 and FeSO 4 .7H 2 O to 1.1 and kneading them in a coating pan for 2 h to yield a first mixture; followed by washing with water for 3 times and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is then ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0070] (2) mixing 75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 35 parts by weight of anatase-type TiO 2 , 10 parts by weight of K 2 O, and 10 parts by weight of Yang Gan soil to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0071] The anatase-type TiO 2 and K 2 O in the present example are prepared by example 2.
Example 5
[0072] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 59 parts by weight; anatase-type TiO 2 in an amount of 15 parts by weight; K 2 O in an amount of 8 parts by weight; and attapulgite in an amount of 5 parts by weight.
[0073] The method for preparing the desulfurizer for catalytic conversion and absorption of carbonyl sulfide comprises:
[0074] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 454 mL of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; followed by suction filtration to yield a filter cake, and washing the filter cake with water for 3 times and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0075] (2) mixing 59 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 15 parts by weight of anatase-type TiO 2 , 8 parts by weight of K 2 O, and 5 parts by weight of attapulgite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0076] The anatase-type TiO 2 and K 2 O in the present example are prepared by calcining a mixture of 18.4 parts by weight of metatitanic acid B of example 1 and 11.7 parts by weight of K 2 CO 3 at 500° C.
Example 6
[0077] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 59 parts by weight; anatase-type TiO 2 in an amount of 5 parts by weight; K 2 O in an amount of 5 parts by weight; and bentonite in an amount of 10 parts by weight.
[0078] The method for preparing the desulfurizer for catalytic conversion and absorption of carbonyl sulfide comprises:
[0079] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 454 mL of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; followed by suction filtration to yield a filter cake, washing the filter cake with water for 3 times and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0080] (2) mixing 59 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5 parts by weight of anatase-type TiO 2 , 5 parts by weight of K 2 O, and 10 parts by weight of bentonite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0081] The anatase-type TiO 2 and K 2 O in the present example are prepared by calcining a mixture of 6.4 parts by weight of metatitanic acid A of example 1 and 7.3 parts by weight of K 2 CO 3 at 700° C.
Example 7
The Preparation of Anatase Type TiO 2 , K 2 O and γ-Al 2 O 3
[0082] The anatase type TiO 2 and K 2 O and γ-Al 2 O 3 are prepared by calcining metatitanic acid A prepared by example 1, K 2 CO 3 and pseudo-boehmite at a temperature of 500° C. respectively.
Example 8
[0083] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 50 parts by weight; anatase-type TiO 2 in an amount of 5 parts by weight; K 2 O in an amount of 2 parts by weight; γ-Al 2 O 3 in an amount of 5 parts by weight; and bentonite in an amount of 5 parts by weight.
[0084] The method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide comprises:
[0085] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 454 mL of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; then filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 which has a XRD pattern as shown in FIG. 1 ; and
[0086] (2) mixing 50 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5 parts by weight of anatase-type TiO 2 , 2 parts by weight of K 2 O, 5 parts by weight of γ-Al 2 O 3 , and 5 parts by weight of bentonite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0087] The anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in the present example are prepared by example 7.
Example 9
[0088] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 75 parts by weight; anatase-type TiO 2 in an amount of 15 parts by weight; K 2 O in an amount of 8 parts by weight; γ-Al 2 O 3 in an amount of 20 parts by weight; and Yang Gan soil in an amount of 10 parts by weight.
[0089] The method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide comprises:
[0090] (1) mixing 500 g of FeSO 4 .7H 2 O solid with 333 g of NaHCO 3 solid by controlling the alkali ratio of NaHCO 3 and FeSO 4 .7H 2 O to 1.1 and kneading them in a coating pan for 2 h to yield a first mixture; followed by washing with water for 3 times and filtering the first mixture to yield a filter cake, and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0091] (2) mixing 75 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 15 parts by weight of anatase-type TiO 2 , 8 parts by weight of K 2 O, 20 parts by weight of γ-Al 2 O 3 , and 10 parts by weight of Yang Gan soil to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0092] The anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in the present example are prepared by example 7.
Example 10
[0093] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 59 parts by weight; anatase-type TiO 2 in an amount of 15 parts by weight; K 2 O in an amount of 8 parts by weight; γ-Al 2 O 3 in an amount of 16 parts by weight; and attapulgite in an amount of 5 parts by weight.
[0094] The method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide comprises:
[0095] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 454 mL of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; followed by suction filtration to yield a filter cake, and washing the filter cake with water for 3 times and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0096] (2) mixing 59 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5 parts by weight of anatase-type TiO 2 , 8 parts by weight of K 2 O, 16 parts by weight of γ-Al 2 O 3 and 5 parts by weight of attapulgite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0097] The anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in the present example are prepared by calcining a mixture of 6.1 parts by weight of metatitanic acid B of example 1, 11.7 parts by weight of K 2 CO 3 and 18.8 parts by weight of pseudo-boehmite at 500° C.
Example 11
[0098] The desulfurizer of the present example comprises magnetic iron oxide red Fe 21.333 O 32 in an amount of 59 parts by weight; anatase-type TiO 2 in an amount of 5 parts by weight; K 2 O in an amount of 2 parts by weight; γ-Al 2 O 3 in an amount of 5 parts by weight; and bentonite in an amount of 10 parts by weight.
[0099] The method for preparing the desulfurizer for catalytic conversion and absorption of carbon disulfide comprises:
[0100] (1) putting 500 g of FeSO 4 .7H 2 O solid into a beaker, adding 454 mL of water into the beaker and putting the beaker into a water bath at 40° C. until the solid therein is completely dissolved to form a FeSO 4 solution, adding 190 g of Na 2 CO 3 into the FeSO 4 solution by controlling the alkali ratio of the Na 2 CO 3 and FeSO 4 to 1, and reacting for 2 h under stirring to form a first mixture; followed by suction filtration to yield a filter cake, and washing the filter cake with water for 3 times and calcining the filter cake at a temperature of 350° C. for 3 h to yield the magnetic iron oxide red Fe 21.333 O 32 , which is ground and screened to obtain Fe 21.333 O 32 powder of 200 mesh; and
[0101] (2) mixing 59 parts by weight of the magnetic iron oxide red Fe 21.333 O 32 with 5 parts by weight of anatase-type TiO 2 , 2 parts by weight of K 2 O, 5 parts by weight of γ-Al 2 O 3 and 10 parts by weight of attapulgite to form a second mixture, followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm, and drying the balls to produce the desulfurizer.
[0102] The anatase-type TiO 2 , K 2 O and γ-Al 2 O 3 in the present example are prepared by calcining a mixture of 6.1 parts by weight of metatitanic acid A of example 1, 2.9 parts by weight of K 2 CO 3 and 5.9 parts by weight of pseudo-boehmite at 700° C.
[0103] The alkaline substance of the present invention for preparing magnetic iron oxide red Fe 21.333 O 32 is not limited to the above mentioned Na 2 CO 3 or NaOH, and also may be selected from the group consisting of (NH 4 ) 2 CO 3 , K 2 CO 3 , NH 4 HCO 3 , KHCO 3 , hydroxides of Group IA except for Na, and any combination thereof. As a preferred embodiment, the anatase-type TiO 2 is prepared using FeSO 4 recycled as a by-product from titanium dioxide production. Alternatively, the anatase-type TiO 2 can also be commercially available industrial grade metatitanic acid.
[0104] FIG. 1 shows the XRD pattern of the magnetic iron oxide red Fe 21.333 O 32 prepared in the present invention.
Test Example 1
[0105] In order to demonstrate technical effect of the desulfurizer for conversion and absorption of carbonyl sulfide, the present invention provides the test example 1, the experiment conditions of which are described as follows.
[0106] An evaluation test is performed under normal temperatures and normal pressures by using N 2 as background gas and by using a standard gas containing 3000 ppm (8571 mgS/m 3 ) of carbonyl sulfide at a space velocity of 500 h −1 . The desulfurization exhaust gas is detected by chromatography using WDL-94 trace sulfur analyzer. The test terminates when the outlet gas contains 20 ppm of carbonyl sulfide. The WDL-94 trace sulfur analyzer has a minimal measurement of 0.02 ppm.
[0107] {circle around (1)} COS Hydrolysis Conversion Rate
[0000] COS hydrolysis conversion rate (%)=(inlet concentration of COS−outlet concentration of COS)/inlet concentration of COS×100%
[0108] {circle around (2)} H 2 S Removal Rate
[0000] H 2 S removal rate (%)=(inlet concentration of COS−outlet concentration of COS−outlet concentration of H 2 S)/(inlet concentration of COS−outlet concentration of COS)×100%
[0109] {circle around (3)} Sulfur Capacity
[0110] Sulfur capacity is calculated when the COS concentration in the outlet gas reaches 20 ppm according to the below formula:
[0000]
X
=
V
1
-
C
×
C
×
32
×
2
22.4
×
G
×
100
[0111] wherein X represents breakthrough sulfur capacity (%); C represents COS content (%) in a gas mixture; V represents volume (L) of gas exclusive of COS measured by a wet gas flow meter after COS is removed; the value 32 is molar mass (g/mol) of sulphur; 22.4 is molar volume (L/mol) of ideal gas under standard condition; G represents the mass (g) of a desulfurizer sample (dry sample).
[0112] The results are listed in the following table:
[0000]
Outlet
COS hydrolysis
H 2 S removal
concentration
Sulfur
conversion rate
rate
of COS
capacity
Example 1
>99.9%
>99.9%
<0.02
28%
Example 2
>99.9%
>99.9%
<0.02
30%
Example 3
>99.9%
>99.9%
<0.02
33%
Example 4
>99.9%
>99.9%
<0.02
33%
Example 5
>99.9%
>99.9%
<0.02
49%
Example 6
>99.9%
>99.9%
<0.02
51%
Test Example 2
[0113] In order to demonstrate technical effect of the desulfurizer for catalytic conversion and absorption of carbon disulfide, the present invention provides the test example 2, the experiment conditions of which are described as follows:
[0114] An evaluation test is performed under normal temperatures and normal pressures by using N 2 as background gas and by using a standard gas containing 3000 ppm (8571 mgS/m 3 ) of CS 2 at a space velocity of 500 h −1 . The desulfurization exhaust gas is detected by chromatography using WDL-94 trace sulfur analyzer. The test terminates when the CS 2 concentration in the outlet gas reaches 20 ppm. The WDL-94 trace sulfur analyzer has a minimal measurement of 0.02 ppm.
[0115] {circle around (1)} CS 2 Hydrolysis Conversion Rate
[0000] CS 2 hydrolysis conversion rate (%)=(inlet concentration of CS 2 −outlet concentration of CS 2 )/inlet concentration of CS 2 ×100%
[0116] {circle around (2)} H 2 S Removal Rate
[0000] H 2 S removal rate (%)=(inlet concentration of CS 2 −outlet concentration of CS 2 −outlet concentration of COS−outlet concentration of H 2 S)/(inlet concentration of CS 2 −outlet concentration of CS 2 −outlet concentration of COS)×100%
[0117] {circle around (3)} Sulfur Capacity
[0118] Sulfur capacity is calculated when the CS 2 concentration in the outlet gas reaches 20 ppm according to the below formula:
[0000]
X
=
V
1
-
C
×
C
×
32
×
2
22.4
×
G
×
100
[0119] wherein X represents breakthrough sulfur capacity (%); C represents COS content (%) in a gas mixture; V represents volume (L) of gas exclusive of COS measured by a wet gas flow meter after COS is removed; the value 32 is molar mass (g/mol) of sulphur; 22.4 is molar volume (L/mol) of ideal gas under standard condition; G represents the mass (g) of a desulfurizer sample (dry sample).
[0120] The results are listed in the following table:
[0000]
Outlet
CS 2 hydrolysis
H 2 S removal
concentration
Sulfur
conversion rate
rate
of CS 2
capacity
Example 1
>99.9%
>99.9%
<0.02
20%
Example 7
>99.9%
>99.9%
<0.02
19%
Example 8
>99.9%
>99.9%
<0.02
19%
Example 9
>99.9%
>99.9%
<0.02
19%
Example 10
>99.9%
>99.9%
<0.02
36%
Example 11
>99.9%
>99.9%
<0.02
38%
Comparative Example 1
[0121] In order to further demonstrate technical effect of the desulfurizer for conversion and absorption of carbonyl sulfide, the present invention provides the comparative example 1 which is described as follows:
[0122] Taking 100 g of γ-Al 2 O 3 powder particles as carrier of the desulfurizer, impregnating 10 g of K 2 CO 3 on the γ-Al 2 O 3 by using an incipient impregnation method, followed by drying at 120° C. to obtaining the desulfurizer. An evaluation test is performed with the desulfurizer under same conditions of test example 1. The results indicate in the condition of 3000 ppm of CS 2 , COS hydrolysis conversion rate is 88%, H 2 S removal rate is 92%, and sulfur capacity is 16%.
[0123] By comparison it can be seen that, the desulfurizer for conversion and absorption of carbonyl sulfide has a higher COS hydrolysis conversion rate, a higher H 2 S removal rate and a higher sulfur capacity when applied in a high-concentration carbonyl sulfide condition.
Comparative Example 2
[0124] In order to further demonstrate technical effect of the desulfurizer for catalytic conversion and absorption of carbon disulfide, the present invention provides the comparative example 2 which is described as follows:
[0125] Taking 86 g of γ-Al 2 O 3 powder particles as carrier of the desulfurizer, impregnating a mixed solution of 17.44 g of Zr(NO 3 ) 4 .5H 2 O and 5.32 g of La(NO 3 ) 3 .6H 2 O on the γ-Al 2 O 3 by using an incipient impregnation method for 2 h, followed by drying for 4 h at 100° C. and calcining for 4 h at 550° C. to obtaining a carrier loaded with Zr and La; then impregnating 10.3 g of K 2 CO 3 on the carrier loaded with Zr and La by using an incipient impregnation method for 2 h, followed by drying for 4 h at 100° C. and calcining for 4 h at 550° C. to obtain a material having a composition of 7 wt % K 2 O-5 wt % ZrO 2 -25 wt % LaO-86 wt % γ-Al 2 O 3 , followed by roll molding at room temperature to form balls having diameter of 4 to 6 mm and drying the balls to produce the desulfurizer. An evaluation test is performed with the desulfurizer under same conditions of the test example 2. The results indicate in the condition of 3000 ppm of CS 2 , CS 2 hydrolysis conversion rate is 89%, H 2 S removal rate is 92%, and sulfur capacity is 16%.
[0126] By comparison it can be seen that, the desulfurizer for catalytic conversion and absorption of carbon disulfide has a higher CS 2 hydrolysis conversion rate, a higher H 2 S removal rate and a higher sulfur capacity when applied in a high-concentration carbon disulfide condition.
[0127] It is obvious the above embodiments are merely examples for clear illustration, rather than limit the application. For those skilled in the art, changes and modifications may be made on the basis of the above description, and it is not necessary and could not exhaust all embodiments, thus obvious changes and modifications derived from the above embodiments still fall within the protection scope of the invention. | Provided is a high-concentration carbonyl sulfide conversion-absorption type desulfurizer for use at medium-low temperature and preparation method thereof. The desulfurizer comprises 50%-75% magnetic iron oxide red (Fe 21.333 O 32 ), 5%-10% alkali metal oxide (K 2 O), 5-35% anatase TiO 2 , and 5-10% shaping binder. The method of preparing the desulfurizer comprises: uniformly mixing a metatitanic acid prepared using ferrous sulfate recycled as a by-product from titanium dioxide production with K 2 CO 3 , calcining to activate at 500° C.-700° C., mixing with the magnetic iron oxide red and binder, roll molding at room temperature to form balls which are dried at 100° C.-150° C. to obtain the desulfurizer. The desulfurizer has a hydrolysis conversion of carbonyl sulfide higher than 99%, and has a higher sulfur capacity more than 25%. | 1 |
BACKGROUND OF THE INVENTION
[0001] Diabetes mellitis is known to affect approximately 14 million adults in the United States alone. There are two types of this disease: one is Type I or insulin dependent diabetes mellitus (IDDM) and the other is Type II or non-insulin dependent diabetes mellitis (NIDDM). This disease is characterized by hyperglycemia both in the fasted state and post-prandial increase in blood glucose levels. Additionally, diabetes has been associated with many health problems like neuropathy, retinopathy and coronary heart disease. The ability to control blood glucose levels in a diabetic patient would serve to ameliorate the effects of hyperglycemia and benefit the long-term health of these patients.
[0002] Currently, the main defects that account for elevated levels of blood glucose are decreased insulin secretion from beta cells of the pancreas, resistance to insulin-mediated uptake of blood glucose by muscle cells and uncontrolled gluconeogenesis in the liver and to a lesser extent in the kidneys caused at least in part by resistance to the uptake of insulin. Anti-diabetic agents that could treat these defects of NIDDM would contribute to the control of diabetes to the benefit of those in need of such intervention.
[0003] Glucose utilization, namely the break down of glucose in the process known as glycolysis and the de novo biosynthesis of glucose known as gluconeogenesis are important metabolic pathways and directly affect the diabetic condition in humans. The understanding of their metabolic control has been enhanced by the discovery that some sugar bisphosphate compounds like fructose-2,6-bisphosphate and ribose-1,5-bisphosphate activate glycolysis by stimulating 6-phosphofructokinase and deactivate gluconeogenesis by inhibiting fructose-1,6-bisphosphatase.
[0004] 5-phosphoribosyl-1-methylenephosphonate, corresponding to compound Ia (X═CH 2 , A=CH 2 OP(O)(OH) 2 , B═OH, R1=H) has been shown to activate 6-phosphofructo-1-kinase with a Ka=6.5 μM and inhibit fructose-1,6-bisphosphatase with a Ki=85 μM. Further it has been shown that such a phosphorylated compound can enter into cultured hepatoma cells (FAO) and inhibit glucose production. Thus it is an object of this invention to provide stable, isosteric compounds related in structure to ribose-1-phosphate, a precursor of ribose-1,5-bisphosphate, which will possess similar biological activity and can be phosphorylated at the C(5) hydroxy in either outside or inside a cell in order to attain a structure like that of ribose-1,5-bisphosphate, which are readily synthesized.
BRIEF DESCRIPTION OF THE DRAWING
[0005] FIG. 1 shows the results of a glucose tolerance test done with compounds 1.1 and 3.1
SUMMARY OF THE INVENTION
[0006] Novel isosteric and stable anomers of ribose-1-phosphate of the following formula I
have been shown to inhibit glucose production in cultured cells and in vivo. These compounds have also been shown to inhibit some cancer cell lines. Thus the compounds of this invention are directed toward the use in humans as a method of treating diabetes and cancer. These compounds, as analogues of ribose-1-phosphate, a metabolite occurring in cells, are also directed toward ameliorating the effects of ischemia, and other diseases for which increased levels of ribose-1-phosphate and its subsequent metabolite, ribose-1,5-bisphosphate have been shown to decrease. These compounds are also directed to be treatments for metabolic disorders, which are responsive to lowered blood glucose levels or to the inhibition of gluconeogenesis.
[0007] In another aspect these compounds are also useful in inhibiting the growth of cancer cells.
[0008] Ribose-1-phosphate (Rib-1-P) and its further metabolite, ribose-1,5-bisphosphate (Rib-P 2 ) are important regulators of cellular metabolism. Rib-1-P is produced by the phosphorolysis of inosine and related nucleosides. Rib-1-P is subsequently used to help make DNA or is shuttled into the pentose phosphate pathway to provide carbon for glycolytic intermediates. Additionally, Rib-P 2 levels have been shown to greatly increase during ischemia in brain cell and may function to protect cells from ischemic damage. Also, Rib-P 2 has been shown to activate 6-phosphofructokinase and inhibit fructose-1,6-bisphosphatase. Both enzymes are involved in regulating carbohydrate metabolism in liver.
[0009] Since ribose-1-phosphate is quite labile in a biological system, being subject to enzyme or general acid/base hydrolysis, a stable version of it would be desirable. Such a compound could be used to provide a ribose-1-phosphate mimic that would function like the naturally occurring compound. Replacing the bridge oxygen of ribose-1-phosphate with CH 2 , CHF, CF 2 or some other suitable chemical group would provide for a non-hydrolyzable analogue of ribose-1-phosphate. It is possible that this stable form of ribose-1-phosphate could be phosphorylated in a cell to become a stable analogue of ribose-1,5-bisphosphate. Additionally, it has been shown that 5-iodo-ribose-1-phosphate inhibits human purine nucleoside phosphorylase. Thus compounds of formula I in which the C(5) hydroxy is substituted by halogens or other electron-rich groups increase the efficacy of bonding to an enzyme. Further, substitutions of F at the C(2) carbon for the hydroxy group are known to confer significant changes on the electronic character of a molecule while retaining many of the characteristics of hydroxy group, namely its hydrogen bonding character and its general bond length (1.43 Å C—F vs. 1.35 Å C—O).
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
[0010] In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
[0011] The term ‘biological system’ includes mammalian or plant cells, and living organisms. Such organisms include but are not limited to humans, animals and bacteria and viruses.
[0012] The term “aryl” refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
[0013] Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
[0014] Heterocyclic aryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
[0015] The term “biaryl” represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups.
[0016] The term “alicyclic” means compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl, and norbornyl are suitable alicyclic groups. Such groups may be optionally substituted.
[0017] The term “optionally substituted” or “substituted” includes groups substituted by one to four-substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, halogen, lower alkylthio, oxa, ketone, carboxy esters, carboxyl, carboxamido, nitro, acyloxy, alkylamino, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphonate, sulfonate, carboxamidoalkylaryl, carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, lower alkoxyalkyl, and lower perhaloalkyl.
[0018] The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.
[0019] The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
[0020] The terms “arylamino” (a), and “aralkylamino” (b), respectively, refer to the group —NRR′ wherein respectively, (a) R is aryl and R′ is hydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and R′ is hydrogen or aralkyl, aryl, alkyl.
[0021] The term “acyl” refers to —C(O)R where R is alkyl and aryl.
[0022] The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
[0023] The term “oxa” refers to ═O in an alkyl group
[0024] The term “alkylamino” refers to —NRR′ where R and R′ are independently selected from hydrogen or alkyl.
[0025] The term “carbonylamine” or “carbonylamino” refers to —CONR 2 where each R is independently hydrogen or alkyl
[0026] The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.
[0027] The term “oxyalkylamino” refers to —O-alk-NR—, where “alk” is an alkylene group and R is H or alkyl.
[0028] The term “alkylsulfonate” refers to the group -alk-S(O)2-O— where “alk” is an alkylene group.
[0029] The term “alkylaminoalkylcarboxy” refers to the group -alk-NR-alk-C(O)—O— where “alk” is an alkylene group, and R is a H or lower alkyl.
[0030] The term “alkylaminocarbonyl” refers to the group -alk-NR-C(O)— where “alk” is an alkylene group, and R is a H or lower alkyl.
[0031] The term “oxyalkyl” refers to the group —O-alk- where “alk” is an alkylene group.
[0032] The term “alkylcarboxyalkyl” refers to the group -alk-C(O)—O-alkyl where each alk is independently an alkylene group.
[0033] The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted.
[0034] The term “bidentate” refers to an alkyl group that is attached by its terminal ends to the same atom to form a cyclic group. For example, propylene imine contains a bidentate propylene group.
[0035] The term “cyclic alkyl” refers to alkyl groups that are cyclic.
[0036] The term “heterocyclic” and “heterocyclic alkyl” refer to cyclic alkyl groups containing at least one heteroatom. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a heteroatom or through a carbon atom in the ring.
[0037] The term “alkenyl” refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkene groups may be optionally substituted.
[0038] The term “alkynyl” refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkyne groups may be optionally substituted.
[0039] The term “alkylene” refers to a divalent straight chain, branched chain or cyclic saturated aliphatic radical.
[0040] The term “acyloxy” refers to the ester group —O—C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
[0041] The term “alkylaryl” refers to the group -alk-aryl- where “alk” is an alkylene group.
[0042] “Lower alkylaryl” refers to such groups where alkylene is lower alkyl.
[0043] The term “alkylamino” refers to the group -alk-NR— wherein “alk” is an alkylene group.
[0044] The term “alkyl(carboxyl)” refers to carboxyl substituted off the alkyl chain. Similarly, “alkyl(hydroxy)”, “alkyl(phosphonate)”, and “alkyl(sulfonate)” refers to substituents off the alkyl chain.
[0045] The term “alkylaminoalkyl” refers to the group -alk-NR-alk- wherein each “alk” is an independently selected alkylene, and R is H or lower alkyl. “Lower alkylaminoalkyl” refers to groups where each alkylene group is lower alkyl.
[0046] The term “alkylaminoaryl” refers to the group -alk-NR-aryl- wherein “alk” is an alkylene group. In “lower alkylaminoaryl”, the alkylene group is lower alkyl.
[0047] The term “alkyloxyaryl” refers to an alkylene group substituted with an aryloxy group. In “lower alkyloxyaryl”, the alkylene group is lower alkyl.
[0048] The term “alkylacylamino” refers to the group -alk-N—(COR)— wherein alk is alkylene and R is lower alkyl. In “lower alkylacylamino”, the alkylene group is lower alkyl.
[0049] The term “alkoxyalkylaryl” refers to the group -alk-O-alk-aryl- wherein each “alk” is independently an alkylene group. “Lower aloxyalkylaryl” refers to such groups where the alkylene group is lower alkyl.
[0050] The term “alkylacylaminoalkyl” refers to the group -alk-N—(COR)-alk- where each alk is an independently selected alkylene group. In “lower alkylacylaminoalkyl” the alkylene groups are lower alkyl.
[0051] The term “alkoxy” refers to the group -alk-O— wherein alk is an alkylene group.
[0052] The term “alkoxyalkyl” refers to the group -alk-O-alk- wherein each alk is an independently selected alkylene group. In “lower alkoxyalkyl”, each alkylene is lower alkyl.
[0053] The term “alkylthio” refers to the group -alk-S— wherein alk is alkylene group.
[0054] The term “alkylthioalkyl” refers to the group -alk-S-alk- wherein each alk is an independently selected alkylene group. In “lower alkylthioalkyl” each alkylene is lower alkylene.
[0055] The term “aralkylamino” refers to an amine substituted with an aralkyl group.
[0056] The term “alkylcarboxamido” refers to the group -alk-C(O)N(R)— wherein alk is an alkylene group and R is H or lower alkyl.
[0057] The term “alkylcarboxamidoalkyl” refers to the group -alk-C(O)N(R)-alk- wherein each alk is an independently selected alkylene group and R is lower alkyl. In “lower alkylcarboxamidoalkyl” each alkylene is lower alkyl.
[0058] The term “alkylcarboxamidoalkylaryl” refers to the group -alk1-C(O)—NH-alk2Ar— wherein alk1 and alk2 are independently selected alkylene groups and alk2 is substituted with an aryl group, Ar. In “lower alkylcarboxamidoalkylaryl”, each alkylene is lower alkyl.
[0059] The term “heteroalicyclic” refers to an alicyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.
[0060] The term “aminocarboxamidoalkyl” refers to the group —NH—C(O)—N(R)—R wherein each R is an independently selected alkyl group. “Lower aminocaboxamidoalkyl” refers to such groups wherein each R is lower alkyl.
[0061] The term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group.
[0062] The term “perhalo” refers to groups wherein every C—H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include —CF 3 and —CFCl 2 .
[0063] The term “guanidine” refers to both —NR—C(NR)—NR 2 as well as —N═C(NR 2 ) 2 where each R group is independently selected from the group of —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all optionally substituted.
[0064] The term “amidine” refers to —C(NR)—NR 2 where each R group is independently selected from the group of —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all optionally substituted.
[0065] The term “pharmaceutically acceptable salt” includes salts of compounds of formula I and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base.
[0066] The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the “drug” substance either as a result of spontaneous chemical reaction(s) or by enzyme catalyzed or metabolic reaction(s). Reference is made to various prodrugs such as acyl esters, carbonates, and carbamates, included herein. The groups illustrated are exemplary, not exhaustive, and one skilled its the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formula I, fall within the scope of the present invention.
[0067] The term “prodrug ester” as employed herein includes but is not limited to, the following groups and combinations of these groups.
[0068] [1] Acyloxyalkyl esters, which are well described in the literature (Farquhar et al., J. Pharm. Sci. 72,324-325 (1983)) and are represented by formula A
[0069] wherein R, R_, and R″ are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155, WO 90/10636).
[0070] Other acyloxyalkyl esters are possible in which an alicyclic ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g. Freed et al., Biochem. Pharm. 38: 3193-3198 (1989)).
[0071] wherein R is —H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or alicyclic.
[0072] [3] Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R′, and R″ are independently H, alkyl, aryl, alkylaryl, and alicyclic, have been studied in the area of β-lactam antibiotics (Tatsuo Nishimura et al. J. Antibiotics, 1987, 40(1), 81-90; for a review see Ferres, H., Drugs of Today, 1983,19, 499.). More recently Cathy, M. S., et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester prodrugs on (9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to 30% in dogs.
[0073] [4] Aryl esters have also been used as phosphonate prodrugs (e.g. Erion, DeLambert et al., J. Med. Chem. 37. 498, 1994; Serafinowska et al., J. Med. Chem. 38: 1372, 1995).
[0074] Phenyl as well as mono and poly-substituted phenyl phosphonate ester prodrugs have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where Y is a carboxylic ester ortho to the phosphate. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996).
[0075] wherein Y is H, alkyl, aryl, alkylaryl, alkoxy, acetoxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, alkylamino, and alicyclic.
[0076] [5] Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group [Formula D, X═H, OR or O(CO)R or O(CO)OR] can generate the 4-hydroxy compound more readly through the action of enzymes, e.g,. oxidases, esterases, etc. Examples of this class of prodrugs are described by Mitchell et al., J. Chem. Soc. Perkin Trans. [2345 (1992); Brook, et al. WO 91/19721.
[0077] wherein X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acetoxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and
R′ and R″ are independently H, alkyl, aryl, alkylaryl, halogen, and alicyclic.
[0079] [6] Thio-containing phosphonate phosphonate ester prodrugs have been described that are useful in the delivery of prodrugs to hepatocytes. These phosphonate ester prodrugs contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de-esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res., 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis. Benzaria, et al., J. Med. Chem., 39:4958 (1996). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytcs. The cyclic disulfide shown below has not been previously described and is novel.
[0080] wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
[0081] Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al. ( J. Med. Chem. 38, 1372 (1995)); Starrett et al. ( J. Med. Chem. 37, 1857 (1994)); Martin et al. J. Pharm. Sci. 76, 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59, 1853 (1994)); and EPO patent application 0 632 048 A1. Some of the structural classes described are optionally substituted, including fused lactones attached at the omega position and optionally substituted 2-oxo-1,3-dioxolenes attached through a methylene to the phosphorus oxygen such as:
[0082] 2-oxo-4,5-didehydro-1,3-3-phthalidyl 2-oxotetrahydrofuran-5-yl dioxolanemethyl
[0083] wherein R is —H, alkyl; cycloalkyl, or alicyclic; and
[0084] wherein Y is —H, alkyl, aryl, alkylaryl, cyano, alkoxy, acetoxy, halogen, amino, alkylamino, alicyclic, and alkoxycarbonyl.
[0085] [7] Propyl phosphonate ester prodrugs can also be used to deliver prodrugs into hepatocytes. These phosphonate ester prodrugs may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F. The R and X groups can form a cyclic ring system as shown in formula F. One or more of the oxygens of the phosphonate can be esterified.
[0086] wherein R is alkyl, aryl, heteroaryl;
X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acetoxy, amino.
[0089] [8] The cyclic propyl phosphonate esters as in Formula G are shown to activate to phosphonic acids. The activation of prodrug can be mechanistically explained by in vivo oxidation and elimination steps. These prodrugs inhibit glucose production in isolated rat hepatocytes and are also shown to deliver prodrugs to the liver following oral administration.
[0090] wherein
[0091] V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R 9 ; or
[0092] together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
[0093] together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
[0094] Z is selected from the group consisting of —CH 2 OH, —CH 2 OCOR 3 , —CH 2 OC(O)R 3 , —CH 2 OC(O)SR 3 , —CH 2 OCO 2 R 3 , —SR 3 , —S(O)R 3 , —CH 2 N 3 , —CH 2 NR 2 2 , —CH 2 Ar, —CH(Ar)OH, —CH(CH═CR 2 R 2 )OH, —CH(C═CR 2 )OH, and —R 2 ; with the provisos that:
[0095] a) V, Z, W are not all —H; and
[0096] b) when Z is —R 2 , then at least one of V and W is not —H or —R 9 ;
[0097] R 2 is selected from the group consisting of R 3 and —H;
[0098] R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; and
[0099] R 9 is selected from the group consisting of alkyl, aralkyl, and alicyclic.
[0100] [9] Phosphoramidate derivatives have been explored as potential phosphonate prodrugs (e.g. McGuigan et al., Antiviral Res. 1990, 14: 345; 1991, 15: 255. Serafinowska et al., J. Med. Chem., 1995, 38, 1372). Most phosphoramidates are unstable under aqueous acidic conditions and are hydrolyzed to the corresponding phosphonic acids. Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their potential for greater stability compared to non cyclic phosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37: 1857).
[0101] Other prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al. Bioorg Med. Chem. Let., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al. Bioorg. Med. Chem. Lett., 7:99-104 (1997).
[0102] X group nomenclature as used herein in formula I describes this group attached to the phosphonate and ends with this group attached to the C(1) position of the ribose ring.
DETAILED DESCRIPTION OF THE INVENTION
[0103] Novel Analogues of Ribose-1-Phosphate
[0104] Preferred compounds of the present invention are inhibitors of gluconeogenesis, stimulators of insulin secretion and can relieve insulin resistance in cells. These compounds are also inhibitors of cancer cell growth and are of formula I:
[0105] wherein X is selected from the group consisting of CH 2 , CHF, CF 2 , S NH, alkyl, alkenyl, alkynyl, alkyl(carboxyl), alkyl(hydroxy), alkyl(phosphonate), alkyl(sulfonate, aryl, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alicyclic, 1-monohaloalkyl, 1,1 dihaloalkyl, carbonylalkyl, aminocarbonylamino, alkylaminocarbonyl, alkylcarbonylamino, aralkyl and alkylaryl, all optionally substituted; A is (CH 2 ) n -A′ where n is from 1-4 and A′ is hydroxy, halogen, phosphate, alkyl, alkoxy, amino, azido or alkenyl; B is OH or F. R1 is independently selected from the group consisting of alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R 2 ) 2 -aryl, -alk-aryl, —C(R 2 ) 2 OC(O)NR 2 2 , —NR 2 —C(O)—R 3 , —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —O—C(O)OR 3 , —C(R 2 ) 2 OC(O)SR 3 , -alk-S—C(O)R 3 , -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
[0106] wherein
[0107] V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R 9 ; or
[0108] together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
[0109] together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
[0110] Z is selected from the group consisting of —CH 2 OH, —CH 2 OCOR 3 , —CH 2 OC(O)R 3 , —CH 2 OC(O)SR 3 , —CH 2 OCO 2 R 3 , —SR 3 , —S(O)R 3 , —CH 2 N 3 , —CH 2 NR 2 2 , —CH 2 Ar, —CH(Ar)OH, —CH(CH═CR 2 R 2 )OH, —CH(C═CR 2 )OH, and —R 2 ;
[0111] with the provisos that:
[0112] a) V, Z, W are not all —H; and
[0113] b) when Z is —R 2 , then at least one of V and W is not —H or —R 9 ;
[0114] R 2 is selected from the group consisting of R 3 and —H;
[0115] R 3 is selected from the group consisting of alkyl aryl, alicyclic, heteroalicyclic, and aralkyl;
[0116] R 4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
[0117] R 5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
[0118] R 6 is independently selected from the group consisting of —H, and lower alkyl;
[0119] R 7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ;
[0120] R 8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —(O)R 10 , or together said R 8 groups form a bidendate alkylene;
[0121] R 9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
[0122] R 10 is selected from the group consisting of —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl;
[0123] R 11 is selected from the group consisting of alkyl, aryl, —OH, —NH 2 and —OR 3 ; and pharmaceutically acceptable prodrugs and salts thereof.
[0124] Preferred Compounds of Formula 1
[0125] Suitable alkyl groups include groups having from 1 to about 20 carbon atoms. Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having 3 to about 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 5 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur.
[0126] Preferred X groups include 1-haloalkyl, 1,1 dihaloalkyl, alkyl, amino, alkylamino, thio, alkylthio. Particularly preferred is alkyl substituted with 1 to 3 substituents selected from halogen, phosphonate, —CO 2 H, —SO 3 H, and —OH. Particularly preferred 1-haloalkyl groups is fluoromethyl. Particularly preferred 1,1-dihaloalkyl groups is difluoromethyl. Particularly preferred alkyl is methyl.
[0127] Preferred A groups include A=CH 2 -A′ and A′ is hydroxy, halogen, phosphate, alkyl, alkenyl.
[0128] Preferred B groups include B is OH or F.
[0129] Preferred R1 is independently selected from the group consisting of alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —C(R 2 ) 2 -aryl, -alk-aryl, —C(R 2 ) 2 OC(O)NR 2 2 , —NR 2 —C(O)—R 3 , —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —O—C(O)OR 3 , —C(R 2 ) 2 OC(O)SR 3 , -alk-S—C(O)R 3 , -alk-S—S-alkylhydroxy, and -alk-S—S—S-alkylhydroxy, or together R1 and R1 are -alk-S—S-alk- to form a cyclic group, wherein each “alk” is an independently selected alkylene, or together R1 and R1 are
[0130] wherein
[0131] V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R 9 ; or
[0132] together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
[0133] together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
[0134] Z is selected from the group consisting of —CH 2 OH, —CH 2 OCOR 3 , —CH 2 OC(O)R 3 , —CH 2 OC(O)SR 3 , —CH 2 OCO 2 R 3 , —SR 3 , —S(O)R 3 , —CH 2 N 3 , —CH 2 NR 2 2 , —CH 2 Ar, —CH(Ar)OH, —CH(CH═CR 2 R 2 )OH, —CH(C═CR 2 )OH, and —R 2 ;
[0135] with the provisos that:
[0136] a) V, Z, W are not all —H; and
[0137] b) when Z is —R 2 , then at least one of V and W is not —H or —R 9 ;
[0138] R 2 is selected from the group consisting of R 3 and —H;
[0139] R 3 is selected from the group consisting of alkyl aryl, alicyclic, heteroalicyclic, and aralkyl;
[0140] R 4 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;
[0141] R 5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;
[0142] R 6 is independently selected from the group consisting of —H, and lower alkyl;
[0143] R 7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ;
[0144] R 8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —(O)R 10 , or together said R 8 groups form a bidendate alkylene;
[0145] R 9 is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;
[0146] R 10 is selected from the group consisting of —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl;
[0147] R 11 is selected from the group consisting of alkyl, aryl, —OH, —NH 2 and —OR 3 ; and pharmaceutically acceptable prodrugs and salts thereof.
[0148] Preferred R1 groups include —H, alkylaryl, aryl, —C(R 2 ) 2 -aryl, and —C(R 2 ) 2 —OC(O)R 3 . Preferred such R1 groups include optionally substituted phenyl, optionally substituted benzyl, —H, —C(R 2 ) 2 OC(O)OR 3 , and —C(R2)2OC(O)R3. Preferably, said alkyl groups are greater than 4 carbon atoms. Another preferred aspect is where at least one R1 is aryl or —C(R 2 ) 2 -aryl. Also particularly preferred are compounds where R1 is alicyclic where the cyclic moiety contains carbonate or thiocarbonate. Another preferred aspect is when at least one R1 is —C(R 2 ) 2 —OC(O)R 3 , —C(R 2 ) 2 —OC(O)OR 3 or —C(R 2 ) 2 —OC(O)SR 3 . Also particularly preferred is when R1 and R1 together are optionally substituted, including fused, lactone attached at the omega position or are optionally substituted 2-oxo-1,3-dioxolenes attached through a methylene to the phosphorus oxygen. Also preferred is when at least one R is -alkyl-S—S-alkylhydroxyl, -alkyl-S—C(O)R 3 , and -alkyl-S—S—S-alkylhydroxy, or together R1 and R1 are -alkyl-S—S-alkyl- to form a cyclic group. Also preferred is where R1 and R1 together are
[0149] to form a cyclic group, wherein
[0150] V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —R 9 ; or
[0151] together V and Z are connected to form a cyclic group containing 3-5 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus; or
[0152] together V and W are connected to form a cyclic group containing 3 carbon atoms substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, and aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;
[0153] Z is selected from the group consisting of —CH 2 OH, —CH 2 OCOR 3 , —CH 2 OC(O)R 3 , —CH 2 OC(O)SR 3 , —CH 2 OCO 2 R 3 , —SR 3 , —S(O)R 3 , —CH 2 N 3 , —CH 2 NR 2 2 , —CH 2 Ar, —CH(Ar)OH, —CH(CH═CR 2 R 2 )OH, —CH(C═CR 2 )OH, and —R 2 ;
[0154] with the provisos that:
[0155] a) V, Z, W are not all —H; and
[0156] b) when Z is —R 2 , then at least one of V and W is not —H or —R 9 ;
[0157] R 2 is selected from the group consisting of R 3 and —H;
[0158] R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; and
[0159] R 9 is selected from the group consisting of alkyl, aralkyl, and alicyclic.
[0160] Particularly preferred are such groups wherein V and W both form a 6-membered carbocyclic ring substituted with 0-4 groups, selected from the group consisting of hydroxy, acyloxy alkoxycarbonyl, and alkoxy; and Z is R2. Also particularly preferred are such groups wherein V and W are hydrogen; and Z is selected from the group consisting of hydroxyalkyl, acyloxyalkyl, alkyloxyalkyl, and alkoxycarboxyalkyl. Also particularly preferred are such groups wherein V and W are independently selected from the group consisting of hydrogen, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that at least one of V and W is optionally substituted aryl or optionally substituted heteroaryl.
[0161] In one preferred aspect, R1 is not lower alkyl of 1-4 carbon atoms.
[0162] Esters:
[0163] In the following examples of preferred compounds, the following prodrugs are preferred:
[0164] Acyloxyalkyl esters;
[0165] Alkoxycarbonyloxyalkyl esters;
[0166] Aryl esters,
[0167] Benzyl and substituted benzyl esters;
[0168] Disulfide containing esters;
[0169] Substituted (1,3-dioxolen-2-one)methyl esters;
[0170] Substituted 3-phthalidyl esters;
[0171] Cyclic-[2_-hydroxymethyl]-1,3-propanyl diesters and hydroxy protected forms;
[0172] Lactone type esters; and all mixed esters resulted from possible combinations of above esters.
[0173] Bis-pivaloyloxymethyl esters;
[0174] Bis-isobutyryloxymethyl esters;
[0175] Cyclic-[2_-hydroxymethyl]-1,3-propanyl diester;
[0176] Cyclic-[2_-acetoxymethyl]-1,3-propanyl diester;
[0177] Cyclic-[2_-methyloxycarbonyloxymethyl]-1,3-propanyl diester;
[0178] Bis-benzoylthiomethyl esters;
[0179] Bis-benzoylthioethyl esters;
[0180] Bis-benzoyloxymethyl esters;
[0181] Bis-p-fluorobenzoyloxymethyl esters;.
[0182] Bis-6-chloronicotinoyloxymethyl esters;
[0183] Bis-5-bromonicotinoyloxymethyl esters;
[0184] Diethyl esters
[0185] Bis-thiophenecarbonyloxymethyl esters;
[0186] Bis-2-furoyloxymethyl esters;
[0187] Bis-3-furoyloxymethyl esters;
[0188] Diphenyl esters;
[0189] Bis-(4-methoxyphenyl)esters;
[0190] Bis-(2-methoxyphenyl)esters;
[0191] Bis-(2-ethoxyphenyl)esters;
[0192] Mono-(2-ethoxyphenyl)esters;
[0193] Bis-(4-acetamidophenyl)esters;
[0194] Bis-(4-aceyloxyphenyl)esters;
[0195] Bis-(4-hydroxyphenyl)esters;
[0196] Bis-(2-acetoxyphenyl)esters;
[0197] Bis-(3-acetoxyphenyl)esters;
[0198] Bis-(4-morpholinophenyl)esters;
[0199] Bis-[4-(1-triazolophenyl)esters;
[0200] B is-(3-N,N-dimethylaminophenyl)esters;
[0201] Bis-(2-tetrahydronapthyl)esters;
[0202] Bis-(3-chloro-4-methoxy)benzyl esters;
[0203] Bis-(3-bromo-4-methoxy)benzyl esters;
[0204] Bis-(3-cyano-4-methoxy)benzyl esters;
[0205] Bis-(3-chloro-4-acetoxy)benzyl esters;
[0206] Bis-(3-bromo-4-acetoxy)benzyl esters;
[0207] Bis-(3-cyano-4acetoxy)benzyl esters;
[0208] Bis-(4-chloro)benzyl esters;
[0209] Bis-(4-acetoxy)benzyl esters;
[0210] Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;
[0211] Bis-(3-methyl-4-acetoxy)benzyl esters;
[0212] Bis-(benzyl)esters;
[0213] Dimethyl esters
[0214] Bis-(3-methoxy-4-acetoxy)benzyl esters;
[0215] Bis-(3-chloro-4-acetoxy)benzyl esters;
[0216] cyclic-(2,2-dimethylpropyl)phosphonoamidate;
[0217] cyclic-(2-hydroxymethylpropyl)ester;
[0218] Bis-(6_-hydroxy-3 — ,4_-disulfide)hexyl esters;
[0219] Bis-(6_-acetoxy-3 — ,4_-disulfide)hexyl esters;
[0220] (3 — ,4_-Dithia)cyclononane esters;
[0221] Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters;
[0222] Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters;
[0223] Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;
[0224] Bis-3-(5,6,7-trimethoxy)phthalidyl esters;
[0225] Bis-(cyclohexyloxycarbonyloxymethyl)esters;
[0226] Bis-(isopropyloxycarbonyloxymethyl)esters;
[0227] Bis-(ethyloxycarbonyloxymethyl)esters;
[0228] Bis-(methyloxycarbonyloxymethyl)esters;
[0229] Bis-(isopropylthiocarbonytoxymethyl)esters;
[0230] Bis-(phenyloxycarbonyloxymethyl)esters;
[0231] Bis-(benzyloxycarbonyloxymethyl)esters;
[0232] Bis-(phenylthiocarbonyloxymethyl)esters;
[0233] Bis-(p-methoxyphenyloxycarbonyloxymethyl)esters;
[0234] Bis-(m-methoxyphenyloxycarbonyloxymethyl)esters;
[0235] Bis-(o-methoxyphenyloxycarbonyloxymethyl)esters;
[0236] Bis-(o-methylphenyloxycarbonyloxymethyl)esters;
[0237] Bis-(p-chlorophenyloxycarbonyloxymethyl)esters;
[0238] Bis-(1,4-biphenyloxycarbonyloxymethyl)esters;
[0239] Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
[0240] Bis-(N-Phenyl,N-methylcarbamoyloxymethyl)esters;
[0241] Bis-(2-trichloroethyl)esters;
[0242] Bis-(2-bromoethyl)esters;
[0243] Bis-(2-iodoethyl)esters;
[0244] Bis-(2-azidoethyl)esters;
[0245] Bis-(2-acetoxyethyl)esters;
[0246] Bis-(2-aminoethyl)esters;
[0247] Bis-(2-N,N-diaminoethyl)esters;
[0248] Bis-(2-aminoethyl)esters;
[0249] Bis-(methoxycarbonylmethyl)esters,
[0250] Bis-(2-aminoethyl)esters;
[0251] Bis-[N,N-di(2-hydroxyethyl)]amidomethylesters;
[0252] Bis-(2-aminoethyl)esters;
[0253] Bis-(2-methyl-5-thiozolomethyl)esters;
[0254] Bis-(bis-2-hydroxyethylamidomthyl)esters;
[0255] Most preferred are the following:
[0256] Bis-pivaloyloxymethyl esters;
[0257] Bis-isobutyryloxymethyl esters;
[0258] cyclic-(2-hydroxymethylpropyl)ester;
[0259] cyclic-(2-acetoxymethylpropyl)ester;
[0260] cyclic-(2-methyloxycarbonyloxymethylpropyl)ester;
[0261] cyclic-(2-cyclohexylcarbonyloxymethylpropyl)ester;
[0262] cyclic-(2-aminomethylpropyl)ester;
[0263] cyclic-(2-azidomethylpropyl)ester;
[0264] Bis-benzoylthiomethyl esters;
[0265] Bis-benzoylthioethylesters;
[0266] Bis-benzoyloxymethyl esters;
[0267] Bis-p-fluorobenzoyloxymethyl esters;
[0268] Bis-6-chloronicotinoyloxymethyl esters;
[0269] Bis-5-bromonicotinoyloxymethyl esters;
[0270] Bis-thiophenecarbonyloxymethyl esters;
[0271] Bis-2-furoyloxymethyl esters;
[0272] Bis-3-furoyloxymethyl esters;
[0273] Diphenyl esters;
[0274] Bis-(2-methyl)phenyl esters;
[0275] Bis-(2-methoxy)phenyl esters;
[0276] Bis-(2-ethoxy)phenyl esters;
[0277] Bis-(4methoxy)phenyl esters;
[0278] Bis-(3-bromo-4-methoxy)benzyl esters;
[0279] Bis-(4-acetoxy)benzyl esters;
[0280] Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;
[0281] Bis-(3-methyl-4-acetoxy)benzyl esters;
[0282] Bis-(3-methoxy-4-acetoxy)benzyl esters;
[0283] Bis-(3-chloro-4-acetoxy)benzyl esters;
[0284] Bis-(cyclohexyloxycarbonyloxymethyl)esters;
[0285] Bis-(isopropyloxycarbonyloxymethyl)esters;
[0286] Bis-(ethyloxycarbonyloxymethyl)esters;
[0287] Bis-(methyloxycarbonyloxymethyl)esters;
[0288] Bis-(isopropylthiocarbonyloxymethyl)esters;
[0289] Bis-(phenyloxycarbonyloxymethyl)esters;
[0290] Bis-(benzyloxycarbonyloxymethyl)esters;
[0291] Bis-(phenylthiocarbonyloxymethyl)esters;
[0292] Bis-(p-methoxyphenyloxycarbonyloxymethyl)esters;
[0293] Bis-(m-methoxyphenyloxycarbonyloxymethyl)esters;
[0294] Bis-(o-methoxyphenyloxycarbonyloxymethyl)esters;
[0295] Bis-(o-methylphenyloxycarbonyloxymethyl)esters;
[0296] Bis-(p-chlorophenyloxycarbonyloxymethyl)esters;
[0297] Bis-(1,4-biphenyloxycarbonyloxymethyl)esters;
[0298] Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
[0299] Bis-(6_-hydroxy-3 — ,4_-disulfide)hexyl esters; and
[0300] (3 — ,4_-Disulfide)cyclononane esters.
[0301] Bis-(2-bromoethyl)esters;
[0302] Bis-(2-aminoethyl)esters;
[0303] Bis-(2-N,N-diaminoethyl)esters;
[0304] Examples of preferred compounds include but are not limited to those described in Table 1 including salts and prodrugs thereof:
TABLE 1 X A B 1. CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 2. CHF CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 3. CHCl CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 4. CHBr CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 5. CHI CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 6. CF 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 7. CCl 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 8. CBr 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 9. CI 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 10. CHNH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 11. S CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH2OPO(OH) 2 OH or F 12. NH CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH2OPO(OH) 2 OH or F 13. CH 2 CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH2OPO(OH) 2 OH or F 14. CHFCHF CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH2OPO(OH) 2 OH or F 15. CF 2 CF 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 16. CHBrCHBr CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 17. CBr 2 CBr 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 18. CHICHI CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 19. CI 2 CI 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 20. CH 2 CH(OH) CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 21. CH 2 CH(CH 3 ) CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 22. ethyldialkyl CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 23. CHS-CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 24. CHS-CHS CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 25. CH 2 —S—CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 26. CHNH 2 CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 27. CHOCH 3 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 28. CH(OCH 3 )CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 29. CH(OCH 2 CH 3 )CH 2 CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 30. n-proplyhydroxy CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 31. n-propylhalo CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 32. n-propyldihalo CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 33. n-propyltrihalo CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F 34. n-propylthio CH 2 OH or CH 2 NH 2 or CH 2 F or CH 2 Br or CH 2 I or CH 2 OPO(OH) 2 OH or F
[0305] In a less preferred form of Formula I
[0306] A for the above listed can also be CH 2 OCH 3 or CH 2 OCH 2 CH 3 or CH 2 CH═CH 2 .
[0307] The most preferred forms of Formula I are where A is CH 2 OH or CH 2 OPO(OH) 2 ; B is OH; X is CHF or CF 2 and R1 is H or an ester selected from the esters lists.
[0308] Alternatively, the most preferred forms of Formula I are where A is CH 2 OH; B is OH; X is CH 2 and R1 is an ester selected from the esters lists.
[0309] Preparation of Phosphonate Prodrugs:
[0310] Prodrug esters can be introduced at different stages of the synthesis. Because of their lability, prodrugs are often prepared from compounds of formula 5 where R1 is H. Advantageously, these prodrug esters can be introduced at an early stage, provided that it can withstand the reaction conditions of the subsequent steps.
[0311] Compounds of formula I where R1 is H, can be alkylated with electrophiles (such as alkyl halides, alkyl sulfonates etc) under nucleophilic substitution reaction conditions to give phosphonate esters. For example prodrugs of formula 1 where R1 is acyloxymethyl group can be synthesized through direct alkylation of the free phosphonic acid of formula 5, with the desired acyloxymethyl halide (e.g. Cl, Br, I; Elhaddadi, et al Phosphorus Sulfur, 1990, 54(1-4): 143; Hoffmann, Synthesis, 1988, 62) in presence of base e.g. N,N_-dicyclohexyl-4-morpholinecarboxcamidine, Hunigs base etc. in polar aprotic solvents such as DMF (Starrett, et al, J. Med. Chem., 1994, 1857). These carboxylates include but not limited to acetate, propylate, isobutyrate, pivalate, benzoate, and other carboxylates. Alternately, these acyloxymethylphosphonate esters can also be synthesized by treatment of the nitrophosphonic acid (A is NO2 in formula 5; Dickson, et al, J. Med. Chem., 1996, 39: 661; Iyer, et al, Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al, Bioorg. Chem., 1984, 12: 118). This can be extended to many other types of prodrugs, such as compounds of formula 1 where R1 is 3-phthalidyl, 2-oxo-4,5-didehydro-1,3-dioxolanemethyl, and 2-oxotetrahydrofuran-5-yl groups, etc. (Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al. ( J. Med. Chem. 38: 1372 (1995)); Starrett et al. ( J. Med. Chem. 37: 1857 (1994)); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994)); and EPO 0632048A1). N,N-Dimethylformamide dialkyl acetals can also be used to alkylate phosphonic acids (Alexander, P., et al Collect. Czech. Chem. Commun., 1994, 59, 1853).
[0312] Alternatively, these phosphonate prodrugs or phosphoramidates can also be synthesized, by reaction of the corresponding dichlorophosphonates and an alcohol or an amine (Alexander, et al, Collect. Czech. Chem. Commun., 1994, 59: 1853). For example, the reaction of dichlorophosphonate with phenols and benzyl alcohols in the presence of base (such as pyridine, triethylamine, etc) yields compounds of formula 1 where R1 is aryl (Khamnei, S., et al J. Med. Chem., 1996,39: 4109; Serafinowska, H. T., et al J. Med. Chem., 1995, 38: 1372; De Lombaert, S., et al J. Med. Chem., 1994,37: 498) or benzyl (Mitchell, A. G., et al J. Chem. Soc. Perkin Trans. 1, 1992, 38: 2345). The disulfide-containing prodrugs, reported by Puech et al., Antiviral Res., 1993, 22: 155, can also be prepared from dichlorophosphonate and 2-hydroxyethyl disulfide under the standard conditions.
[0313] Such reactive dichlorophosphonate intermediates, can be prepared from the corresponding phosphonic acids and the chlorinating agents e.g. thionyl chloride (Starrett, et al, J. Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al, Tetrahedron Lett., 1990, 31: 3261), and phosphorus pentachloride (Quast, et al, Synthesis, 1974, 490). Alternatively, these dichlorophosphonates can also be generated from disilyl phosphonate esters (Bhongle, et al, Synth. Commun., 1987, 17: 1071) and dialkyl phosphonate esters (Still, et al, Tetrahedron Lett., 1983, 24: 4405; Patois, et al, Bull. Soc. Chim. Fr., 1993, 130: 485).
[0314] Furthermore, these prodrugs can be prepared from Mitsunobu reactions (Mitsunobu, Synthesis, 1981, 1, Campbell, J. Org. Chem., 1992, 52: 6331), and other acid coupling reagents include, but not limited to, carbodiimides (Alexander, et al, Collect. Czech. Chem. Commun., 1994; 59: 1853; Casara, et al, Bioorg. Med. Chem. Lett., 1992, 2: 145; Ohashi, et al, Tetrahedron Lett., 1988, 29: 1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts (Campagne, et al, Tetrahedron Lett., 1993, 34: 6743). The prodrugs of formula 1 where R1 is the cyclic carbonate or lactone or phthalidyl can also be synthesized by direct alkylation of free phosphonic acid with desired halides in the presence of base such as NaH or diisopropylethylamine (Biller and Magnin U.S. Pat. No. 5,157,027; Serafinowska et al. J. Med. Chem. 38: 1372 (1995); Starrett et al. J. Med. Chem. 37: 1857 (1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994); and EPO 0632048A1).
[0315] R1 can also be introduced at an early stage of synthesis, when feasible. For example, compounds of formula I where R1 is phenyl can be prepared by phosphorylation of 2,5-anhydro-6-O-(t-butyldiphenylsilyl)-1-1deoxy-1,1-difluoro-3,4-O-isopropylidene-D-ribo-hex-1eniol via strong base treatment (e.g. BU 3 SnH) followed by phenylseleniumdiethylphosphonate as shown in the following scheme.
[0316] It is envisioned that compounds of formula I can be mixed phosphonate esters by combining the above described prodrugs (e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, etc.). For example, the chemically combined phenyl-benzyl prodrugs are reported by Meier et al. Bioorg. Med. Chem. Lett., 1997; 7: 99.
[0317] The substituted cyclic propyl phosphonate esters of formula 5, can be synthesized by reaction of the corresponding dichlorophosphonate and the substituted 1,3-propanediol. The following are some of the methods to prepare the substituted 1,3-propanediols.
[0318] Synthesis of the 1,3-Propanediols Used in the Preparation of Certain Prodrugs
[0319] The discussion of this step includes various synthetic methods for the preparation of the following types of propane-1,3-diols: i) 1-substituted; ii) 2-substituted; and iii) 1,2- or 1,3-annulated. Different groups on the prodrug part of the molecule i.e., on the propanediol moiety can be introduced or modified either during the synthesis of the diols or after the synthesis of the prodrugs.
i) 1-Substituted 1.3-Propanediols
[0320] Propane-1,3-diols can be synthesized by several well known methods in the literature. Aryl Grignard additions to 1-hydroxypropan-3-al gives 1-aryl-substituted propane-1,3-diols (path a). This method will enable conversion of various substituted aryl halides to, 1-arylsubstituted-1,3-propanediols (Coppi, et. al., J. Org. Chem., 1988, 53, 911). Aryl halides can also be used to synthesize 1-substituted propanediols by Heck coupling of 1,3-diox-4-ene followed by reduction and hydrolysis (Sakamoto, et. al., Tetrahedron Lett., 1992,33, 6845). A variety of aromatic aldehydes can be converted to 1-substituted-1,3-propanediols by vinyl Grignard addition followed by hydroboration (path b). Substituted aromatic aldehydes are also utilized by lithiuim-t-butylacetate addition followed by, ester reduction (path e) (Turner., J. Org. Chem., 1990, 55 4744). In another method, commercially available cinnamyl alcohols can be converted to epoxy alcohols under catalytic asymmetric epoxidation conditions. These epoxy alcohols are reduced by Red-AI to result in enantiomerically pure propane-1,3-diols (path c). Alternatively, enantiomerically pure 1,3-diols can be obtained by chiral borane reduction of hydroxyethyl aryl ketone derivatives (Ramachandran, et. al., Tetrahedron Lett., 1997, 38 761). Pyridyl, quinoline, and isoquinoline propan-3-ol derivatives can be oxygenated to 1-substituted propan-1,3-diols by N-oxide formation followed by rearrangement under acetic anhydride conditions (path d) (Yamamoto, et. al., Tetrahedron, 1981, 37, 1871).
ii) 2-Substituted 1,3-Propanediols
[0321] Various 2-substituted propane-1,3-diols can be made from commercially available 2-(hydroxymethyl)-1,3-propanediol. Triethyl methanetric arboxylate. can be converted to the triol by complete reduction (path a) or diol-monocarboxylic acid derivatives can be obtained by partial hydrolysis and diester reduction (Larock, Comprehensive Organic Transformations , VCH, New York, 1989). Nitrotriol is also known to give the triol by reductive elimination (path b) (Latour, et. al., Synthesis, 1987, 8, 742). The triol can be derivatized as a mono acetate or carbonate by treatment with alkanoyl chloride, or alkylchoroformate, respectively (path d) (Greene and Wuts, Protective Groups in Organic Synthesis , John Wiley, New York, 1990). Aryl substitution can be made by oxidation to the aldehyde followed by aryl Grignard additions (path c) and the aldehyde can also be converted to substituted amines by reductive amination reactions (path e). ##STR20##
iii) Annulated 1,3-Propanediols
[0322] Prodrugs of formula 1 where V-Z or V—W are fused by three carbons are made from cyclohexanediol derivatives. Commercially available cis, cis-1,3,5-cyclohexanetriol can be used for prodrug formation. This cyclohexanetriol can also be modified as described in the Ocase of 2-substituted propane-1,3-diols to give various analogues. These modifications can either be made before or after formation of prodrugs. Various 1,3-cyclohexanediols can be made by Diels-Alder methodology using pyrone as the diene (Posner, et al., Tetrahedron Lett., 1991, 32, 5295). Cyclohexyl diol derivatives are also made by nitrile oxide olefin-additions (Curran, et. al., J. Am. Chem. Soc., 1985, 107, 6023). Alternatively, cyclohexyl precursors can be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
[0323] (2) Deprotection of Phosphonate Esters
[0324] Compounds of formula 1 where R1 is H may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions. For example, alkyl phosphonate esters are generally cleaved by reaction with silyl halides followed by hydrolysis of the intermediate silyl phosphonate esters. Depending on the stability of the products, these reactions are usually accomplished in the presence of acid scavengers such as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc. Various silyl halides can be used for this transformation, such as chlorotrimethylsilane (Rabinowitz J. Org. Chem., 1963, 28: 2975), bromotrimethylsilane (McKenna et al. Tetrahedron Lett., 1977, 155), iodotrimethylsilane (Blackburn et al. J. Chem. Soc., Chem. Commun., 1978, 870). Phosphonate esters can also be cleaved under strong acid conditions, such as hydrogen halides in acetic acid or water, and metal halides (Moffatt et al. U.S. Pat. No. 3,524,846, 1970). Phosphonate esters can also be converted to dichlorophosphonates with halogenating agents (e.g. PCl 5 , SOCl 2 , BBr 3 , etc. Pelchowicz et al. J. Chem. Soc., 1961, 238) and subsequently hydrolyzed to give phosphonic acids. Reductive reactions are useful in cleaving aryl and benzyl phosphonate esters. For example, aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak et al. Synthesis, 1982, 412; Elliott et al. J. Med Chem., 1985, 28: 1208.) or dissolving metal reduction conditions (Shafer et al. J. Am. Chem. Soc., 1977, 99: 51 18). (Elliott et al. J. Med. Chem., 1985,28: 1208). Electrochemical (Shono et al. J. Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta et al. Synth. Commun., 1980, 10: 299) conditions have also been used to cleave various phosphonate esters.
[0325] The synthesis of compounds such as those found in formula I may, depending on the route of synthesis, produce anomeric mixtures. These mixtures may be separated and the anomers are denoted as Ia in which X is below the plane of the ribose ring or Ib in which X is above the plane of the ribose ring.
[0326] The synthesis of ribosyl phosphoramidates utilizes the Staudinger reaction (Casero F, Cipolla L, Lay L, Nicotra F, Panza L and Russo G, J. Org. Chem. 61, 3428 (1981)) of suitably protected ribosyl azides with trimethyl phosphite followed by deprotection.
[0327] As a way of treating either type II diabetes or cancer or any metabolic inbalance, the above mentioned compounds may be formulated in a drug delivery system to a human in order to cure or control either disease. These formulations may include but are not limited to pills, patches, injections or inhalants. Compounds of the invention are administered orally in a total daily dose of about 0.1 mg/kg/dose to about 100 mg/kg/dose, preferably from about 0.3 mg/kg/dose to about 30 mg/kg/dose. The most preferred dose range is from 0.5 to 10 mg/kg (approximately 1 to 20 nmoles/kg/dose). The use of time-release preparations to control the rate of release of the active ingredient may be preferred. The dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), compounds are administered to the affected tissue at a rate from 0.3 to 300 nmol/kg/min, preferably from 3 to 100 nmoles/kg/min. Such rates are easily maintained when these compounds are intravenously administered as discussed below.
[0328] For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.
[0329] Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient, which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents; such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
[0330] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
[0331] Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous-suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[0332] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or ia mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
[0333] Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0334] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
[0335] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
[0336] The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
[0337] The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain 20 to 2000 mmol (approximately 10 to 1000 mg) of active material compounded with an appropriate and convenient amount of carrier material-which may vary from about 5 to about 95% of the total compositions. It is preferred that the pharmaceutical composition be prepared which provides easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 0.05 to about 50 mmol (approximately 0.025 to 25 mg) of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
[0338] As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
[0339] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl ethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide. slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of formula I when such compounds are susceptible to acid hydrolysis.
[0340] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0341] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
[0342] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
[0343] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0344] Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a modulator of glucose metabolism.
[0345] It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
[0346] Utility:
[0347] The Utility of Compound 2 as a Treatment for Diabetes is Shown in the Following Data:
[0348] Studies of Compound 2 have shown that it activates 6-phosphofructo-1-kinase (6PF1K) and inhibits fructose-1,6-bisphosphatase (FBPase). Additionally, in vitro studies have shown the compound 2, when incubated with FAO hepatoma cells, inhibits glucose production. Given the dual functionality of compound 2, it is possible to account for the inhibition of glucose production in FAO cells by assuming that it directly inhibits FBPase or that by activating 6PF1K, compound 2 is increasing the rate of glycolysis. It is well known that by increasing the rate of glycolysis, the rate of gluconeogenesis decreases (Hanson et al. (1984) J. Biol. Chem. 259, 218-223).
[0349] Ka is the concentration of substrate giving half-maximal activation.
TABLE 2 Activation of 6-phosphofructo-1-kinase by Compound 2.1 Substrate Ka (μM) fructose-2,6-bisphosphate 0.09 ribose-1,5-bisphosphate 3.5 Compound 2 6.5
[0350]
TABLE 3
Inhibition of Fructose-1,6-bisphosphatase by Compound 2.1
Maximum
Decrease in
K I (μM)
Activity (%)
At 5 μM Fru-1,6-
bisphosphate
Rib-1,5-P 2
87
50
Compound 2.1
87
50
At 20 μM Fru-1,6-
bisphosphate
Rib-1,5-P 2
87
50
Compound 2.1
87
50
[0351]
TABLE 4
Inhibition of Glucose Production in FAO cells by Compound 2.1
Ia (μM)
Percent inhibition of glucose production
0
0
60
20 ± 15
125
35 ± 10
250
40 ± 10
500
35 ± 10
100
60 ± 15
[0352] The Utility of Compound 1.1 as a Treatment for Diabetes is Shown in the Following Data:
[0353] Glucose Tolerance Test
[0354] Compound 1.1 was shown to reduce blood glucose levels in diabetic Zucker (fa/fa) that were fasted, injected with compound 1.1 and then challenged with an infusion of glucose.
[0355] Thirty-six 16 wk old male Zucker (fa/fa) rats were randomly assigned to one of the following groups:
1. Vehicle (0.9% NaCl) 2. Metformin—320 mg/kg 3. Compound 1.1—10 mg/kg Acid 4. Compound 1.1—100 mg/kg Acid 5. Compound 3.1—10 mg/kg Ester 6. Compound 3.1—100 mg/kg Ester
[0362] Animals were fasted for 16-18 hr and lightly anesthetized with a mixture of ketamine/xylazine at a dose of 0.5 ml/kg (45 mg/kg ketamine, 5 mg/kg xylazine). Animals received their respective treatments via IP injection (1.5 ml/kg) followed by an IP injection of glucose at 1.5 g/kg. Blood glucose was measured at 0, 30, 60, 90, and 120 minutes post-glucose.
TABLE 2 Blood Glucose (mg/dL) Agent at 120 minutes Vehicle (0.9% NaCl) 500 Metformin - 320 mg/kg 400 Compound 1.1 - 10 mg/kg Acid 460 Compound 1.1 - 100 mg/kg Acid 400 Compound 2.1 - 10 mg/kg Ester 500 Compound 2.1 - 100 mg/kg Ester 500
[0363] The Utility of Compounds 3.1 and 4.1 as Stimulators of Insulin Secretion is Shown in the Following Data:
[0364] Stimulation of Insulin Secretion
[0365] INS-1 clonal pancreatic B-cells were grown in well plates or T-25 flasks incubated overnight with INS-1 cell media with 3 mM glucose and 500 μM of compound 3 or compound 4. Insulin samples were collected for 10 minutes at 18 second intervals. Insulin release was greater for both compound 3.1 and compound 4.1 compared to controls, by about 50 percent, under these conditions. At 16 mM glucose the activating effect disappeared.
[0366] The Utility of Compound 4.1 as an Inhibitor of Lipid Levels in Liver Cells is Shown in the Following Data:
[0367] Inhibition of Intracellular Lipid Synthesis
[0368] The utility of compound 4.1 as treatment for the reduction of intracellular lipids is shown by the following data: incubation of 500 μM compound 4 in HTC hepatoma cells overnight resulted in a 26% decrease in triglyceride levels and near 20% decrease in cholesterol levels compared to control. This effect was quantitatively similar to the effect that 500 μM metformin had on these cells.
Triglyceride Cholesterol (μg/mg protein) (μg/mg protein) Control 60 48 500 μM Metformin 42 38 500 μM Compound 4.1 44 39
[0369] The Utility of Compound 4.1 as an Inhibitor of cPNP is Shown in the Following Data:
[0370] Inhibition of Calf Spleen Purine Nucleoside Phosphorylase (cPNP)
[0371] Compound 4.1 (27 μM) was incubated with calf spleen purine nucleoside phosphorylase with increasing concentrations of inorganic phosphate. The results are shown below indicate that compound is likely a competitive inhibitor of cPNP:
Pi (μM) Control Compound 4.1 20 170* 18* 50 237 31 200 298 96 1500 327 176 *activity in arbitrary units
[0372] The Utility of Compound 4.1 as an Anticancer Agent is Shown in the Following Data:
Compound cell line IC50 1.1 HL-60, Leukemia 170 μM 3.1 NCI-H226 10(−7)M NCI/ADR-RES 10(−7)M OVCAR-8 10(−8)M HT-29 10(−7)M 4.1 Rh1, Ewing Sarcoma 170 μM
EXAMPLE 1
Synthesis of Ribose-1-methylenediethylphosphonate
[0373] A solution of 15 g of dried D-ribose and 210 mg of p-toluene sulfonic acid(PTSA) and 40 ml of 2,2-dimethoxypropane in 160 ml N,N dimethylformamide(DMF) is stirred for 3 h at room temperature. An excess of AMBERLITE IRA-410(OH− form) was added to neutralize the acid. The resin was dried to prevent possible hydrolysis of product. The resin was filtered after two hours. The DMF was removed in vacuo at 60° C. and the syrup was chromatographed on silica gel (250 g) using CHCl 3 /CH 2 Cl 2 (3:1). The Hasegawa paper used silicic acid CHCl 3 /ethanol (50:1). The product is 2,3-O isopropylidene-D-ribofuranose (2a,2b).
[0374] The product was dissolved in pyridine and an equal-molar amount of pivaloyl chloride was added. The reaction was stirred overnight. The solvent was removed and the product 5-pivaloyl 2,3-O isopropylidene-D-ribofuranose (3a, 3b) was purified on silica gel.
[0375] Tetraethylenemethylenebisphosphonate (TEMBP) was dissolved in dry THF and an equal-molar amount of NaH was added to the solution. After 30 minutes an equal-molar quantity of 3a.3b dissolved in THF was added all at once and the mixture was stirred for 1.5 hr.
[0376] The reaction was stopped with NH 4 OAC(aq) The THF was removed under vacuum and chloroform was added. The mixture was poured into a separatory flask and the organic layer was recovered. The organic layer was dried over MgSO 4 . The chloroform was removed and the residue was placed on a silica gel column and the product was purified.(4a,4b)
[0377] To dry ethyl alcohol, NaOEt was added. 4a, 4b was dissolved in ethyl alcohol and added to the former solution. After 1.5 hr the reaction was stopped with water. The alcohol was removed and the residue was dissolved in chloroform. This solution was placed in a separatory flask and washed with NH 4 OAC(aq). The organic layer was recovered, dried and the solvent removed. The residue was purified on silica gel resulting in the separation of the two anomers 5a and 5b.
[0378] Sa was dissolved in methanol. A 20 fold(w/w) excess of Dowex AG 50 (H+ form) resin was added and the reaction was left overnight. 1H-NMR confirmed the removal of the acetonide group giving 6a. 1H-NMR (CDCl 3 ) δ: 4.2 (m, 1H), 4.0 (m, 3H), 3.75(dd, 1H), 3.7(m, 4H), 3.6(dd, 1H), 2.2(m, 2H), 1 3(t, 6H); 13 C-NMR (CDCl 3 ) δ: 28.81, 72.53, 77.63, 77.63, 80.44, 64.97, 51.10 and 52.60 (OCH 2 CH 3 ), 61.56 and 62.34 (OCH 2 CH 3 ); 31 P-NMR (D 2 O) δ: 20.136 (s, 1P)
[0379] Compound 5b was dissolved in methanol. A 20 fold(w/w) excess of Dowex AG 50 (H+ form) resin was added and the reaction was left overnight. 1H-NMR confirmed the removal of the acetonide group giving 6b. 1H-NMR (CDCl 3 ) δ: 4.1 (m, 1H), 3.9 (m, 1H), 3.8-3.4 (m, 8H), 2.2(m, 2H), 1.3 (t, 6H); 13 C-NMR (CDCl 3 ) δ: 37.53, 79.36, 75.58, 783.15, 86.85, 68.51, 52.07 and 52.69 (OCH 2 CH 3 ), 63.44 and 64.27 (OCH 2 CH 3 ); 31 P-NMR (D 2 O) δ: 19.188 (s, 1P)
EXAMPLE 2
Synthesis of the difluoromethylene phosphonate
[0380] 2,3-isopropylidine-α-D-ribonolactone (2): Starting with commercially available α-D-ribonolactone (10.0 g, 67 mmol) and p-toluenesulfonic acid (200 mg) was dissolved in anhydrous acetone (150 ml) and cooled to 0-C. 2,2-Dimethoxy propane (7.55 g, 80.4 mmol) was added to the reaction slowly over a period of 5 minutes. The reaction was stirred for 2 hours at room temperature then sodium bicarbonate powder (250 mg) was added to the reaction, stirred for five minutes, filtered and concentrated. Column chromatography of the crude material gave 2,3-isopropylidine-α-D-ribonolactone(1.06 g, 82%).
[0381] 5-O-(t-butyldiphenylsilyl)-2,3-isopropylidine-α-D-ribonolactone (3): Compound 2 (19 g, 0.1 mol) and imidazole were dissolved in dichlorobenzene (100 ml) and cooled to −10 C. Then a solution of t-butyldiphenylsilylchloride (33.3 g, 0.12 mol) in dichloromethane (100 ml) was added to the rection mixture slowly over a period of 10 minutes. The reaction was stirred at room temperature for a period of 5 hours and then the solid was filtered off and the filtrate concentrated. Chromatography of the crude product yielded a colorless liquid (35 g, 83%).
[0382] 2,5-anhydro-6-O-(t-butyldiphenylsilyl)-1deoxy-1,1-difluoro-3,4-O-isopropylidene-D-ribo-hex-1-eniol (4): To a solution of 3 (2.0 g,4.691 mmol) in tetrahydrofuran (75 ml), cooled to −20 C, was added dibromodifluoromethane (23 ml, 23.5 mmol) using a cooled syringe. To the vigorously stirred solution was added tris(dimethylamino)phosphene (8.5 ml, 46.9 mmol) after which a dense white precipitate formed immediately. The mixture was stirred at room temperature for 30 minutes and then a vacuum applied for another thirty minutes. Argon was then passed into the reaction vessel for five minutes. Tris(dimethylamino)phosphene (200 uL) was added followed by zinc powder (3.04 g, 46.9 mmol), both added to the reaction mixture which was heated to reflux for fifteen hours. The reaction mixture turned dark brown and was allowed to cool to room temperature. Diethyl ether (50 ml)was then added. The ether layer was decanted and the residue was washed with ether (30 ml) three times. The combined ether layers were washed with saturated copper sulfate solution followed by water and brine. The product was concentrated and chromatographed yielding compound 4 as a colorless oil. 1HNMR δ: 1.02(s, 9H), 1.40 (s,3H), 1.49 (s,3H), 3.75 (dd, J=19.5, 3.6, 1H), 3.85 (dd, J=19.5, 3.6, 1H), 4.45 (bs,1H), 4.91 (m, 1H), 5.40 (m, 1H), 7.39-7.48 (m,6H), 7.60-7.65(4H). 13C: d: 135.57, 135.54,130.07,130.01,127.95,127.93, 113.12,87.35, 81.58,78.41 ,65.04,26.85,26.65,25.75,19.07.
[0383] Diethyl (2,3-O-isopropylidene-5-Otert-butyldiphenylsilanyl)-D-ribofuranos-1yl)difluoromethylenephosphonate (5): A solution of 4 (2.0 g, 4.35) and diethyl(phenylselenyl)phosphonate (3.8 g,13.05 mmol) in dry benzene (10 ml) was degassed at reflux four one hour. To this refluxing solution was added a solution of AIBN (0.5 mmol) and tri-butyltin hydride (73 ml, 4.0 mmol) in dry degassed benzene (3.5 ml) over ten hours via syringe pump. The mixture was refluxed for four hours after the addition and concentrated. Chromatography of the crude gave a colorless oil (0.6 g, 27%). 1H-NMR δ: 1.05 (s, 9H), 1.25-1.39 (m, 9H), 1.54 (s, 3H), 3.68-3.78 (m, 2H), 4.18-4.32 (m, 5H), 4.35-4.43 (m, 1H), 4.60 (m, 1H), 4.94 (m, 1H), 7.4 (m, 6H), 7.68 )m, 4H); 13CNMR δ: 135.65,135.63,135.61,135.58,133.15,133.12,129.85,129.83,127.98,127. 97,127.80,127.78,11433,85.93,81.67,64.77,64.72,63.66,27.39,26.84,26.80,25.45,19.24,1 6.42,16.38,16.34; 19FNMR d: −118.25,−121.27; 31PNMR d: 5.5 (t, 1P).
[0384] Diethyl (D-ribo-furanos-1-yl)difluoromethylenephosphonate (6): A solution of 5 (2.7 g. 4/51 mmol) mixed in with a 2:1 ratio of trifluoroacetic acid and water (10 ml) was refluxed for six hours and then concentrated to dryness. The crude product was purified by silca gel col . . . Mn chromatography, yielding diethyl-D-ribo-furanos-1yl) difluoromethylene phosphonate (900 mg, 74%). [α] 25 D +3.69 (con. 0.179 M in MeOH). 1HNMR (CDCl 3 ) δ: 1.4 (m, 6H), 1.78 (bs, 1H, OH), 3.65 (dd, J=27.9, 3H, H+2OH), 3.65 (d, J=7, 1H), 3.88 (d, J=22), 4.04 (d, J=1 1), 4.60 (m, 6H), 4.90 (m, 1H); 13 C-NMR (CDCl 3 ) d: 85.4,71.71,71.24,66.85,6632,61.56, 17.23; 19 F-NMR −118 (d, 1F), −124 (d, IF); 31 P δ: 5.5 (t, 1P) High Resolution Mass Spec: 321.0904 (expected: 321.0960); elemental analysis: C 37.55, H 6.17; expected C 37.51, H 5.98.
[0385] D-ribo-furanos-1-yl-difluoromehtylenephosphonate (7): A solution of 5 (200 mg, 0.33 mmol) in dimethyl formamide (5 ml) was cooled to 10° C. and trimethylsilylchloride was added in excess (1 ml). The reaction was heated for ten hours at 60° C. The reaction was concentrated and recrystallized from a ethyl acetate and methanol (3:1) mixture to yield D-ribo-furanos-1-yl-difluoromethylenephosphonate. (80 mg, 75%) [α] 25 ZD +6.92 (con. 0.133M in MeOH). 1HNMR (CDCl 3 ) δ: 3.61 (dd, J=11,11,1H), 3.82 (d,J=23, 1H), 3.6 (m, 1H), 4.05 (t, J=12), 4.2-4.7 (m, 1H), 4.05 (m, 1H); 13 C-NMR (CD 3 OD) δ: 83 . 41 , 71 . 02 , 70 . 71 , 66 . 85 , 66 . 32 , 61 . 53 ; 19 F-NMR −119.24 (d, 1F), −125.05 (d, 1F); 31P d: 5.5 (t, 1P); 31 P δ: 2.4 (t, 1P); High Resolution Mass Spec: 265.9985 (required 265.9290); elemental analysis: C 26.98, H 4.15; required C 27.28, H 4.20.
[0386] Compounds prepared from literature sources (Meyer, R B, et al., (1984) J. Med. Chem. 27,1095-1098, and Linn, G. (1993) Synthesis of Phosphonate Analogues of Ribose-1-5-bisphosphate, Ph.D. thesis, City University of New York:
[0387] 1.1 ribose-1-methylenephosphonate: Formula Ia, where X═CH 2 , A=CH 2 OH, B═OH, R1=H
[0388] 2.1 5-phosphoribosyl-1-methylenephosphonate: Formula Ia, where X═CH 2 , A=CH 2 OPO(OH) 2 , B═OH, R1=H
[0389] Compounds Made from This Invention:
[0390] 3.1 ribose-1-methylenediethylphosphonate: Formula Ia, where X═CH 2 , A=CH 2 OH, B═OH, R1=Ethyl
[0391] 4.1 ribose-1-difluoromethylenephosphonate: Formula Ia, where X═CF 2 , A=CH 2 OH, B═OH, R1=H | Novel D-ribose-1-phosphate analogue compounds of formula I, pharmaceutically acceptable prodrugs and salts thereof, and their use as hypoglycemic agents and anticancer agents and regulators of carbohydrate metabolism are useful for the treatment of diabetes in humans and for the treatment of various metabolic disorders that involve the regulation of cellular metabolism, e.g. cancer | 2 |
This application is a division of application Ser. No. 08/116,517 filed Sep. 7, 1993 U.S. Pat. No. 5,523,291.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to injectable compositions having primary utility for soft tissue augmentation.
2. Related Background
Over the years, many attempts have been made to develop injectable compositions for soft tissue augmentation, especially breast augmentation. Although in recent years the emphasis in breast augmentation has been on surgically implantable breast prostheses, injectable compositions offer the very important advantage of being able to avoid a surgical procedure.
Some of the early attempts to make injectable compositions for breast augmentation involved the use of silicone gel. However, silicone injected subcutaneously has a tendency to migrate into the surrounding tissue causing, among other problems, granulomas. Accordingly, injectable liquid gels are no longer in use.
Subsequently, injectable collagen in suspension became the composition of choice. However, natural collagen has a great tendency to be resorbed. Therefore, in order to have soft tissue augmentation that did not dissipate shortly after injection, it was found necessary to cross-link the collagen with agents such as glutaraldehyde. Cross-linking inhibits resorption. However, recently the use of glutaraldehyde cross-linked collagen has itself come under attack.
SUMMARY OF INVENTION
The present invention addresses the problems encountered in the prior art by using injectable compositions containing non-cross-linked collagen together with significant amounts of elastin. Elastin has a much lower tendency than collagen toward resorption. Moreover, it is believed that elastin attracts fibroblasts which in turn produce new native connective tissue. Thus, when a composition according to the present invention is injected subcutaneously into soft tissue, as the injected collagen is being resorbed, new native connective tissue is being generated, until a steady state situation has been achieved.
Another advantage of using elastin is that, in suspension, it has a lower viscosity and hence flows much more readily than collagen. This characteristic of elastin makes it easier to inject higher solids content compositions than is possible when using collagen alone.
As indicated above, one use for the compositions of the present invention is for breast augmentation. Another cosmetic application is as a dermal implant to remove wrinkles, primarily around the face and neck. In addition, there are medical applications as well. For example, compositions of the present invention can be used in connection with overcoming urinary incontinence. In this latter application, a composition according to the present invention would be injected into the area of the urethral sphincter.
Other possible uses for the compositions of the present invention include load-bearing tissue augmentation, for example, under a corn, and general and specific contour improvements, for example, for nose contour corrections and to correct viral pockmarks and acne scars. For load bearing tissue augmentation, the composition of the present invention would be injected between the load bearing tissue, for example the corn, and the load exerting medium, for example the bone. To alleviate skin contour defects, such as viral infection pock marks and acne scars, the composition of the present invention would be injected into the soft tissue beneath the imperfection. Similarly, to change the contour of a person's nose, the composition of the present invention would be injected into the soft tissue of the nose.
While collagen has been used previously for the above-described applications, it has generally been in the form of cross-linked collagen. Even with cross-linked collagen, however, the resorption time is often unacceptably short, especially after repeated injections. Indeed, injections of cross-linked collagen must frequently be repeated several times over a short time span before adequate augmentation can be achieved. In addition, glutaraldehyde cross-linked collagen tends to cause tissue reactions in some patients and, also, there is some concern about potential immunological problems associated with the use of collagen that has been cross-linked with glutaraldehyde. Cross-linking agents like glutaraldehyde are known to be toxic and there is concern that repeated injections of glutaraldehyde-containing compositions may produce progressively more severe immune reactions and increasingly rapid resorption. The compositions of the present invention, on the other hand, are believed to have much longer resorption times and to produce no significant immunological or tissue reaction problems.
DETAILED DESCRIPTION
It is well known that the ligamentum nuchae is made up largely of elastin, with only a relatively small amount of collagen. Indeed, more than 70% of the dry weight of this ligament is elastin. Because of the relatively high elastin content and relatively low collagen content, it is an ideal starting material to use in making an injectable composition according to the present invention.
To make a preferred injectable composition according to the present invention, the ligamentum nuchae may be cleaned using a procedure similar to that taught in U.S. Pat. No. 5,028,695, the disclosure of which is incorporated herein by reference. Generally, it is first cleaned of blood and adherent tissue. It is then chemically treated to remove the non-elastinous and non-collagenous components. The chemical treatment generally involves first treating the ligament with a strong alkali solution, then with an acid, and then with a neutralizing agent. The alkali sequence may be repeated several times if desired. Chemical treatment is followed by mechanical working to separate the elastin fibers. The separated fibers are then suspended in a suitable biocompatible carrier, for example a mixture of water and glycerin.
Although the preferred starting material is the ligamentum nuchae, other ligaments and tendons may also be used. For example, the peritoneum, omentum and other animal membranes, especially those which have significant amounts of elastin, could be used. Also, elastin and collagen from different sources could be mixed together to produce a mix having whatever proportions are deemed advantageous for a particular application. It is believed, however, that the composition should have a minimum of perhaps as little as about 10% elastin (dry weight) and might have as much as 90% or perhaps even higher of elastin.
While, as noted above, it is believed preferable not to use any cross-linking agents, there may be applications where cross-linking can be tolerated or might even be desirable. In that event, the cross-linking agent should be one which forms strong stable bonds with the collagen so that the cross-linking agent does not leach out and so that the cross-linked collagen is non-cytotoxic and does not provoke an immune or cellular response. Such cross-linking agents might include hexamethylene diisocyanate, some polyepoxy compounds, for example, polyethylene glycol diglycidyl ether, and some water soluble carbodiimides, for example, 1-ethyl-3 3-dimethyl amino propyl!carbodiimide.HCl in the presence of N-hydroxysuccinimide.
EXAMPLE
A portion of bovine ligamentum nuchae weighing about 10 kg. was soaked overnight in about 40 l of tap water at room temperature to remove adherent blood and other water soluble components. Soaking in water also assures a more or less natural degree of hydration which is believed to facilitate the subsequent chemical treatments.
After the initial soak, the ligament was washed twice for about 10 minutes each, again in tap water, before being placed in 50 l. of 4% (w/w) solution of sodium hydroxide (NaOH) in tap water. It was permitted to remain in this strongly alkaline soak for 48 hrs. at room temperature.
The alkaline soak was followed by three 10 minute washes in 50 l. of tap water and was then subjected to a second alkaline soak, this one in a 2% (w/w) solution of NaOH in tap water at room temperature for 72 hrs. There then followed three more 10 minute washes in tap water to remove the solubilized components.
After the second alkaline soak and subsequent washes, the ligament was placed in a solution of hydrochloric acid (HCl) for about 4 hrs. The HCl solution for this soak was prepared by mixing 4 l. of concentrated (37%) HCl with 36 l. of tap water. The acid soaked ligament was then washed in tap water until the pH of the water was between about 2.5 and 3.
At that point, the ligament was placed in a sodium bicarbonate (NaHCO 3 ) soak to neutralize the remaining acid. The NaHCO 3 soak was prepared by adding 350 gm. of NaHCO 3 to 50 l. of tap water. The ligament was left in this neutralizing bath overnight and then it was again washed in tap water to remove the resulting salts. Washing continued until mixing with a silver nitrate (AgNO 3 ) solution produced no precipitates.
A kolloid mill was then used to break up the natural collagen/elastin matrix and separate the elastin fibers. Acetone extractions were then used to remove the water and the fibers were then air dried in an oven at about 75° C.
Finally, 150 gm. of the dried fibers were suspended in 2 l. of a water/glycerine mixture comprised of 1 l. water and 1 l. glycerine. This suspension was then ready for use in accordance with the present invention.
It is believed that the collagen in the composition according to this present invention acts as a stimulant during the initial phase after injection. It tends to cause some mild tissue reaction and increased vascular activity. Of course, this leads to resorption, but in the process, fibroblasts, which appear to have an affinity for elastin, invade the injected composition and attach themselves to the elastin fibers. Hence, these fibroblasts lay down an organized matrix of new native connective tissue. Eventually, the injected collagen has been resorbed and all that reins is the injected elastin in a new native connective tissue structure.
It will readily become apparent to those skilled in this art that numerous modifications, alterations and changes can be made with respect to the specifics of the above description without departing from the inventive concept described herein. Accordingly, all such variants should be viewed as being within the scope of the invention as set forth in the claims below. | Injectable implant compositions for soft tissue augmentation comprise elastin and collagen and a biocompatible carrier. An injectable implant composition for soft tissue augmentation is derived from the ligamentum nuchae which has been treated to remove non-collagenous and non-elastinous proteins. Methods of making an injectable implant composition for soft tissue augmentation from the ligamentum nuchae are described. | 0 |
FIELD OF THE INVENTION
The present invention relates to a process for optimizing the value of natural gas.
BACKGROUND OF THE INVENTION
The present invention is directed to a process for converting gas resources in remote locations to fuels and petrochemicals. Although the operating cost for producing fuels and petrochemicals from remote natural gas is significantly lower than producing the same products from oil, high capital costs discourage such conversion of natural gas. Reducing such capital costs would provide an incentive for utilizing natural gas as a relatively inexpensive source of fuels and petrochemicals.
Natural gas is often co-produced with oil in remote offsite locations where reinjection of the gas is either expensive or not feasible. A desirable option for treating such gas is its conversion to methanol, using Fischer-Tropsch technology, which is simpler than gas liquefaction. Methanol can be produced at reasonable cost in plants ranging from 500 to 50,000 tons a day. While larger plants have a large cost advantage, small plants are nevertheless viable if the gas cost is sufficiently negative, e.g., reinjection of natural gas is too costly or impossible. Accordingly, it has been suggested as economically feasible to place methanol plants on barges for offshore producing locations.
Despite such advantages, methanol's market is limited to only about 100 million tons per year, significantly less than that which could be produced from all natural gas sources, and therefore not suited to the scale of co-produced natural gas. However, methanol can be converted to gasoline, olefins, or a mixture of both. Indeed, a commercial plant for converting natural gas to gasoline has operated in New Zealand. Such methanol conversion processes are generally designed as integrated large-scale plants, where natural gas is converted to methanol that is then converted to hydrocarbon products.
For offshore and other difficult gas producing locations, it is preferable to provide a process, which is simple to operate. Because methanol production from natural gas is the simplest way to convert gas to liquid, it is highly desirable for on-site use. However, methanol's lack of a large-scale market militates against such conversion in the absence of a means to economically convert methanol to more readily marketable products.
U.S. Pat. No. 3,898,057 incorporated herein by reference, discloses a process for converting natural gas to a mixture of carbon monoxide and hydrogen at the site of production, converting the mixture to methanol, and transporting the methanol to a place of consumption where it is burnt or reconverted into methane.
SUMMARY OF THE INVENTION
Despite current practices, there exist certain advantages to totally separating the methanol conversion step from the production of methanol, and conducting such methanol conversion in a separate unit within a large existing refinery or in a large, dedicated methanol refinery, either of which is located in a region readily accessible to petrochemical markets, e.g., the Gulf Coast, Rotterdam, Singapore, etc.
A significant portion of costs associated with converting methanol is attributable to services or products supplied from outside sources such as steam, electricity, and fresh water. These are often available to a refinery more cheaply than at or near a natural gas producing site due to the refinery's economies of scale as well as location with respect to the supply of such services or products. In addition, gasoline product tankage and distribution infrastructure is already available at the refinery as well as facilities to handle light gas by-products.
Another reason refineries are advantageous locales for converting methanol stems from their enhanced profitability by converting methanol to gasoline as well as other higher value products as compared to solely producing a product for its fuel value as is done where methane is converted to a liquid fuel at the production site for natural gas. For example, refineries can co-produce chemicals, such as ethylene, propylene, and aromatics, having higher value than motor fuels. Moreover, the location of many refineries near petrochemical complexes or petrochemical pipelines provides a readily accessible, proximal market for such chemicals. Transporting methanol from a remote location, say, at least 10 miles, at least 20 miles or even at least 100 miles, to a refinery located near chemical markets is less expensive than transporting petrochemicals from local conversion plants for ethylene or propylene near natural gas sources. Indeed, such ethylene or propylene made near the natural gas producing site can require grassroots polymerization facilities in order to render these products transportable. In contrast, a methanol refinery located near ethylene and propylene merchant markets can readily dispose of ethylene and propylene without further processing. In general, the methanol refinery of the present invention is advantageously located where a critical mass of other refineries and petrochemical plants already exist. The methanol refinery is dependent upon a supply of low cost methanol such as that which can be economically produced from gas fields having no access by pipeline to suitably sized markets.
Decoupling gas conversion to methanol from expensive methanol upgrading processes that require investments significantly greater than the cost of the gas conversion plant provides additional benefits. Integrating methanol conversion into a refinery is particularly advantageous where the refinery can vary its product distribution according to market demand or refinery requirements. Such flexibility is lacking where methanol is converted in a remote location such as a natural gas production site.
Although a single natural gas producing site may not economically justify a methanol conversion plant in addition to methane conversion, a single methanol conversion plant could service multiple remote natural gas producing sites that transport their site-produced methanol to the plant. Such an arrangement would allow the use of a larger-scale methanol conversion plant with its attendant economies. Thus a properly situated methanol refinery would create a market for smaller natural gas producing sites that are individually unable to support individual dedicated methanol conversion plants.
According to the invention it has now been found that natural gas containing methane can be converted to higher value products by a process which comprises: i) converting said methane to methanol at or near a site of gas production; ii) transporting said methanol to a refinery remote from said site of gas production (say by at least 10 miles, at least 20 miles, at least 100 miles, or even at least 1000 miles) and proximal to petrochemical markets (say within 100 miles, preferably within 20 miles, or even more preferably within 5 miles), said refinery producing ethylene and propylene product streams and comprising an alkylation unit, e.g., one which can utilize a propylene feed; and iii) converting said methanol to gasoline boiling range fuel product and petrochemicals, such as ethylene, propylene, butenes and xylenes.
In another aspect, the present invention further comprises substituting the butenes produced from methanol for at least some of the propylene feed (producible from crude oil), in the refinery's alkylation unit to provide gasoline boiling range fuel product.
In yet another preferred embodiment, the present invention further comprises collecting individual streams of ethylene, propylene, and gasoline boiling range fuel product.
In yet another preferred embodiment, the present invention allows the refinery to produce larger quantities of gasoline low in sulfur and benzene. The C 4 + stream produced from methanol conversion contains very low levels of sulfur, e.g., less than 10 ppm, preferably less than 5 ppm sulfur, and more preferably no sulfur at all. Such a stream can also contain very low levels of benzene, e.g., less than 2.5 weight percent, preferably less than 1 weight percent. Blending this clean stock with gasoline fractions derived from crude oil can allow existing refineries to operate more efficiently by reducing the amount of energy and processing required to produce gasoline. A C 4 + gasoline boiling range product stream containing less than 10 ppm sulfur produced by the present process can be blended with a second gasoline boiling range product stream which contains at least 10 ppm sulfur to provide a gasoline boiling range product stream having a reduced sulfur content compared to said second gasoline boiling range product stream.
In another aspect, the present invention relates to a process for treating methane-containing natural gas which comprises: i) converting said methane to methanol at or near plural sites of natural gas production; ii) transporting said methanol from said plural sites to a single refinery remote from said sites of production, said refinery producing ethylene and propylene and comprising an alkylation unit; and iii) converting said methanol to gasoline boiling range fuel product and at least one petrochemical selected from the group consisting of ethylene, propylene, butenes and xylenes.
The above and other objects, features and advantages of the present invention will be better understood from the following detailed descriptions, taken in conjunction with the accompanying drawings, all of which are given by illustration only, and are not limitative of the present invention.
BRIEF DESCRIPTION OF THE DRAWING
The FIGURE depicts a process for converting natural gas to higher value products in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Methane Conversion to Methanol
The present invention contemplates the use of any suitable method for converting methane to methanol. Such a method can employ synthesis gas as an intermediate. The synthesis gas can be generated using steam methane reforming, partial oxidation or gasification, or a combined reforming or autothermal reforming process.
Steam methane reforming is the catalytic reaction of natural gas with steam to produce a synthesis gas or “syngas”, which includes H 2 , CO 2 , CO, CH 4 , and H 2 O with an H 2 to CO ratio of about 3:1 or higher. The steam methane reformation reaction is endothermic. Therefore, external heat is required. The natural gas and steam are typically fed into alloy tubes that contain a nickel based catalyst for the reforming reaction. The catalyst tubes are placed inside a refractory lined structure. A portion of the natural gas is used as fuel to provide the heat required for the reaction:
H 2 O( g )+CH 4 →3H 2 +CO
The drawbacks of steam methane reforming include its limitation to low pressure applications on the order of about 100-400 psig. Steam methane reforming also produces a syngas with a high CH 4 impurity content in a range of about 3-15 percent, and requires the external supply of CO 2 for methanol syngas requirements.
Partial oxidation or gasification is a non-catalytic reaction of natural gas with oxygen under controlled oxygen conditions. The reaction is exothermic as shown in the following reaction:
CH 4 +1/2O 2 →CO+2H 2
The partial oxidation process can be operated at high pressure to minimize or eliminate the syngas compression needed to reach the desired elevated pressure suitable for methanol production, typically about 200-2000 psig. However, the syngas produced from the partial oxidation process has a lower H 2 to CO ratio with little or no CH 4 content. Typically, the CH 4 varies from about 0-0.5 percent, and the H 2 to CO ratio varies from about 1.5-2.0. As a result, external H 2 would be needed to meet the methanol syngas requirements.
The combined reforming process uses a combination of conventional steam methane reforming, often referred to as “primary reforming,” in combination with oxygenated catalytic reforming, often referred to as “secondary reforming,” to generate stoichiometric ratioed synthesis gas for the production of methanol. See U.S. Pat. No. 4,888,130.
In a preferred aspect of the combined reforming process, a portion of the natural gas feedstock is fed to the primary reformer and the effluent is blended with the balance of the natural gas and oxygen prior to entering the secondary reformer. The drawback of the combined reforming process is that it is limited to moderate pressure applications, on the order of about 400 to 600 psig.
At higher pressures, reduced operating temperatures are necessary, and because increased amounts of CH are present in the feed to the secondary reformer, it is more likely that soot or carbon formation will be increased. This can damage or deactivate the catalyst and lead to greater feed consumption to produce the required amount of carbon monoxide.
Most commercial methanol synthesis plants operate in a pressure range of about 700-2000 psig using various copper based catalyst systems depending on the technology used. A number of different state-of-the-art technologies are known for synthesizing methanol, and are commonly referred to as the ICI (Imperial Chemical Industries) process, the Lurgi process, and the Mitsubishi process.
The methanol syngas, also referred to as “stoichiometric ratioed synthesis gas”, from the syngas generation unit is fed to a methanol synthesis reactor at the desired pressure of about 700 to 2000 psig, depending upon the process employed. The syngas then reacts with a copper based catalyst to form methanol. The reaction is exothermic. Therefore, heat removal is ordinarily required. The raw or impure methanol is then condensed and purified to remove impurities such as higher alcohols including ethanol, propanol, and the like. The uncondensed vapor phase comprising unreacted methanol syngas is recycled to the feed.
The operation of compressing the methanol synthesis gas requires expensive equipment that is costly to maintain. Moreover, the need to compress the methanol synthesis gas to reach suitable operating pressures for the methanol synthesis operation further increases the production cost of methanol. For optimal methanol production, U.S. Pat. No. 5,496,859 teaches using a stoichiometric ratioed syngas supplied to the methanol synthesis unit generally conforming to the following specifications: (H 2 −CO 2 )/(CO+CO 2 )=1.9-2.1, and N 2 , Ar and CH 4 ≦3.0% and H 2 O. This process partially oxidizes natural gas in a gasifier to produce hot pressurized syngas which is passed through a steam reforming catalytic reactor to produce a reformer syngas, a portion of which is recycled as feed to the gasifier while the remaining portion is combined with partially cooled gasifier syngas exiting the catalytic reactor to form a stoichiometric ratioed syngas. The ratio adjusted syngas then enters a methanol synthesis unit at conditions necessary to convert it to methanol with little or no external compression.
Transportation of Methanol to Methanol Refinery
Methanol is shipped from the synthesis plant to the methanol conversion refinery by any suitable means such as dedicated large tankers, supertankers or pipelines. The cost to ship is expected to be similar to the cost of shipping crude oil.
Methanol Conversion to Gasoline Boiling Range Hydrocarbons and Petrochemicals
U.S. Pat. No. 6,046,372 incorporated herein by reference, provides many examples using modified medium pore zeolite catalysts, e.g., a shape-selective crystalline silicate catalyst selected from the group consisting of ZSM-5, ZSM-11, ZSM-12, ZSM-23, ZSM-35, ZSM-48, and MCM-22, to produce ethylene, propylene, p-xylene, and gasoline precursors from methanol at commercially attractive partial pressures between 15 and 170 psia. The reference teaches that ethylene+propylene selectivity is optimized by using between 1 and 20 wt % toluene co-feed, ZSM-5 catalysts with d/r 2 values between 0.5 and 20, and temperatures between 380° and 500° C.
U.S. Pat. No. 5,248,647 incorporated herein by reference, describes the use of SAPO-34 type catalysts for the conversion of methanol or dimethyl ether to C 2 C 5 olefins at commercially attractive conversions of methanol exceeding 98%. The patent teaches that ethylene+propylene selectivity is optimized at temperatures between 400° and 500° C. and methanol pressures between 5 and 40 psia. The '372 and '647 referenced methanol conversion methods are especially suited to use in the present invention.
Preferably, the present invention can employ an olefin production zone containing a metal aluminophosphate catalyst selected from the group consisting of SAPO-34, SAPO-17, SAPO-18, and mixtures thereof, the catalyst being described in U.S. Pat. Nos. 4,440,871, 5,126,308, and 5,191,141 and hereby incorporated by reference.
U.S. Pat. No. 3,928,483 describes the use of shape-selective zeolites such as ZSM-5 for the conversion of methanol or dimethyl ether to gasoline. U.S. Pat. Nos. 3,911,041, 4,025,571, 4,025,575, and 4,052,479 describe the use of shape-selective zeolites in converting methanol and/or dimethyl ether to olefins, to aromatic hydrocarbons, or to mixtures thereof. The foregoing patents are incorporated herein by reference as background material.
U.S. Pat. No 4,499,314 incorporated herein by reference, discloses that the addition of various promoters, including aromatic compounds, such as toluene, accelerate the conversion of methanol to hydrocarbons over zeolites, such as ZSM-5, which have a pore size sufficient to permit sorption and diffusion of the promoter. In particular, the '314 patent teaches that the increased conversion resulting from the addition of the promoter allows the use of lower severity conditions, particularly lower temperatures, which increase the yield of lower olefins (column 4, lines 17-22). Thus in Example 1 of the patent the addition of toluene as a promoter reduces the temperature required to achieve full methanol conversion from 295° C. to 288° C. while increasing the ethylene yield from 11 wt % to 18 wt %. In the Examples of the '314 patent the methanol feedstock is diluted with water and nitrogen such that the methanol partial pressure is less than 2 psia.
While the present invention contemplates the use of any suitable method for converting methanol, the above methanol conversion processes are especially well-suited to use in the present invention to provide a variety of products of enhanced value from a methane-containing natural gas feedstock.
The following examples will serve to further illustrate processes and some advantages of the present invention.
EXAMPLE 1
Conventional On-Site Conversion of Natural Gas to Methanol and Conversion of Methanol to Gasoline and Petrochemicals
11 billion pounds of methane-containing natural gas is converted to 1.5 billion pounds of polyethylene, 1.2 billion pounds of polypropylene, and 4.1 billion pounds of gasoline at a remote location near the production site of the natural gas. Polyethylene and polypropylene are required products because ethylene and propylene cannot be shipped economically. Costs are: 2 billion dollars for methanol synthesis, 0.7 billion dollars for methanol conversion, 1.5 billion dollars for a polyethylene plant, and 1 billion dollars for a polypropylene plant—representing a total project cost of 5.2 billion dollars.
EXAMPLE 2
On-Site Conversion of Natural Gas to Methanol and Remote Conversion of Methanol to Gasoline and Petrochemicals
Referring now to the FIGURE, 11 billion pounds of methane-containing natural gas produced at production site 10 are contacted with oxidant 22 and converted to 15.5 billion pounds of methanol at an on-site methane to methanol conversion site 20 . The methanol produced is transported by transportation means 30 to a refinery complex 40 which according to this embodiment comprises an FCC unit 50 which produces ethylene overhead via line 52 , propylene+butylenes via line 53 , FCC gasoline via line 54 and FCC bottoms via line 56 , and an alkylation unit 60 which can utilize the propylene+butylenes as a feed along with isobutane via line 62 obtained from elsewhere in the refinery complex, to produce alkylate via line 64 .
The feedstock for the FCC unit is shown by the line 57 . Typical feeds to an FCC unit include without limitation relatively high boiling oil or residuum either on its own or mixed with other fractions. By way of example and without limitation, include gas oils such as atmospheric gas oil, vacuum gas oils, and coker gas oils.
The refinery complex comprises a methanol refinery 70 wherein the transported methanol from line 30 is converted in a molecular sieve based fluid bed methanol-to-olefin (MTO) unit 100 to 1.5 billion pounds of ethylene, 1.2 billion pounds of propylene, (which can be taken off vial line 72 ) and 4.1 billion pounds of gasoline and gasoline precursors (including 0.8 billion lbs butenes) taken off via line 74 . An additional 0.8 billion pounds of propylene are freed up for sale to local merchant markets by displacement from the alkylation unit 60 by substituting butenes produced from methanol conversion via line 76 . Costs are: 2 billion dollars for methanol synthesis at the remote location and 0.5 billion dollars to add the required molecular sieve based fluid bed MTO unit to the existing refinery, representing a total project cost of 2.5 billion dollars.
The Examples demonstrate that using a methanol refinery can reduce the required capital for a major gas to liquids project by as much as 50%. Current technology requires double the capital investment in order to co-produce large amounts of petrochemicals from natural gas. The present process allows co-production of large amounts of petrochemicals using only incrementally increased capital than is required for production of fuels alone.
In addition to greatly reduced capital requirements, the present process allows the synergies between methanol conversion and crude refining to be captured. These include but are not limited to the production of alkylate from MTO butenes, and the use of the MTO low sulfur C5+ stream to enable the refinery to reduce the amount of processing required to produce low sulfur gasoline from crude oil. | A process for treating methane-containing natural gas is provided which comprises: i) converting methane to methanol at or near a site of natural gas production; ii) transporting the methanol to a refinery remote from said site of production, said refinery producing ethylene and propylene and comprising an alkylation unit which can utilize a propylene feed; and iii) converting said methanol to gasoline boiling range fuel product and petrochemicals, including ethylene, propylene, butenes and xylenes. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of copending application Ser. No. 864,332 filed Dec. 27, 1977, now abandoned, having the same title and applicants and owned by the same assignee.
The disclosure of the copending application is incorporated herein by reference.
FIELD AND BACKGROUND OF THE INVENTION
The field and background of the invention herein are the same as those of the copending application which is incorporated herein by reference. A short summary thereof is included hereinafter.
The invention provides means for mounting printing cylinders which, although formed of very thin metal sleeves and readily collapsible, nevertheless are maintained in a relatively rigid condition in a printing press by means of air pressure.
The sleeves are electrodeposited metal such as nickel, copper, iron or other pure metal a fraction of a millimeter thick made by known processes such as described in U.S. Pat. No. 2,287,122. Sleeves of plated metal may be used such as for example, tin, chromium or other metals on nickel.
The method of utilizing the sleeves for printing is different from known methods where the pigment is forced through perforated designs in the sleeves because each sleeve is coated with a microthin coating of a photoconductive material of the type which is disclosed in U.S. Pat. No. 4,025,339. On this account the sleeves are imperforate.
The invention herein is directed to a structure which is simple and economical in construction. The problem of mounting the sleeve in a cylindrical configuration is solved in an elegant manner which provides for airtight clamping to a flanged disc at each end of an elongate framework. The framework is readily mounted in a printing press with the sleeve preinflated and/or capable of having the inflation maintained during use.
The invention herein also encompasses means for maintaining the pressure in the sleeve constant notwithstanding changes in temperature and even minor leaks during use and means for varying the circumference of the cylinder minutely by adjustment of internal fluid pressure during use. This latter capability enables the adjustment and refinement for repeat length during operation of the printing press.
The invention also contemplates novel structure coupling the framework to the press in a simple but highly effective manner and a system for using the sleeve of the invention.
SUMMARY OF THE INVENTION
A sleeve of thin-walled metal that is imperforate and highly flexible has a photoconductive coating on the exterior thereof that does not materially affect the flexibility. Such sleeve is mounted on a framework or mandrel in cylindrical form and maintained inflated so that the framework may be coupled into a printing press and the sleeve serves as ink transfer means, especially for effective use in a multicolor printing press.
The supporting device includes a central hollow shaft with hubs at its ends mounting flanged discs these discs having sleeve clamping means on the periphery thereof. The sleeve clamping means include clamping rings on the interior of the discs which can be taken up by fasteners manipulated from the exterior of the discs. The structure at the ends of the central hollow shaft include means for introducing air or other fluid under pressure to the interior of the sleeve either prior to mounting the device in the press or while the device is in use. The invention includes a printing press including means for maintaining the pressure within the sleeve constant, means for stopping the press if the pressure departs from a desired value and means for using the pressure to achieve a degree of registration.
Novel means for coupling the device into the press and a press system for using the invention are disclosed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a median sectional view through a printing apparatus constructed in accordance with the invention taken generally along the line 1--1 of FIG. 2 and in the indicated direction, parts being broken away;
FIG. 2 is an end elevational view of the same taken from the left hand side;
FIG. 3 is a fragmentary detailed view of the sleeve clamping means; and
FIG. 4 is a highly diagrammatic view of a printing press having the device 10 installed therein, the structure being such as to utilize an external source of pressure.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Generally the apparatus of the invention is designated 10 and comprises a central hollow shaft 12 of metal having a plurality of lateral passageways 13 for air. Other fluids may be used, but for convenience only air will be referred to hereinafter because it is most convenient to use the same in printing establishments.
The ends of the central shaft 12 are closed off by plugs 14 and 16 to which the shaft is welded as indicated at 18 and 20, respectively. A flanged disc is connected to each of these plugs by suitable means, the disc 22 being shown on the left and the disc 24 on the right. These discs 22 and 24 are identical and their construction and functions will be explained in detail later. At this point it is to be noted that the plugs 14 and 16 are generally cylindrical and that each of the discs 22 and 24 includes a hollow cylindrical hub shown at 26 and 28 which telescopically engages the respective plugs 14 and 16 on the exterior thereof, airtight connection being maintained by suitable packing such as O-rings 30.
The discs 22 and 24 include internal radial strengthening ribs 32 and 34 integral with the web or body of each disc, the latter being imperforate to retain the air pressure which is to be maintained on the interior of the device 10.
As noted, the structures at opposite ends of the shaft 12 are different. These represent two embodiments of the invention capable of being used together or separately. In other words, the structure at the left hand end may be used solely or duplicated at the right hand end; the structure at the right hand end may be used solely or duplicated at the left hand end; one of each structure may be used together at opposite ends.
Considering now the structure at the left hand end of the device 10, the plug 14 has a cylindrical axial recess formed in its outer end at 36 and a coaxial socket 38 in the center of the recess 36 in which there is disposed a simple air valve 40 of the so-called Schraeder type which communicates by way of the passageway 42 with the interior 44 of the hollow shaft 12. As explained, the shaft has the lateral passageways 13 by means of which the outer annular chamber 46 and the inner chamber 44 are in communication. As understood, a thin metal sleeve 48 of electrodeposited nickel or the like with an outer photoconductive coating is adapted to be clamped into cylindrical configuration on the device 10 and maintained in inflated condition by air pressure. This is effected by introducing air under pressure by way of the valve 40 into the chamber 44.
The disc 22 has an inwardly directed radial flange 49 which is engaged over the axial end of the plug 14 and provided with perforations and threaded sockets to aid in the assembly of the device. For example, in the device shown, there is a perforation in alignment with each of the ribs 32 thus providing six equally spaced perforations aligned with threaded sockets in the axial end of the plug 14. One such perforation is indicated at 50 and a threaded socket at 52. These perforations and sockets receive machine screws 54 which pass through an outer cap or centering flange member 56 thereby securing the disc 22 to the plug 14.
The centering flange member 56 has a central spigot 58 which is cylindrical on its exterior to fit into the recess 36 and is tapered on the interior as indicated at 60 and provided with a keyway at 62. There is also a radial flange portion 63 overlying the flange 49. The member 56 has the aligned perforations in the flange portion 63 for the screws 54 but in addition has several other perforations 64 which are intended to be aligned with threaded sockets 66 formed in the flange 49 to receive other machine screws 68 that pass through the flange portion 63. These screws 68 are only three in number as shown in FIG. 2 and their function is to enable the proper alignment of the disc 22 and the flange member 56 but more importantly, to aid in assembly. The two parts 22 and 56 can be assembled together before the disc 22 is engaged onto the plug.
Looking now at FIG. 3 which is an enlarged view of the outer section of the disc 22, there is an annular thickened rim 70 which has an interior (on the right hand face) axially extending annular seat or groove 72 formed fully around its circumference and coaxially centered. There is an elastomeric ring 74 seated in the bottom (left hand end) of the groove 72, the ring 74 being provided with spaced passageways 76 aligned with perforations 78 provided in the rim 70 and opening to an external shallow furrow 80 provided on the exterior of the rim 70. There is a pressure ring 82 of cylindrical configuration which has a plurality of threaded studs 84 secured into its left hand axial end in spaced circumferential position to align with the passageways 76 and perforations 78. The studs 84 extend through these passageways and perforations when the ring 82 is assembled to the disc 22 and are engaged by the nuts 86.
Before the nuts 86 are tightened, the assembly of the apparatus 10 with the sleeve 48 is effected, the sleeve 48 being easily slipped into place as the assembled disc 22, flange member 56 and ring 82 are properly positioned. Thereafter, taking up on the nuts 86 presses the ring 82 against the elastomeric ring 74 which expands in attempting to extrude out of the groove 72 thereby firmly clamping the sleeve 48 in place.
Assuming that the same structure and procedure has been utilized in assembly of the right hand end of the device 10, it can be pumped up to a pressure of say about half an atmosphere through the use of the valve 40 and installed in the printing press. The tapered socket 62 provides for centering and the keyway provides for positive driving coupling of the device with suitable mechanical driving means associated with the printing press.
The right hand end of the device need not have a valve equivalent to the valve 40 but could have a blind end in the equivalent of the tapered socket 60 in the axial end of the plug 16. As a matter of fact, there need not be a second keyway at this location.
In the view of FIG. 1, however, a second form of structure is illustrated which enables various functions to be effected by means of another valve.
Referring now to the right hand end of the device 10 shown in FIG. 1, the only structural difference between that end and the left hand end lies in the valve device mounted at the right hand end. There is a valve housing 90 set into the right hand plug 16 which has a port 92 leading to the chamber 44. The movable valve 94 is seated at the right hand end of the chamber 96 by means of the O-rings 98 against the axial intake port 100 and held there by a spring 102. The spring 102 is of a strength to maintain any pressure which is in the chambers 44 and 46 if the device 10 is removed from a press in which it is installed. When installed in a press, the stem 104 of the valve member 106 pushes the valve 94 off its seat and holds the port 100 open.
The valve member 106 has a coaxial passageway and itself is slidable in the port 100, being kept air tight therein by suitable O-rings. Its external face 110 has O-rings to enable it to make a frictional and air tight connection with a fitting that can supply external air pressure to the device 10. The fitting is not shown in FIG. 1 but is symbolized by the fitting 112 in FIG. 4 as a rotary air connection. The spring 102 keeps the valve member 106 in engagement with the fitting 112.
From this description it is obvious that air can be maintained and supplied to the interior of the sleeve 48 through the valve member 106 from outside sources to pump up the sleeve 48 and maintain it in such condition.
FIG. 4 is a highly diagrammatic view of a printing press having the device 10 installed therein, the structure being such as to utilize an external source of pressure.
The device 10 is shown mounted on the frame 114 of a printing press 116, only a very small part of which is diagrammed. The substrate in the form of a web of paper 118 is being guided through the press 116 and may pass over idler and drive rollers, an idler roller being indicated at 120 and a drive roller being indicated at 122 mounted to the frame 114. The press drive 124 may be mechanical, electrical pneumatic or a combination of these, suitable controlled as customary with modern printing presses. The mechanical drive extending to the several rotary parts is indicated by the broken lines 126.
A pressure source is shown at 128 supplying pressure to the fitting 112 by way of the pressure regulator 130 and the air lines 132 and 134. The exact pressure within the sleeve 48 will be controlled by the pressure regulator 130 whose set value may be established manually as by a control 136 or may be varied automatically for certain purposes by way of the line 138.
The pressure switch 140 is sensitive to sudden changes in the pressure in the line 134, being connected to the line 134 by a conduit 142. A large hole suddenly occurring in the sleeve 48 or the bursting thereof will cause a sudden dropping of pressure in the chamber 46. The drop will be experienced by the line 134 and the regulator will attempt to equalize the pressure. This radical change sensed by the switch 140 can be made to operate the switch to turn off the press drive and prevent damage.
Slight air leaks in the chamber 46 can be taken care of by the regulator 130 as a routine matter.
The press 116 will normally have some form of transducer system (not shown) to indicate registration of multiple impressions and a signal from such system can be picked up and transmitted by a line, electrical or pneumatic, as shown at 144 to a sensor 146. This sensor 146 may in turn provide a signal which operates a register adjusting device 148 which is nothing more than an automatic adjustment for the set point of the pressure regulator. It has been found that since the sleeve 48 is made out of metal that is very thin, it is capable of being inflated slightly beyond its normal diameter by a small amount, say a few thousandths of a millimeter. Registration can be affected by this means, to augment ordinary registration control means rather than to replace the same.
The pressure adjustment effected by the register adjust device 148 is applied to the pressure regulator 130 by way of the line 138.
Variations are capable of being made without departing from the spirit or scope of the invention as defined by the appended claims. | Printing apparatus utilizing flexible metal sleeves for ink transfer comprises means for mounting the sleeves in cylindrical configuration on a structure which enables the cylindrical configuration to be maintained by air pressure. The sleeves are of the type which is made by electrodepositing metal in a form that is very thin, readily collapsible and imperforate.
The sleeve of the apparatus is provided on its exterior with a coating of flexible, microcrystalline, wholly inorganic photoconductive material such as sputtered ultrapure cadmium sulfide.
The sleeve is mounted in a press having means to cooperate with the sleeve for maintaining its pressure and for stopping the press if the pressure should drop below a predetermined value. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 U.S.C. §119 of U.S. Provisional Application Ser. No. 61/435,987 filed on Jan. 25, 2011, the content of which is hereby incorporated by reference.
BACKGROUND
[0002] The production of liquid crystal displays such as, for example, active matrix liquid crystal display devices (AMLCDs) is very complex, and the properties of the substrate glass are extremely important. First and foremost, the glass substrates used in the production of AMLCD devices need to have their physical dimensions tightly controlled. The downdraw sheet drawing processes and, in particular, the fusion process described in U.S. Pat. Nos. 3,338,696 and 3,682,609, both to Dockerty, are capable of producing glass sheets that can be used as substrates without requiring costly post-forming finishing operations such as lapping and polishing. Unfortunately, the fusion process places rather severe restrictions on the glass properties, which require relatively high liquidus viscosities.
[0003] In the liquid crystal display field, thin film transistors (TFTs) based on poly-crystalline silicon are preferred because of their ability to transport electrons more effectively. Poly-crystalline based silicon transistors (p-Si) are characterized as having a higher mobility than those based on amorphous-silicon based transistors (a-Si). This allows the manufacture of smaller and faster transistors. P-Si displays are at the core of state-of-the-art handheld devices. The p-Si thin film transistor array consumes very low power, permits very fine features (critical for small displays), and provides high brightness.
[0004] The process used to make p-Si TFTs invariably includes a thermal excursion to quite high temperature to encourage the silicon to crystallize. In some processes, temperature alone is used to produce crystallization, and in such processes the peak temperatures are very high, very typically greater than 650° C. compared to the 350° C. peak temperatures employed in the manufacture of a-Si transistors. At these temperatures, most AMLCD glass substrates undergo a process known as compaction and will deform excessively unless supported from below. Compaction, also referred to as thermal stability or dimensional change, is an irreversible dimensional change (shrinkage or expansion) in the glass substrate due to changes in the glass' fictive temperature. The magnitude of compaction depends both on the process by which a glass is made and the viscoelastic properties of the glass. In the float process for producing sheet products from glass, the glass sheet is cooled relatively slowly from the melt and, thus, “freezes in” a comparatively low temperature structure into the glass. The fusion process, by contrast, results in very rapid quenching of the glass sheet from the melt, and freezes in a comparatively high temperature structure. As a result, a glass produced by the float process possesses less compaction when compared to glass produced by the fusion process. In the glass product itself, the compaction ultimately may produce poor registry with the color filter and, if large enough, adversely affect device performance. Thus, it would be desirable to minimize the level of compaction in a glass substrate that is produced by a downdraw process. A commercial glass product, Jade® (Corning Incorporated, Corning N.Y.), was developed expressly to address this problem. It has a very high annealing point compared to conventional amorphous silicon substrate glasses, and thus shows low compaction even when reheated above the strain point of conventional amorphous silicon substrates.
[0005] While the Jade® product has proven sufficient for many p-Si processes, there is still a demand for even lower levels of compaction and/or the capability of withstanding heat treatments at even higher temperatures, sometimes in excess of 700° C. Annealed low annealing point p-Si substrate glasses can be optimized to provide these lower levels of compaction but their deformation at elevated temperature is only marginally improved with this increased anneal. The Jade® product has better deformation at elevated temperatures than annealed low annealing point glasses but has too much compaction for some applications and may need even more resistance to deformation under the extreme conditions of some newly developed cycles. In order to provide the desired lower compaction in existing processes as well as enabling the development of new higher temperature processes, a glass with an annealing point in excess of 785° C. is desired.
SUMMARY
[0006] In accordance with the purposes of the disclosed materials, compounds, compositions, articles, devices, and methods, as embodied and broadly described herein are alkali-free, boroalumino silicate glasses exhibiting desirable physical and chemical properties for use as substrates in flat panel display devices, such as, active matrix liquid crystal displays (AMLCDs) and active matrix organic light emitting diode displays (AMOLEDs). In accordance with certain of its aspects, the glasses possess good dimensional stability as a function of strain point. Specifically, the glasses described herein are fusion-compatible glasses with an anneal point in excess of 785° C., with a temperature at 200 poise of 1730° C. or less, with a density less than 2.65 g/cc, and with etch rates in fluoride-based mineral acids within 10% of the range exhibited by conventional a-Si substrate materials. Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below.
[0008] FIG. 1 is a comparison of the compaction of a glass typical of this invention with typical p-Si glasses.
[0009] FIG. 2 shows thermal sag (measured as “Deflection” in the y-axis) at 700° C. of commercially available p-Si glasses relative to glasses typical of this invention. It is clear the GBII glass has superior sag behavior at 700° C. than either other p-Si glass, thereby enabling higher temperature thermal cycles in customers' processes.
[0010] FIG. 3 illustrates the (SiO 2 +Al 2 O 3 )/(1-B 2 O 3 ) vs. RO—Al 2 O 3 , in mole-% for glasses of the present disclosure.
DETAILED DESCRIPTION
[0011] The materials, compounds, compositions, articles, devices, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein and to the Figures.
[0012] Before the present materials, compounds, compositions, articles, devices, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
[0013] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.
[0014] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
[0015] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers or prepared by methods known to those skilled in the art.
[0016] Also, disclosed herein are materials, compounds, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein.
[0017] Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated in the accompanying Examples and Figures.
[0018] Described herein are alkali-free glasses and methods for making the same that possess high strain points and, thus, good dimensional stability (i.e., low compaction). A high strain point glass can prevent panel distortion due to compaction/shrinkage during thermal processing subsequent to manufacturing of the glass.
[0019] The compositions represented by ranges of the present disclosure comprise SiO 2 , Al 2 O 3 , B 2 O 3 , MgO, CaO, SrO and BaO, and fining agents may include tin oxide (SnO 2 ), iron oxide (Fe 2 O 3 ), cerium oxide (CeO 2 ) various halides (principally F, Cl and Br), As 2 O 3 or Sb 2 O 3 . In one embodiment, the composition comprises an alkali-free glass comprising in mol percent on an oxide basis:
[0000] 70≦SiO 2 ≦74.5
[0000] 10.5≦Al 2 O 3 ≦13.5
[0000] 0≦B 2 O 3 ≦2.5
[0000] 3≦MgO≦7
[0000] 3≦CaO≦7
[0000] 0≦SrO≦4
[0000] 1.5≦BaO≦6
[0000] 0≦SnO 2 ≦0.3
[0000] 0≦CeO 2 ≦0.3
[0000] 0≦As 2 O 3 ≦0.5
[0000] 0≦Sb 2 O 3 ≦0.5
[0000] 0.01≦Fe 2 O 3 ≦0.08
[0000] F+Cl+Br≦0.4
[0000] wherein
[0000] 1.05≦(MgO+CaO+SrO)/Al 2 O 3 ≦1.7 a)
[0000] 0.2≦MgO/(MgO+CaO+SrO+BaO)≦0.45 b)
[0000] where Al 2 O 3 , MgO, CaO, SrO and BaO represent the mol percents of the representative oxide components. In another embodiment, the MgO/RO: is 0.29≦MgO/(MgO+CaO+SrO+BaO)≦0.39.
[0020] In one embodiment, the compositions are further constrained as follows:
[0000] SiO 2 +Al 2 O 3 =86.97−0.713*(MgO+CaO+SrO+BaO—Al 2 O 3 )±0.8
[0021] In another embodiment, glasses within the disclosed ranges are substantially free of arsenic oxide (As 2 O 3 ) or antimony oxide (Sb 2 O 3 ) such that the concentration of either or both of these oxides is less than 0.05 wt %. When this is the case, it may be preferable to add other multivalent oxides such as SnO 2 , Fe 2 O 3 and/or CeO 2 to ensure a minimum number of gaseous inclusions in the final glass.
[0022] In one embodiment, the glasses of the present disclosure exhibit a density less than 2.65 g/cc. In another embodiment the glasses exhibit densities of less than 2.6 g/cc.
[0023] Compositions falling within the above defined ranges are shown in Table 1.
[0024] The temperature corresponding to 200 poise is often used as a rough guideline for the appropriate melting temperature of a glass. The 200 poise temperatures of the glasses in Table 1 are, for the most part, very high, generally greater than about 1670° C. A surprising result obtained for the inventive glasses is that at the low B 2 O 3 contents of the inventive ranges, the melting rate of the most refractory batch materials, notably SiO 2 (or sand), is accelerated relative to glasses with higher B 2 O 3 contents. Because of this, and because of the comparatively low resistivity of these glasses compared to glasses with higher B 2 O 3 contents, when the inventive glasses are melted in a joule-boosted CU melter with a platinum finer and optical stirrer, excellent glass quality is obtained for melter temperatures anywhere between about 200 and 450 poise.
[0025] The temperature corresponding to 35,000 poise viscosity is regarded as a metric for the temperature at which glass is delivered to the trough of the isopipe. It is generally desirable that this temperature be as low as possible to minimize creep of the isopipe refractory over time. The inventive glasses generally have 35,000 poise temperatures between about 1280° C. and 1345° C., but at the high end of this range, it might be necessary to use a special refractory for the isopipe to obtain acceptable isopipe lifetime. Therefore, in one embodiment, the inventive glasses have 35,000 poise temperatures less than 1320° C., and in another embodiment, less than 1310° C.
[0026] Fusion-drawn glass has a high fictive temperature, and this results in a substantial disequilibrium of the glass structure when reheated to temperatures close to the annealing point. If as-drawn glass is to be used in a p-Si process, the only means to minimize compaction are to anneal the glass at a temperature close to the annealing point, and thereby partially or entirely structurally relax the glass, or to increase the anneal point of the glass such that the rate of structural relaxation is reduced, and the magnitude of structural relaxation in the p-Si process is minimized. Unfortunately, the annealing point required to produce low levels of compaction in p-Si processes depends upon the details of the process, and is difficult to predict without running glasses with a variety of annealing points through the thermal cycle of interest. In general, to provide a consistent product to customers with different p-Si processes, the best means to minimize compaction is to make the annealing point as high as reasonably achieved consistent with manufacturability and other customer-related constraints. The inventive glasses have annealing temperatures greater than about 790° C., greater than any commercially-available substrate for AMLCD applications, and thus are great enough to produce minimal compaction in p-Si processes. In another embodiment, the annealing temperature exceeds 800° C. In yet another embodiment the annealing temperature exceeds 810° C. In another embodiment the annealing temperature exceeds 815° C.
[0027] Each oxide constituent in the inventive glasses serves an important purpose. Silica, or SiO 2 , is the primary glass forming oxide, and contributes viscosity to the molten glass. For a given liquidus temperature, increasing viscosity serves to increase liquidus viscosity, and thus to improve compatibility with the fusion process. However, if viscosity becomes too high, then melting-related defects such as fining bubbles may appear, and erosion of refractories and degradation of platinum may become too extreme to permit long-term manufacturing in a continuous process. Furthermore, as silica increases, the liquidus temperature may increase due to increasing stability of cristobalite, a crystalline polymorph of SiO 2 that is an undesirable devitrification phase in a continuous process. Compared to every oxide except boron oxide (B 2 O 3 ), SiO 2 decreases density and coefficient of thermal expansion, and relative to B 2 O 3 it improves durability. SiO 2 ranges between 70 and 74.5 mol % in the inventive glasses.
[0028] Aluminum oxide, or Al 2 O 3 , also serves as a glass former in the inventive glasses. Like SiO 2 , it contributes viscosity, and when carefully balanced against SiO 2 concentration and the relative and absolute concentrations of alkaline earths, can be used to reduce liquidus temperature, thus enhancing liquidus viscosity. An increase in Al 2 O 3 relative to every oxide except SiO 2 results in improved durability in the kinds of acid-based etchants commonly used to etch display glasses in amorphous-silicon-based etching processes. Like SiO 2 , an increase in Al 2 O 3 relative to the alkaline earths generally results in decreased density, decreased coefficient of thermal expansion, and improved durability. Of particular importance, increasing Al 2 O 3 at the expense of any component save SiO 2 will generally increase the anneal point, and thus a minimum amount of Al 2 O 3 is required to obtain the high anneal points required for the p-Si application. Because of the need to balance Al 2 O 3 against other oxides, the full range of Al 2 O 3 content of the inventive glasses is between 10.5 and 13.5 mol %.
[0029] Boron oxide, or B 2 O 3 , is also a glass-forming oxide, and is used to reduce viscosity and, more importantly, to reduce liquidus temperature. In general, an increase in B 2 O 3 of 1 mol % decreases the temperature at equivalent viscosity by 10-14° C., depending on the details of the glass composition and the viscosity in question. However, B 2 O 3 can lower liquidus temperature by 18-22° C. per mol %, and thus has the effect of decreasing liquidus temperature more rapidly than it decreases viscosity, thereby increasing liquidus viscosity. As one moves to extremely low B 2 O 3 contents, keeping all other oxides within their respective ranges, it generally becomes increasingly difficult to obtain a liquidus viscosity as high as 130 kpoise, or more preferably greater than 170 kpoise, a prerequisite for compatibility with the fusion process as practiced today. If one were to increase boron oxide concentration at the expense of other glass components, CTE and density will generally decrease, but anneal point will decrease sharply, by as much as 14° C. per mol %, which is highly detrimental for p-Si substrate applications. On the other hand, relative to the other components that can reduce viscosity, principally the alkaline earth oxides, increasing boron oxide actually improves durability in fluoride-containing acids, making the glass more compatible with etching processes designed for amorphous silicon substrate glasses. For these reasons, B 2 O 3 is preferably kept between 0 and 2.5 mol %. In one embodiment, the glass is essentially free of B 2 O 3 .
[0030] A surprising discovery is that glasses with comparatively low liquidus temperatures—and hence high liquidus viscosities—can be obtained in boron-free glasses. As noted above, boron oxide decreases liquidus temperature more rapidly than it decreases viscosity, so in general additions of B 2 O 3 improve liquidus viscosity. Furthermore, boron tends to reduce the composition dependence of liquidus temperature, such that a change in the relative concentration of a particular oxide in a boron-free glass will tend to cause a larger change to liquidus temperature than a change in a boron-containing glass. The unexpected result described herein is that for a narrow range of oxides other than B 2 O 3 , low liquidus temperatures can be obtained, and as these glasses are very viscous for reasons stated above, the corresponding liquidus viscosities can be very high and appropriate for the fusion process. For example, the liquidus viscosities of the glasses in Table 1 are about 130,000 poise or more, thus making them compatible with the fusion process. In addition, the fusion process operates over a particular range of viscosity: glass is delivered to the trough of the isopipe at a viscosity corresponding to 20,000-35,000 poise, and glass leaves the root of the isopipe in the form of a viscous ribbon at a viscosity corresponding to 100,000 poise or more. At the very high delivery temperatures of the inventive glasses, the rate of radiative heat loss is greater per unit area than for less viscous glasses simply because a substantial fraction of the black body radiation of the glass is at visible and near-infrared wavelengths, at which wavelengths the glass is substantially transparent. Therefore, practical implementation of the inventive glasses in the fusion process may require high liquidus viscosities compared to those that might otherwise work for amorphous silicon substrate glasses. Thus, in one embodiment, the glass composition has a liquidus viscosity of at least 170,000 poise.
[0031] Alkaline earth oxides, MgO, CaO, SrO and BaO, are essential constituents for manufacturing. Like B 2 O 3 , increasing alkaline earths relative to SiO 2 or Al 2 O 3 always decreases the viscosity of a glass melt at fixed temperature. Since high temperature is the main factor limiting the lifetimes of glass tanks and forming equipment, it is always desirable to reduce melting and forming temperatures as much as possible consistent with delivering an appropriate suite of glass properties to a customer. Unlike SiO 2 , Al 2 O 3 and B 2 O 3 , increases in alkaline earths relative to the glass forming components generally degrade properties that are important for p-Si applications: CTE and density generally increase as alkaline earth oxides increase relative to SiO 2 , Al 2 O 3 and B 2 O 3 , anneal point generally decreases, and durability moves increasingly far from standard amorphous silicon substrate glasses. The only final glass properties that benefits from higher alkaline earth concentration is Young's modulus, and for some combinations of alkaline earth increases, specific modulus. Young's modulus determines the stiffness of a sheet of glass, and thus making it as high as possible is valuable for glass handling. At fixed temperature, the sag of a sheet of glass with widely spaced supports beneath it is dictated by the specific modulus, or the ratio of Young's modulus and density. High alkaline earth concentrations generally increase density, and so work against the expected increase in Young's modulus. However, MgO and CaO increase density much more slowly than the large alkaline earths, Sr and Ba, and thus the relative proportions of the alkaline earths can be manipulated to obtain an optimal combination of Young's modulus and density, consistent with fusion compatibility. In one embodiment, the specific modulus is greater than 30 GPa cm 3 /gm. In another embodiment, the specific modulus is greater than 31 GPa cm 3 /gm. In yet another embodiment, the specific modulus is greater than 31.5 GPa cm 3 /gm.
[0032] Mixtures of alkaline earths are also required to obtain low liquidus temperatures. The reasons behind this are complex. Without wishing to be bound by theory, the inventive ranges for the various alkaline earths have the effect of putting two or more crystalline phases on the liquidus for most glasses within the inventive ranges, one of which is cristobalite (SiO 2 ), and one of which is an alkaline earth aluminosilicate. In barium-rich glasses, the alkaline earth aluminosilicate is often hexacelsian and solid solutions therein, expressed approximately as Ba 1−x−y ,Sr x ,Ca y Mg z Al 2−z Si 2+z O 8 , where x, y and z are generally less than 0.5. In glasses with low barium concentrations, and thus correspondingly high CaO+SrO concentrations, the alkaline earth aluminosilicate is often anorthite or solid solutions therein, expressed approximately as Ca 1−x−y Sr x Ba y Al 2 Si 2 O 8 . For Mg-rich compositions, the liquidus phase is sometimes cordierite or solid solutions therein, approximately Mg 2 Al 4 Si 5 O 18 . The best liquidus temperatures are generally obtained when two or more different aluminosilicate phases and cristobalite are on or close to the liquidus temperature. The relative competition of each phase for glass constituents has the effect of destabilizing other phases, and thus reduces not only the liquidus temperature, but the tendency to devitrify when undercooled in a manufacturing process.
[0033] At a fixed level of alkaline earth oxides, melting and forming temperatures are generally reduced when Ba, Sr or Ca is replaced with Mg. This is particularly important when (MgO+CaO+SrO+BaO)/Al 2 O 3 (also referred to as RO/Al 2 O 3 ) is close to 1.0, as their high melt temperatures may make them almost impossible to melt. However, MgO is a participant in hexacelsian and cordierite, and at low (MgO+CaO+SrO+BaO)/Al 2 O 3 may stabilize mullite. Therefore, MgO needs to be confined to a narrow range of the total alkaline earth oxide concentration to obtain the best balance of viscosity and liquidus temperature: the molar ratio MgO/(MgO+CaO+SrO+BaO) is preferably kept in the range 0.2 to 0.45. In another embodiment this molar ratio is kept in the range of 0.29 to 0.39. In yet another embodiment, this molar ratio is kept in the range of 0.31 to 0.35.
[0034] The alkaline earth oxide with the greatest beneficial impact on liquidus temperature is barium oxide, BaO. Unfortunately, it also has the effect of increasing melting and delivery temperatures when substituted for any other alkaline earth oxide, and compromises final glass properties such as density, CTE and anneal point more so than any other alkaline earth oxide. Strontium oxide, SrO, can be increased at the expense of barium to offset some of these deleterious effects, but with much diminished benefit to liquidus temperature. Because hexacelsian is substantially a barium-strontium aluminosilicate, with comparatively low CaO and BaO, it is generally desirable to have CaO concentrations comparable to the combined concentration of BaO+SrO. As a result of these considerations, the inventive glass will have BaO between 1.5 and 6 mol %, SrO between 0 and 4 mol %, and CaO between 3 and 7 mol %. Compositions within these limits have attractive physical properties and liquidus viscosities suitable for down draw processes such as the fusion process.
[0035] Even if the melting temperature is comparatively low, the details of the melting equipment may make it difficult to clear gaseous inclusions from a glass melt. Those that remain appear as defects in the final ware. P—Si TFT manufacturers are extremely sensitive to defects that distort the surface of a sheet of glass, and since one cannot predict where a gaseous inclusion will end up relative to the surface of a sheet, gaseous inclusions must be avoided at all cost. Furthermore, for processing simplicity, TFT manufacturers often seek to have color filter glass made from the same substrate material used in the TFT manufacturing process, in which case gaseous inclusions can block pixels, thereby compromising performance of the entire device. To clear gaseous defects from the glass melt before it is made into sheet, it is conventional to add fining agents Fining agents are multivalent cations or halides that release gas at high temperature. Exemplary multivalent fining agents include, but are not limited to, As 2 O 3 , Sb 2 O 3 , SnO 2 , and Fe 2 O 3 . Waste streams containing arsenic and antimony are considered hazardous materials in some countries, and for this reason is may be desirable to limit their concentrations in the inventive glass. In a preferred embodiment of the inventive glasses, As 2 O 3 , Sb 2 O 3 , or combinations thereof are kept at a level of 500 ppm (0.05 wt %) or less.
[0036] Halogens that find use as fining agents include F, Cl and Br. Waste streams that contain halogens may also be regarded as hazardous materials in some countries, and their release during melting processes can cause excessive corrosion of steel ductwork and supports. On the other hand, melt systems can be designed to safely handle off-gas of halogens, and various choices of raw materials can be used to influence their retention in the final glass. Halogens are typically added as stable salts, which may include, but are not limited to, simple salts and hydrated salts of the alkaline earths or aluminum, such as MgF 2 , CaF 2 , SrF 2 , BaF 2 , MgCl 2 , CaCl 2 , SrCl 2 , BaCl 2 , MgCl 2 .4H 2 O, CaCl 2 .4H 2 O, SrCl 2 .4H 2 O, BaCl 2 .4H 2 O, MgBr 2 , CaBr 2 , SrBr 2 , BaBr 2 , MgBr 2 .4H 2 O, CaBr 2 .4H 2 O, SrBr 2 .4H 2 O, BaBr 2 .4H 2 O, AlCl 3 , AlCl 3 .6H 2 O, and other forms familiar to those skilled in the art of raw material selection Fining is generally optimized at a relatively low level of halogen addition, and thus the inventive glasses have F+Cl+Br concentrations between 0 and 0.4 mol %. In a preferred embodiment, F+Cl+Br is less than 200 ppm, or 0.02 wt %.
[0037] FIG. 1 demonstrates a comparison of a glass typical of this invention (X) with typical p-Si glasses. Compaction is measured relative to a base composition 1 in both an internal compaction measurement and in a display manufacturing cycle, where 50% of 11s considered an acceptable level of compaction and less than 25% of 11s preferable. Glasses 1 , 2 , and 3 have been put through the display manufacturing process as well as our the inventor's simulated internal tests and are included to demonstrate the transparency of the internal simulation with actual display maker's feedback. Glass 4 is Corning's Jade® composition and Glass 5 is a typical annealed p-Si composition, both showing acceptable levels of compaction. Glass 6 is a “more annealed” p-Si glass demonstrating lower compaction relative to the “typical” Glass 5 . It is clear that the glasses in this invention (typified by glass X) have comparable, if not superior, compaction performance than either annealed p-Si glass and clearly superior compaction relative to Jade®.
[0038] FIG. 2 demonstrates thermal sag (measured as “Deflection” in the y-axis) at 700° C. of typical p-Si glasses (Glass 6 and Jade®) relative to glasses typical of this invention (“X”). It is clear the X glass has superior sag behavior at 700° C. than either other p-Si glass, thereby enabling higher temperature thermal cycles for use in a display manufacturer's process.
[0039] FIG. 3 demonstrates an interesting relationship that was observed with respect to the ratio of the SiO 2 +Al 2 O 3 content to 1-B 2 O 3 content and the RO—Al 2 O 3 content. Many of the advantageous compositions of the present invention were located on the line y=0.7132x+86.965, as demonstrated graphically in FIG. 3 . Put another way, in one embodiment, the glasses of the present invention fall within the following relationship: SiO 2 +Al 2 O 3 =86.97−0.713*(MgO+CaO+SrO+BaO—Al 2 O 3 )±0.8.
EXAMPLES
[0040] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art.
[0041] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
[0042] Table 1 shows an example of an exemplary inventive glass composition based from to Example 16 in Table 2, and a particular selection of raw materials for making it. As is known to those skilled in the art of glass manufacture, the particular choice of raw materials does not impact the final glass composition as the original raw materials are transformed into a single, uniform glass by the melting process. However, the actual choice of raw materials may be different than indicated in light of the particular requirements imposed by the limitations of a particular melting system, or by the cost of the raw materials, or both.
[0043] The primary source of SiO 2 is sand. The sand can be obtained from one or more of a variety of sources, including sand deposits (beaches or dunes), sandstone, quartzite, or other sources known to those skilled in the art of raw material selection. Sand is often the primary source of alkali contamination in what would otherwise be alkali-free glasses, and therefore a careful selection of source material may be important to minimize this important contaminant. The size of the sand particles may influence the rate of melting, and in particular large sand grains may fail to melt completely, appearing in the wear as a knot or stone. To avoid this, it is generally preferable for more than 90% of all sand grains to pass through a standard #80 U.S. standard mesh size. Alumina itself is generally the least expensive raw material to add Al 2 O 3 to a glass, but other materials such as the aluminosilicate kaolin or hydrous forms of alumina or polymorphs of Al 2 O 3 can be used instead when raw material costs are less important.
[0044] While Example 16 does not intentionally contain B 2 O 3 , other examples do. B 2 O 3 can be batched as boric anhydride (approximately 94+% B 2 O 3 , the balance being mostly H 2 O) or boric acid, approximately B(OH) 3 .
[0045] MgO is generally added as its oxide, while the other alkaline earths are typically batched as carbonates. Suitable carbonate sources for CaO include limestone and precipitated calcium carbonate (a refined limestone product). MgO can be batched with CaO in the form of dolomite, though this may also increase the amount of iron in the glass, and so may be undesirable as compared to a more predictable pure iron source. Most of the strontium and barium will generally be added as carbonates obtained by industrial chemical processes. However, to keep the batch adequately oxidized, it is generally desirable to include a nitrate source as well. Strontium nitrate is indicated in the batch, but barium nitrate will work just as well. In both cases, it is generally desirable to batch no more than about 1 mol % of the alkaline earth oxide as nitrates to reduce NO x emissions, but in other ways nitrates may assist melting, so the exact amount that will work best is generally the subject of trial-and-error investigation.
[0046] SnO 2 is included in its usual role as a fining agent. More SnO 2 generally equates to improved fining capacity, but as it is a comparatively expensive raw material, it is desirable to add no more than is required to drive gaseous inclusions to an appropriately low level. The SnO 2 level of the inventive glass is preferably between 0.02 and 0.3 mol %.
[0047] A low amount of ZrO 2 (zirconia) is included in this example. It serves no practical role in the melting or fining behavior of the glass, and imparts no interesting properties at such a low level. It is useful to include it in a laboratory-scale batch, however, because it will be introduced by contact of hot glass with zirconia-based refractory materials in the melter, and thus monitoring its level in the glass may be important to judging the rate of tank wear over time. A typical amount of ZrO in the final glass of one embodiment is less than 0.05 mol %. In another embodiment, the amount of ZrO is less than 500 ppm.
[0048] The batch shows a low level of iron. Some iron is all but unavoidable due to contamination introduced by raw materials, especially sand and typical sources of MgO. Iron may also be added to benefit fining, hydrogen permeation, or both. If deliberately added, iron oxalate is a particularly useful raw material, but other compounds of iron can be employed as well. Iron can impart color to the glass if it becomes too oxidized, and so the level of iron is preferably between 0.01 and 0.08 mol % to obtain the best balance between gaseous inclusion management and excessive color.
[0049] A significant amount of water accompanies boric acid and sand, and a significant amount of carbon dioxide accompanies the carbonate raw materials. CO 2 is sparingly soluble in glass, so most of it is lost in the earliest stages of melting, and that which is trapped in gaseous inclusions is generally moved by action of the fining agent, e.g., SnO 2 in the present example. A significant level of water may be retained in the glass, however, in the form of dissolved OH − ions. This results in a measurable OH − vibrational band near 3600 cm −1 in the near infrared. The intensity of this band above background through a 1 mm thick path length is referred to as β OH . It generally ranges from as low as 0.2 to as high as 0.7 in conventional amorphous silicon substrate glasses. Dissolved OH − has a large impact on the annealing point for alkali-free glasses, and therefore it is desirable to keep OH − as low as reasonably achievable for any given glass. Conventional electric-boost melters generally employ burners above the glass surface that generate a high water partial pressure and result in higher levels of water incorporation into the glass. Halides can be used to reduce the retained water level, and boosting the power delivered via electrodes and reducing the power delivered via burners can also help. Likewise, selecting a comparatively dry sand can produce enough of a change in dissolved OH − to significantly impact annealing point. β OH for the inventive glass is less than 0.55, in one embodiment, less than 0.5 in another embodiment, and less than 0.45 in yet another embodiment to maximize the annealing point of the final glass.
[0050] While the actual composition and the choice of raw materials in this example is quite specific, it will be obvious to one skilled in the art that alternative raw materials can be used to obtain the same final glass composition, and thus a particular set of raw materials must be selected so as to be best suited for a given melting/fining/forming process. Any other set of raw materials that results in an equivalent composition will therefore produce a glass that satisfies the basic requirement of high annealing point, low density, low CTE, and high durability required for low-temperature polysilicon applications.
[0051] Further and although the intended use for the disclosed glasses is in p-Si applications, it should be noted that the glasses may also be considered for a-Si, color filter substrate or other applications where the disclosed properties may be deemed advantageous.
[0000]
TABLE 1
mol %
batch weight (g)
SiO 2
sand
71.86
596.99
Al 2 O 3
alumina
11.72
174.35
MgO
magnesia
5.17
30.36
CaO
limestone
5.59
84.65
SrO
strontium carbonate
1.42
28.45
BaO
barium carbonate
4.05
119.78
SnO 2
tin (IV) oxide, 10% C.B.
0.15
33
Fe 2 O 3
iron oxalate 10% C.B.
0.02
5.349
ZrO 2
zirconium oxide 20% C.B.
0.02
2.02
Example
Preparation of a Test Sample
[0052] TABLE 2 sets forth exemplary glass compositions in mol percent, as calculated on an oxide basis from the glass batches. These example glasses were prepared by melting 1,000-25,000 gram batches of each glass composition at a temperature and time to result in a relatively homogeneous glass composition, e.g. at a temperature of about 1625° C. for a period of about 4-16 hours in platinum crucibles. Also set forth are relevant glass properties for each glass composition, determined on the glasses in accordance with techniques conventional in the glass art. Thus, the linear coefficient of thermal expansion (CTE) over the temperature range 0-300° C. is expressed in terms of ×10 −7 /° C., the softening point (Soft. Pt.), and the annealing point (Ann. Pt.), and strain point (Str. Pt.) are expressed in terms of ° C. These were determined from fiber elongation techniques (ASTM references E228-85, C338, and C336, respectively). The density (Den.), in terms of g/cm 3 , was measured via the Archimedes method (ASTM C693).
[0053] The 200 poise temperature (Melt. Temp., ° C.) (defined as the temperature at which the glass melt demonstrates a viscosity of 200 poises [20 Pa·s]) was calculated employing the Fulcher equation fit to the high temperature viscosity data (measure via rotating cylinders viscometry, ASTM C965-81). The liquidus temperature (Liq. Temp.) of the glass was measured using the standard liquidus method. This involves placing crushed glass particles in a platinum boat, placing the boat in a furnace having a region of gradient temperatures, heating the boat in an appropriate temperature region for 24 hours, and determining by means of microscopic examination the highest temperature at which crystals appear in the interior of the glass. The liquidus viscosity (Liq. Visc., in poises) was determined from this temperature and the coefficients of the Fulcher equation.
[0054] The remainder of properties listed in Table 2 are achieved through standard tests that are well known to those of skill in the industry.
[0000]
TABLE 2
Example
1
2
3
4
5
6
SiO 2
70.75
72.33
72.19
71.68
73.11
71.75
A l2 O 3
11.96
11.85
11.36
11.46
11.6
12.17
B 2 O 3
1.23
0
1.55
1.6
0
0
MgO
5.88
4.92
4.73
4.44
4.81
5.93
CaO
5.3
5.16
5.22
5.37
5.19
5.28
SrO
2.04
3.11
1.87
2.44
1.35
2.1
BaO
2.68
2.46
2.95
2.81
3.81
2.61
SnO 2
0.11
0.12
0.12
0.15
0.12
0.11
Fe 2 O 3
0.02
0.02
0.01
0.02
0.01
0.02
ZrO 2
0.02
0.02
0
0.02
0
0.03
RO/Al 2 O 3
1.33
1.32
1.3
1.31
1.31
1.31
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.99
3.8
3.46
3.66
3.56
3.75
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.74
84.18
84.87
84.49
84.71
83.92
MgO/(MgO + CaO + SrO + BaO)
0.37
0.31
0.32
0.29
0.32
0.37
Properties
Strain
740
761
742
740
765
764
Anneal
793
818
797
794
820
817
Soft (ppv)
1030.1
1059.5
1043.6
1042.5
1052.8
CTE (disk)
36.2
36.1
35.6
35.3
36.7
35.9
Density
2.595
2.604
2.575
2.586
2.611
2.601
Young's modulus
12.178
12.187
11.904
11.92
12.076
12.371
specific modulus
32.4
32.3
31.9
31.8
31.9
32.8
Viscosity
A
−3.039
−3.318
−3.089
−2.936
−3.179
−2.77
B
6851.7
7509.3
7314.4
6813.9
7321.7
6440.1
To
380.6
364.2
347
391.5
376.7
423.8
200 poise
1664
1701
1704
1693
1713
1694
400 poise
1595
1633
1632
1622
1643
1623
35000 poise
1284
1319
1305
1302
1325
1304
Gradient boat
internal
1210
1240
1225
1210
1250
1220
internal viscosity
166737
180392.2
174482.4
244828.8
160304.6
208231.1
T(35 kp) − T(liq)
74
79
80
92
75
84
Example
7
8
9
10
11
12
13
mol %
SiO 2
71.99
71.21
72.48
71.79
71.33
71.33
73.59
Al 2 O 3
11.59
11.59
11.73
12.61
11.49
11.58
11.37
B 2 O 3
0
1.19
0
1.72
1.29
1.53
0
MgO
5.51
5.32
4.95
3.94
5.21
4.65
4.73
CaO
5.41
5.36
5.53
5.03
5.33
5.79
5.11
SrO
1.18
1.4
1.82
1.21
1.28
1.69
1.32
BaO
4.16
3.78
3.31
3.54
3.91
3.24
3.74
SnO 2
0.11
0.11
0.14
0.12
0.11
0.15
0.12
Fe 2 O 3
0.03
0.02
0.02
0.01
0.02
0.02
0.01
ZrO 2
0.02
0.02
0.02
0.02
0.02
0.02
0
RO/Al 2 O 3
1.4
1.37
1.33
1.09
1.37
1.33
1.31
(RO − Al 2 O 3 )/
4.67
4.32
3.88
1.13
4.3
3.85
3.53
(1 − B 2 O 3 /100)
(SiO 2 + Al 2 O 3 )/
83.58
83.8
84.21
85.88
83.9
84.2
84.96
(1 − B 2 O 3 /100)
MgO/(MgO +
0.34
0.34
0.32
0.29
0.33
0.3
0.32
CaO + SrO + BaO)
Proper-
Strain
759
744
764
752
745
738
765
ties
Anneal
813
797
818
806
798
794
821
Soft (ppv)
1052.3
1038.6
1058
1035.1
1037.3
1073.1
CTE (disk)
36.4
36.5
35.5
33.8
36.8
35.9
Density
2.629
2.612
2.611
2.612
2.594
2.592
Young's
12.12
12.083
12.086
12.003
11.932
12.011
modulus
specific
31.8
31.9
31.9
31.7
31.7
31.9
modulus
Vis-
A
−3.281
−3.058
−2.963
−2.9388
−3.267
−3.416
−3.229
cosity
B
7682.3
7027.4
6997.2
6854.51
7471.1
7756.7
7499
To
329.9
369.3
384.4
397.06
338.2
326.9
368.2
200 poise
1706
1681
1714
1705
1680
1684
1724
400 poise
1636
1611
1642
1634
1611
1616
1654
35000 poise
1312
1294
1316
1313
1295
1301
1333
Gradient
internal
1220
1190
1205
1185
1185
1200
1250
boat
internal
223783.5
319661.5
366379.8
576075.1
359537.7
293826.6
188449
viscosity
T(35 kp) −
92
104
111
128
110
101
83
T(liq)
Example
14
15
16
17
18
19
SiO 2
72.27
73.26
71.86
72.08
72.09
72.78
Al 2 O 3
11.9
11.09
11.72
11.76
12.05
11.39
B 2 O 3
0
1
0
0
0
0
MgO
4.92
4.61
5.17
5.34
5.4
4.91
CaO
6.16
4.98
5.59
5.44
5.38
5.44
SrO
2.13
1.29
1.42
1.6
2.03
1.68
BaO
2.46
3.63
4.05
3.62
2.93
3.65
SnO 2
0.12
0.12
0.15
0.11
0.1
0.11
Fe 2 O 3
0.02
0.01
0.02
0.02
0.01
0.02
ZrO 2
0.02
0
0.02
0.02
0.02
0.02
RO/Al 2 O 3
1.32
1.31
1.38
1.36
1.31
1.38
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.77
3.45
4.51
4.24
3.69
4.29
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.17
85.2
83.58
83.84
84.14
84.17
MgO/(MgO + CaO + SrO + BaO)
0.31
0.32
0.32
0.33
0.34
0.31
Properties
Strain
765
749
760
759
762
762
Anneal
818
806
814
813
816
815
Soft (ppv)
1055.3
1059.6
1052.2
1051.4
1050
1056.8
CTE (disk)
35.9
35.8
37.3
36.1
37.1
37.2
Density
2.591
2.572
2.632
2.619
2.603
2.616
Young's modulus
12.228
11.769
12.158
specific modulus
32.5
31.5
0
32
0
Viscosity
A
−3.143
−3.447
−3.156
−3.201
−3.227
−2.954
B
7180.4
8201
7237.7
7221.9
7345.25
7021.4
To
381.1
290.5
370.5
379.5
368.95
385.6
200 poise
1700
1717
1697
1692
1698
1722
400 poise
1631
1646
1627
1624
1629
1649
35000 poise
1315
1317
1310
1312
1314
1322
Gradient boat
internal
1240
1245
1195
1200
1225
1230
internal viscosity
164814.5
139615.3
419073.2
398867
225630.8
229748.9
T(35 kp) − T(liq)
75
72
115
112
89
92
Example
20
21
22
23
24
25
SiO 2
72.19
71.45
73.18
72.39
72.65
71.59
Al 2 O 3
12.2
12.05
11.95
11.74
11.72
11.73
B 2 O 3
1
1.25
0.5
0
0
1.65
MgO
4.61
4.9
4.56
5.14
4.86
4.75
CaO
4.9
5.5
4.88
5.34
5.59
5.5
SrO
1.3
1.55
1.24
1.22
2.58
2
BaO
3.6
3.15
3.54
4.02
2.43
2.65
SnO 2
0.16
0.12
0.13
0.11
0.12
0.12
Fe 2 O 3
0.02
0.03
0.02
0.01
0.02
0.01
ZrO 2
0.02
0
0
0.02
0.03
0
RO/Al 2 O 3
1.18
1.25
1.19
1.34
1.32
1.27
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
2.23
3.09
2.28
3.98
3.74
3.22
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
85.24
84.56
85.56
84.13
84.37
84.72
MgO/(MgO + CaO + SrO + BaO)
0.32
0.32
0.32
0.33
0.31
0.32
Properties
Strain
752
738
767
761
765
743
Anneal
807
793
821
817
819
797
Soft (ppv)
1050.2
1034.2
1069.5
1060.2
1058.6
1039.8
CTE (disk)
35.4
36.2
34.4
34
36.4
35.9
Density
2.603
2.603
2.577
2.62
2.594
2.574
Young's modulus
12.112
11.951
12.115
12.163
11.929
specific modulus
0
32.1
32
31.9
32.3
32
Viscosity
A
−3.232
−2.868
−3.354
−3.061
−2.77
−3.044
B
7311.1
6597.4
7841.5
7095.3
6633.3
7080.4
To
370.6
398
326.5
388.7
408.9
365.7
200 poise
1692
1674
1713
1712
1717
1690
400 poise
1624
1604
1643
1642
1644
1620
35000 poise
1311
1288
1319
1322
1316
1299
Gradient boat
internal
1220
1205
1230
1225
1240
1220
internal viscosity
237339.4
202869.5
211361.6
264945.4
162685.9
175369.9
T(35 kp) − T(liq)
91
83
89
97
76
79
Example
26
27
28
29
30
31
SiO 2
71.71
72.7
72.21
71.14
72.85
71.97
Al 2 O 3
11.24
11.38
11.62
11.27
11.37
12.02
B 2 O 3
0
0
0
0.91
0
0
MgO
5.95
3.88
5.24
5.68
4.85
4.98
CaO
5.5
5.74
5.47
5.46
5.73
6.23
SrO
1.03
2.83
1.2
1.1
0.92
2.15
BaO
4.38
3.31
4.09
4.27
4.13
2.49
SnO 2
0.11
0.11
0.11
0.11
0.11
0.12
Fe 2 O 3
0.05
0.02
0.02
0.04
0.02
0.02
ZrO 2
0.03
0.02
0.02
0.02
0.02
0.03
RO/Al 2 O 3
1.5
1.38
1.38
1.46
1.37
1.32
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
5.62
4.38
4.38
5.29
4.26
3.83
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
82.95
84.08
83.83
83.17
84.22
83.99
MgO/(MgO + CaO + SrO + BaO)
0.35
0.25
0.33
0.34
0.31
0.31
Properties
Strain
755
761
764
740
760
766
Anneal
807
816
816
793
814
819
Soft (ppv)
1043
1056.7
1047.7
1033.1
1058.9
1056
CTE (disk)
38.2
37
36.2
Density
2.637
2.627
2.625
2.629
2.618
2.593
Young's modulus
12.099
12.052
12.062
11.947
12.006
12.299
specific modulus
31.6
31.6
31.7
31.3
31.6
32.7
Viscosity
A
−2.927
−3.158
−3.245
−3
−2.577
−3.031
B
6767.8
7404.8
7464.1
6922.1
6367.7
7014.5
To
400.7
361.3
354.3
371.5
425.3
383.8
200 poise
1695
1718
1700
1677
1731
1699
400 poise
1625
1647
1631
1607
1655
1629
35000 poise
1307
1323
1313
1289
1320
1310
Gradient boat
internal
1200
1230
1200
1190
1210
1235
internal viscosity
346863.6
232274.4
381015.8
286454.5
345001.5
162076.1
T(35 kp) − T(liq)
107
93
113
99
110
75
Example
32
33
34
35
36
37
SiO 2
71.66
70.82
72
74.05
72.8
72.83
Al 2 O 3
12.19
12.07
11.65
12.03
11.37
11.38
B 2 O 3
0
1
1.65
0
0
0
MgO
6.22
6.01
4.75
4.34
4.29
5.38
CaO
5.33
5.27
5.3
4.73
5.72
5.19
SrO
2.25
2.16
1.5
1.18
2.08
0.88
BaO
2.18
2.5
3
3.53
3.57
4.19
SnO 2
0.12
0.12
0.12
0.11
0.11
0.11
Fe 2 O 3
0.02
0.02
0.03
0.01
0.02
0.02
ZrO 2
0.02
0.03
0
0.02
0.02
0.02
RO/Al 2 O 3
1.31
1.32
1.25
1.15
1.38
1.37
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.79
3.91
2.95
1.75
4.29
4.26
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.85
83.73
85.05
86.08
84.17
84.21
MgO/(MgO + CaO + SrO + BaO)
0.39
0.38
0.33
0.31
0.27
0.34
Properties
Strain
764
745
740
774
760
761
Anneal
816
799
794
830
814
815
Soft (ppv)
1049.4
1034
1034.9
1079
1057.4
1056.4
CTE (disk)
35.9
37
34.8
34.3
36.8
36.9
Density
2.591
2.59
2.582
2.58
2.622
2.621
Young's modulus
12.402
11.99
11.981
12.113
specific modulus
33
32
32
0
31.9
Viscosity
A
−3.426
−3.2055
−2.778
−2.998
−3.145
−2.35
B
7613.4
7086.72
6477.2
7183
7387
5942.8
To
344.8
377.78
407.6
390.8
360.1
455.9
200 poise
1674
1665
1683
1746
1717
1734
400 poise
1608
1598
1612
1673
1645
1656
35000 poise
1300
1292
1292
1343
1321
1318
Gradient boat
internal
1230
1215
1200
1245
1210
1215
internal viscosity
149543.7
181587.2
248974.3
257654.5
352055.2
301123.4
T(35 kp) − T(liq)
70
77
92
98
111
103
Example
38
39
40
41
42
43
SiO 2
71.6
72.61
72.31
71.69
72.31
71.27
Al 2 O 3
11.81
11.81
11.59
11.88
12.04
12.27
B 2 O 3
0
0
0
0
0
1.72
MgO
5.54
4.91
4.82
5.97
4.88
4.2
CaO
5.49
5.3
5.95
5.39
5.38
5.34
SrO
1.23
1.37
0.99
1.93
1.39
1.29
BaO
4.19
3.88
4.18
2.99
3.87
3.76
SnO 2
0.11
0.12
0.11
0.11
0.11
0.12
Fe 2 O 3
0.02
0.01
0.02
0.02
0.01
0.01
ZrO 2
0.02
0
0.02
0.02
0
0.02
RO/Al 2 O 3
1.39
1.31
1.38
1.37
1.29
1.19
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
4.64
3.65
4.35
4.4
3.48
2.36
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.41
84.42
83.9
83.57
84.35
85
MgO/(MgO + CaO + SrO + BaO)
0.34
0.32
0.3
0.37
0.31
0.29
Properties
Strain
759
765
759
762
764
741
Anneal
811
819
813
814
818
794
Soft (ppv)
1049.2
1059.3
1055.6
1050.6
CTE (disk)
37.9
36.7
36.7
36.5
36.7
Density
2.632
2.624
2.627
2.612
2.617
Young's modulus
12.231
12.096
12.124
12.343
12.049
specific modulus
32
31.8
31.8
32.6
31.7
Viscosity
A
−3.603
−3.326
−3.147
−3.062
−2.976
−2.8813
B
8091.9
7540.6
7223.2
6951.8
7088.4
6732.21
To
319.2
361.5
376.4
388.2
371.8
389.92
200 poise
1690
1702
1702
1684
1715
1689
400 poise
1623
1634
1633
1616
1643
1618
35000 poise
1312
1320
1316
1302
1314
1297
Gradient boat
internal
1220
1250
1200
1220
1200
1185
internal viscosity
239891.6
144839.8
420026.6
197486.7
382650.4
385510.9
T(35 kp) − T(liq)
92
70
116
82
114
112
Example
44
45
46
47
48
49
SiO 2
72.03
72.3
71.58
72.23
72.47
72.09
Al 2 O 3
12.77
11.58
11.7
11.62
11.54
12.05
B 2 O 3
1.72
0
1.25
0
0
0
MgO
3.82
4.97
4.86
5.56
5.24
5.47
CaO
4.89
5.68
5.26
5.27
5.35
4.66
SrO
1.18
1.28
1.4
0.96
0.72
1.84
BaO
3.44
4.04
3.8
4.2
4.53
3.75
SnO 2
0.12
0.11
0.13
0.11
0.11
0.1
Fe 2 O 3
0.01
0.02
0.02
0.02
0.02
0.01
ZrO 2
0.02
0.02
0
0.02
0.02
0.02
RO/Al 2 O 3
1.04
1.38
1.31
1.38
1.37
1.3
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
0.57
4.39
3.67
4.37
4.3
3.67
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
86.28
83.88
84.33
83.85
84.01
84.14
MgO/(MgO + CaO + SrO + BaO)
0.29
0.31
0.32
0.35
0.33
0.35
Properties
Strain
750
762
739
757
761
764
Anneal
803
816
794
810
814
818
Soft (ppv)
1055.1
1035.4
1050.4
1057.2
1047
CTE (disk)
35.1
37.2
37.2
36.6
36.6
37.2
Density
2.625
2.614
2.623
2.625
2.63
Young's modulus
12.086
11.984
12.124
12.194
specific modulus
31.7
31.6
31.9
32
Viscosity
A
−3.2039
−3.224
−2.978
−3.099
−3.327
−3.085
B
7359.53
7477.8
6940.6
7233.1
7780
7131.02
To
369.45
353.2
371.6
364.2
323.7
379.69
200 poise
1706
1707
1686
1704
1706
1704
400 poise
1637
1637
1615
1633
1636
1634
35000 poise
1319
1316
1294
1311
1312
1314
Gradient boat
internal
1210
1200
1190
1210
1200
1235
internal viscosity
356215.2
404256.1
318195.5
283651.6
355826.3
178793.4
T(35 kp) − T(liq)
109
116
104
101
112
79
Example
50
51
52
53
54
55
SiO 2
71.99
72.8
72.66
73.6
71.99
71.7
Al 2 O 3
12.5
11.38
11.43
11.38
11.55
12.49
B 2 O 3
0.5
0
0
0
1.64
1.25
MgO
4.75
5.12
5.15
4.73
4.68
4.75
CaO
5.1
5.33
4.8
5.1
5.42
5
SrO
1.3
1.14
2.22
1.32
1.97
2.35
BaO
3.7
4.08
3.58
3.74
2.61
2.25
SnO 2
0.13
0.11
0.11
0.12
0.12
0.16
Fe 2 O 3
0.02
0.02
0.02
0.01
0.01
0.02
ZrO 2
0
0.02
0.02
0
0
0.03
RO/Al 2 O 3
1.19
1.38
1.38
1.31
1.27
1.15
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
2.36
4.29
4.32
3.51
3.18
1.88
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.91
84.18
84.09
84.98
84.93
85.26
MgO/(MgO + CaO + SrO + BaO)
0.32
0.33
0.33
0.32
0.32
0.33
Properties
Strain
762
761
762
765
742
749
Anneal
817
815
816
819
798
804
Soft (ppv)
1057.8
1058.3
1058.2
1060.3
1042.4
1043.7
CTE (disk)
34.9
35.5
36.9
35.8
35.1
34.2
Density
2.604
2.618
2.622
2.608
2.567
2.581
Young's modulus
12.12
12.03
12.099
12.025
11.921
specific modulus
32.1
31.7
31.8
31.8
32
0
Viscosity
A
−3.098
−3.374
−3.181
−3.449
−2.907
−3.169
B
7091.4
7781.6
7401.1
7934.3
6863.9
7018.1
To
391.2
338.5
363.3
337.7
380.6
391
200 poise
1705
1710
1713
1718
1699
1674
400 poise
1635
1641
1643
1649
1627
1607
35000 poise
1319
1321
1321
1330
1302
1301
Gradient boat
internal
1210
1215
1210
1240
1230
1225
internal viscosity
365361.7
319181.5
363172.2
221012.5
149238.4
176192.7
T(35 kp) − T(liq)
109
106
111
90
72
76
Example
56
57
58
59
60
61
SiO 2
72.47
72.75
72.71
71.85
70.99
72.83
Al 2 O 3
11.42
11.68
11.41
11.57
11.79
11.37
B 2 O 3
1
0
0
0
1.2
0
MgO
4.76
4.84
4.95
5.56
5.57
4.87
CaO
5.13
5.08
5.45
5.49
5.36
5.53
SrO
1.33
3.06
1.5
1.22
1.84
0.93
BaO
3.76
2.42
3.82
4.15
3.08
4.31
SnO 2
0.12
0.12
0.11
0.11
0.11
0.11
Fe 2 O 3
0.01
0.02
0.02
0.02
0.02
0.02
ZrO 2
0
0.02
0.02
0.02
0.03
0.02
RO/Al 2 O 3
1.31
1.32
1.38
1.42
1.34
1.38
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.6
3.72
4.31
4.85
4.11
4.27
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.74
84.43
84.12
83.42
83.79
84.2
MgO/(MgO + CaO + SrO + BaO)
0.32
0.31
0.31
0.34
0.35
0.31
Properties
Strain
752
764
759
760
744
760
Anneal
809
818
814
813
796
814
Soft (ppv)
1058.2
1056.5
1055.8
1052.3
1034.1
1059.6
CTE (disk)
34.8
36.1
37.2
38.3
36.1
36.6
Density
2.595
2.598
2.62
2.628
2.6
2.621
Young's modulus
11.92
11.927
12.288
12.14
12.051
12.01
specific modulus
31.7
31.7
32.3
31.9
32
31.6
Viscosity
A
−3.053
−3.214
−3.04
−3.017
−3.07
−3.315
B
7293.1
7452.5
7104.2
6965.6
7012.4
7912.6
To
358.8
357.5
382.9
390.6
370.9
314.4
200 poise
1721
1709
1713
1700
1676
1723
400 poise
1648
1639
1642
1630
1607
1652
35000 poise
1319
1318
1320
1312
1292
1321
Gradient boat
internal
1240
1235
1210
1210
1195
1210
internal viscosity
167235.2
190054.2
354232.1
304687.3
274891.6
331109
T(35 kp) − T(liq)
79
83
110
102
97
111
Example
62
63
64
65
66
67
SiO 2
70.77
72.3
71.68
72.37
73.61
71.53
Al 2 O 3
11.9
11.84
12.13
12.12
12.08
11.9
B 2 O 3
1.06
0
0
0
0
1.35
MgO
6
5.01
5.71
4.92
4.51
4.37
CaO
5.34
5.58
5.63
5.66
4.85
5.36
SrO
1.89
2.1
2.17
2.75
1.26
1.38
BaO
2.87
3.01
2.52
2.02
3.56
3.97
SnO 2
0.11
0.12
0.12
0.12
0.12
0.12
Fe 2 O 3
0.03
0.02
0.02
0.02
0.01
0.01
ZrO 2
0.03
0.02
0.03
0.02
0
0.01
RO/Al 2 O 3
1.35
1.33
1.32
1.27
1.17
1.27
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
4.24
3.86
3.9
3.23
2.1
3.22
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.56
84.14
83.81
84.49
85.69
84.57
MgO/(MgO + CaO + SrO + BaO)
0.37
0.32
0.36
0.32
0.32
0.29
Properties
Strain
742
766
758
767
776
745
Anneal
795
820
815
820
830
800
Soft (ppv)
1029.6
1057.6
1052.7
1059.5
1077.1
1043.5
CTE (disk)
36.3
35.9
36.1
36
35.8
37
Density
2.603
2.604
2.597
2.586
2.591
2.603
Young's modulus
12.136
12.137
12.308
12.258
12.165
11.92
specific modulus
32.1
32.1
32.7
32.7
32.4
31.6
Viscosity
A
−3.035
−2.991
−3.143
−3.049
−3.566
−2.943
B
6870.8
7115.9
6986.1
7170.6
8149.3
6909.4
To
379.2
368.7
398.3
370.2
334.5
379.8
200 poise
1667
1713
1682
1710
1723
1697
400 poise
1598
1641
1614
1639
1656
1626
35000 poise
1286
1313
1307
1315
1339
1303
Gradient boat
internal
1205
1220
1220
1235
1265
1190
internal viscosity
192829.9
233272.2
228564.1
174834.9
155589.2
384607.5
T(35 kp) − T(liq)
81
93
87
80
74
113
Example
68
69
70
71
72
73
SiO 2
71.76
72.75
70.78
71.47
72.9
71.8
Al 2 O 3
11.26
11.42
11.85
11.87
11.69
11.49
B 2 O 3
0
0
0.87
0
0
0
MgO
5.34
5.07
4.97
5.54
4.83
5.61
CaO
5.75
5.34
5.77
5.52
5.25
5.48
SrO
1.52
0.63
1.47
1.23
1.37
1.44
BaO
4.18
4.63
4.12
4.2
3.83
3.98
SnO 2
0.16
0.11
0.14
0.11
0.12
0.16
Fe 2 O 3
0.02
0.02
0.02
0.02
0.01
0.02
ZrO 2
0.02
0.02
0.02
0.03
0
0.02
RO/Al 2 O 3
1.49
1.37
1.38
1.39
1.31
1.44
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
5.53
4.25
4.52
4.62
3.59
5.02
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.02
84.17
83.36
83.34
84.59
83.29
MgO/(MgO + CaO + SrO + BaO)
0.32
0.32
0.3
0.34
0.32
0.34
Properties
Strain
751
761
742
757
765
755
Anneal
805
815
797
810
819
808
Soft (ppv)
1046
1058.3
1040.1
1047.9
1048
CTE (disk)
39.5
37.3
38.7
37.8
36.1
38.6
Density
2.641
2.627
2.632
2.637
2.6
2.631
Young's modulus
12.013
12.237
12.124
specific modulus
31.5
32
32.2
Viscosity
A
−3.1715
−2.639
−2.8291
−2.87
−2.887
−3.2947
B
7306.29
6448.7
6603.21
6677.3
6946
7613.94
To
355.18
421.2
398.09
404.8
391.2
333.99
200 poise
1690
1727
1685
1696
1730
1695
400 poise
1621
1652
1614
1625
1657
1625
35000 poise
1302
1319
1294
1305
1326
1305
Gradient boat
internal
1200
1200
1180
1230
1210
1210
internal viscosity
299805.3
437827.5
412928.1
166623.1
394590
249409.6
T(35 kp) − T(liq)
102
119
114
75
116
95
Example
74
75
76
77
78
79
SiO 2
72.39
73.19
72.74
71.85
71.4
71.79
Al 2 O 3
12.32
11.54
11.38
10.79
11.71
11.53
B 2 O 3
0.5
0
0
0
1.55
1.55
MgO
4.68
4.81
5.18
5.44
4.86
4.8
CaO
5.03
5.19
5.25
5.89
5.38
5.3
SrO
1.28
1.34
0.04
1.55
1.93
1.9
BaO
3.65
3.79
5.26
4.27
3.05
3
SnO 2
0.13
0.12
0.11
0.16
0.12
0.12
Fe 2 O 3
0.02
0.01
0.02
0.02
0.01
0.01
ZrO 2
0
0
0.02
0.02
0
0
RO/Al 2 O 3
1.19
1.31
1.38
1.59
1.3
1.3
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
2.33
3.59
4.35
6.36
3.57
3.52
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
85.14
84.73
84.12
82.64
84.42
84.63
MgO/(MgO + CaO + SrO + BaO)
0.32
0.32
0.33
0.32
0.32
0.32
Properties
Strain
762
770
760
748
743
742
Anneal
817
822
814
801
797
796
Soft (ppv)
1060.3
1068.8
1058.4
1043
1040
1041.7
CTE (disk)
35.8
35.7
36.5
39.8
35.6
34.9
Density
2.596
2.6
2.63
2.645
2.586
2.584
Young's modulus
12.046
12.039
11.954
11.937
11.918
specific modulus
32
31.9
31.3
31.8
31.8
Viscosity
A
−3.115
−3.715
−3.007
−3.2794
−3.16
−3.089
B
7142
8889.8
7290.9
7568.49
7253.8
7373
To
393.1
251
346.7
329.91
358.9
332.6
200 poise
1712
1729
1720
1686
1687
1700
400 poise
1642
1658
1647
1617
1618
1628
35000 poise
1326
1327
1312
1297
1300
1299
Gradient boat
internal
1230
1235
1195
1205
1230
1220
internal viscosity
262346.3
208617
387007
234106.4
146951
165783.7
T(35 kp) − T(liq)
96
92
117
92
70
79
Example
80
81
82
83
84
85
SiO 2
72.18
73.58
72.47
72.1
71.96
71.97
Al 2 O 3
12.2
11.77
11.46
12.05
12.02
11.58
B 2 O 3
0
0.5
0
0
0
0.84
MgO
4.91
4.48
5.34
5.47
4.98
4.68
CaO
5.52
4.81
5.3
5.16
5.23
5.47
SrO
2.07
1.22
0.37
1.34
2.15
1.39
BaO
2.96
3.49
4.9
3.75
3.49
3.9
SnO 2
0.12
0.13
0.11
0.1
0.12
0.14
Fe 2 O 3
0.02
0.02
0.02
0.01
0.02
0.02
ZrO 2
0.02
0
0.02
0.02
0.03
0.02
RO/Al 2 O 3
1.27
1.19
1.39
1.3
1.32
1.33
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.26
2.24
4.45
3.67
3.83
3.89
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.38
85.78
83.93
84.15
83.98
84.26
MgO/(MgO + CaO + SrO + BaO)
0.32
0.32
0.34
0.35
0.31
0.3
Properties
Strain
767
766
761
764
766
748
Anneal
821
822
815
817
819
801
Soft (ppv)
1059
1073.2
1056.3
1046
1059.6
1050.8
CTE (disk)
35.7
33.7
37.3
37.3
37.1
38.6
Density
2.599
2.577
2.62
2.613
2.616
2.613
Young's modulus
12.162
11.981
11.948
12.202
specific modulus
32.3
32.1
31.4
32.2
Viscosity
A
−2.943
−3.293
−3.344
−2.967
−3.087
−2.6835
B
6934.4
7631.6
7736.8
6855.99
7170.9
6479.42
To
388.4
359.5
336.1
403.9
369.3
412.79
200 poise
1711
1724
1707
1705
1700
1713
400 poise
1639
1654
1637
1635
1630
1639
35000 poise
1315
1333
1317
1317
1309
1309
Gradient boat
internal
1240
1245
1220
1220
1220
1195
internal viscosity
158412.7
211547.4
256464
271593.3
219994.1
398087.8
T(35 kp) − T(liq)
75
88
97
97
89
114
Example
86
87
88
89
90
91
SiO 2
71.31
71.28
71.2
72.21
71.69
72.77
Al 2 O 3
11.86
12.27
12.13
11.56
11.89
11.38
B 2 O 3
1.35
1.72
0.5
0
1.25
0
MgO
5.21
4.19
6.03
5.43
4.85
5.56
CaO
5.35
5.34
5.28
5.36
5.11
3.86
SrO
2.01
1.29
2.17
0.74
1.45
3.09
BaO
2.76
3.76
2.52
4.55
3.6
3.19
SnO 2
0.12
0.12
0.12
0.11
0.12
0.11
Fe 2 O 3
0.02
0.02
0.02
0.02
0.03
0.02
ZrO 2
0.01
0.01
0.03
0.02
0
0.02
RO/Al 2 O 3
1.29
1.19
1.32
1.39
1.26
1.38
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.52
2.35
3.89
4.52
3.16
4.32
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.31
85.01
83.75
83.77
84.64
84.15
MgO/(MgO + CaO + SrO + BaO)
0.34
0.29
0.38
0.34
0.32
0.35
Properties
Strain
745
743
750
759
740
762
Anneal
799
798
804
813
794
816
Soft (ppv)
1039.6
1044.9
1040
1055.3
1038.7
1059
CTE (disk)
35.7
34.8
37.7
36.2
36.2
36.3
Density
2.583
2.597
2.6
2.627
2.61
2.615
Young's modulus
12.246
11.874
12.085
12.033
12.076
specific modulus
32.7
31.5
31.7
31.8
31.8
Viscosity
A
−2.812
−3.025
−3.1872
−3.18
−2.898
−3.169
B
6516.6
7014.5
7081.73
7409.1
6712.1
7419
To
413
375.5
377.63
357.2
392
360
200 poise
1688
1693
1668
1709
1683
1716
400 poise
1617
1622
1601
1639
1612
1646
35000 poise
1299
1302
1294
1316
1294
1322
Gradient boat
internal
1205
1185
1210
1220
1210
1225
internal viscosity
260633.5
436742.5
209272
255431.2
203002.4
255787.1
T(35 kp) − T(liq)
94
117
84
96
84
97
Example
92
93
94
95
96
97
SiO 2
72.39
71.74
71.2
73.78
71.65
72.79
Al 2 O 3
11.55
11.37
11.91
11.88
12.18
12.14
B 2 O 3
0
0
1.65
0.63
0
0.5
MgO
5.05
5.83
4.81
4.3
6.07
4.62
CaO
5.48
5.48
5.58
4.64
5.49
4.95
SrO
1.66
1.08
2.03
1.16
2.34
1.26
BaO
3.72
4.32
2.69
3.46
2.11
3.59
SnO 2
0.11
0.11
0.12
0.11
0.12
0.13
Fe 2 O 3
0.02
0.04
0.01
0.01
0.02
0.02
ZrO 2
0.01
0.03
0
0.02
0.02
0
RO/Al 2 O 3
1.38
1.47
1.27
1.14
1.31
1.19
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
4.36
5.34
3.25
1.69
3.83
2.29
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
83.94
83.11
84.5
86.2
83.83
85.36
MgO/(MgO + CaO + SrO + BaO)
0.32
0.35
0.32
0.32
0.38
0.32
Properties
Strain
760
753
741
763
765
764
Anneal
813
806
796
820
817
819
Soft (ppv)
1055.4
1044.7
1039.2
1070.2
1049.5
1062.7
CTE (disk)
36.9
37.8
36
34.3
36.1
34.9
Density
2.622
2.637
2.578
2.574
2.591
2.589
Young's modulus
12.164
12.119
11.97
11.988
12.446
12.04
specific modulus
32
31.7
32
32.1
33.1
32.1
Viscosity
A
−3.214
−3.086
−2.964
−2.597
−3.309
−3.074
B
7473.4
7079.3
6900.9
6453.9
7354.2
7152.6
To
354.4
383.5
376.5
432.9
364.9
386.7
200 poise
1709
1698
1687
1751
1676
1717
400 poise
1639
1628
1616
1674
1609
1647
35000 poise
1318
1311
1296
1337
1301
1326
Gradient boat
internal
1215
1210
1210
1240
1225
1230
internal viscosity
295081.1
301575.6
206739.8
250845.8
174341.6
255669.6
T(35 kp) − T(liq)
103
101
86
97
76
96
Example
98
99
100
101
102
103
SiO 2
72.33
71.5
71.5
71.06
70.87
71.13
Al 2 O 3
11.69
11.78
11.75
11.98
11.75
11.2
B 2 O 3
0
0.85
1.99
1.85
1.31
0.69
MgO
5.26
4.77
4.2
4.45
5.53
5.84
CaO
5.34
5.55
5.28
5.77
5.4
5.52
SrO
1.24
1.41
2.65
1.7
1.77
1.04
BaO
4
3.96
2.49
3.03
3.22
4.41
SnO 2
0.11
0.14
0.12
0.12
0.11
0.11
Fe 2 O 3
0.01
0.02
0.01
0.01
0.02
0.05
ZrO 2
0.02
0.02
0.01
0.01
0.02
0.02
RO/Al 2 O 3
1.36
1.33
1.24
1.25
1.35
1.5
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
4.15
3.94
2.93
3.03
4.23
5.65
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.02
83.99
84.94
84.61
83.72
82.9
MgO/(MgO + CaO + SrO + BaO)
0.33
0.3
0.29
0.3
0.35
0.35
Properties
Strain
763
748
737
740
742
741
Anneal
816
800
793
794
794
793
Soft (ppv)
1056.4
1046.7
1037.9
1037.3
1032.8
1031.1
CTE (disk)
36.2
37.5
35.9
36
35.9
34.9
Density
2.621
2.62
2.574
2.58
2.601
2.633
Young's modulus
12.229
11.87
12.06
12.082
12.053
specific modulus
32.2
31.8
32.2
32
31.6
Viscosity
A
−2.965
−2.7111
−2.963
−2.719
−2.756
−3.099
B
6904.9
6461.74
6934
6302.2
6435.6
7055.7
To
402
416
373.1
430.5
406.1
365.4
200 poise
1713
1705
1690
1686
1679
1672
400 poise
1642
1632
1619
1615
1607
1603
35000 poise
1322
1307
1297
1298
1288
1289
Gradient boat
internal
1220
1190
1200
1200
1190
1185
internal viscosity
299362.9
433911.6
264567.4
295796.8
284263.2
323378.8
T(35 kp) − T(liq)
102
117
97
98
98
104
Example
104
105
106
107
108
109
SiO 2
71.52
73.74
71.43
73.55
72.18
71.34
Al 2 O 3
12.44
11.82
11.43
11.85
11.86
10.98
B 2 O 3
1.72
0
0
0.3
0
0
MgO
4.08
4.54
6.1
4.5
5.52
5.56
CaO
5.19
4.9
5.44
4.83
5.39
5.99
SrO
1.25
1.24
1.43
1.23
1.59
1.58
BaO
3.65
3.62
3.96
3.59
3.3
4.35
SnO 2
0.12
0.11
0.16
0.11
0.11
0.16
Fe 2 O 3
0.01
0.01
0.02
0.01
0.02
0.02
ZrO 2
0.02
0.02
0.02
0.02
0.02
0.02
RO/Al 2 O 3
1.14
1.21
1.48
1.19
1.33
1.59
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
1.76
2.48
5.5
2.31
3.94
6.5
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
85.43
85.56
82.86
85.66
84.04
82.32
MgO/(MgO + CaO + SrO + BaO)
0.29
0.32
0.36
0.32
0.35
0.32
Properties
Strain
745
770
753
768
764
750
Anneal
798
825
806
823
816
802
Soft (ppv)
1071.1
1041
1071.7
1050.7
1039
CTE (disk)
36.4
35.9
38.2
35.7
36.7
40.1
Density
2.59
2.633
2.589
2.616
2.652
Young's modulus
12.047
12.037
12.292
specific modulus
32.1
32.1
32.4
Viscosity
A
−3.3669
−3.093
−3.1455
−2.724
−2.405
−3.1246
B
7769.3
7315.2
7160.06
6678.5
5903.2
7195.68
To
322.18
375.6
372.38
418.1
457.3
356.84
200 poise
1693
1732
1687
1747
1712
1683
400 poise
1624
1660
1618
1672
1636
1613
35000 poise
1304
1333
1304
1337
1307
1295
Gradient boat
internal
1190
1235
1200
1250
1210
1190
internal viscosity
385268
262412.9
320542.7
201376.2
273967.9
325096.6
T(35 kp) − T(liq)
114
98
104
87
97
105
Example
110
111
112
113
114
115
SiO 2
72.75
73.6
72.81
72.64
72.5
71.12
Al 2 O 3
11.41
11.74
11.38
11.37
11.87
11.82
B 2 O 3
0
0
0
0
0
2.01
MgO
4.92
4.62
4.93
5.27
4.91
4.45
CaO
5.54
4.98
5.46
5.07
5.33
5.93
SrO
1.17
1.29
1.37
3.3
1.39
2.25
BaO
4.06
3.64
3.9
2.2
3.87
2.26
SnO 2
0.11
0.12
0.11
0.11
0.12
0.12
Fe 2 O 3
0.02
0.01
0.02
0.02
0.01
0.02
ZrO 2
0.02
0
0.02
0.02
0
0.02
RO/Al 2 O 3
1.38
1.24
1.38
1.39
1.31
1.26
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
4.28
2.79
4.28
4.47
3.63
3.13
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.16
85.34
84.19
84.01
84.37
84.64
MgO/(MgO + CaO + SrO + BaO)
0.31
0.32
0.31
0.33
0.32
0.3
Properties
Strain
760
772
760
760
765
735
Anneal
814
826
815
815
820
791
Soft (ppv)
1056.3
1071
1054.1
1056.4
1033.5
CTE (disk)
36.7
35.7
36.6
36.2
36
36.3
Density
2.622
2.599
2.62
2.599
2.601
2.568
Young's modulus
12.073
12.095
12.127
12.228
12.146
11.956
specific modulus
31.7
32.1
31.9
32.4
32.2
32.1
Viscosity
A
−3.431
−3.385
−2.954
−3.608
−3.184
−3.086
B
7862.3
7779.3
6950.9
8438.4
7438.8
7014.9
To
335
357.4
394.2
282.4
357
375.4
200 poise
1707
1726
1717
1710
1713
1678
400 poise
1638
1657
1645
1641
1643
1609
35000 poise
1321
1339
1321
1318
1320
1295
Gradient boat
internal
1210
1250
1210
1240
1210
1210
internal viscosity
358497.2
213956.8
368424.2
159966.9
344152
208499.1
T(35 kp) − T(liq)
111
89
111
78
110
85
Example
116
117
118
119
120
121
SiO 2
72.29
72.71
71.88
71.32
72.33
71.88
Al 2 O 3
11.87
11.48
11.47
11.64
11.55
11.97
B 2 O 3
0
0
0
0.85
0
0
MgO
4.92
4.95
5.66
4.87
5.05
5.74
CaO
5.67
5.39
5.46
5.67
5.49
5.36
SrO
2.62
1.46
1.12
1.44
1.52
1.89
BaO
2.46
3.82
4.24
4.05
3.9
3
SnO 2
0.12
0.15
0.11
0.14
0.11
0.11
Fe 2 O 3
0.02
0.02
0.03
0.01
0.02
0.02
ZrO 2
0.03
0.02
0.02
0
0.02
0.02
RO/Al 2 O 3
1.32
1.36
1.44
1.38
1.38
1.34
(RO − Al 2 O 3 )/(1 − B 2 O 3 /100)
3.8
4.14
5.01
4.43
4.41
4.02
(SiO 2 + Al 2 O 3 )/(1 − B 2 O 3 /100)
84.16
84.19
83.35
83.67
83.88
83.85
MgO/(MgO + CaO + SrO + BaO)
0.31
0.32
0.34
0.3
0.32
0.36
Properties
Strain
763
763
757
744
763
762
Anneal
818
817
810
798
814
814
Soft (ppv)
1057.3
1055.8
1049.1
1042.4
1055.7
1051.6
CTE (disk)
36
36.6
38.3
38.4
37.2
35.7
Density
2.598
2.613
2.634
2.624
2.623
2.608
Young's modulus
12.197
12.08
12.094
12.118
12.297
specific modulus
32.4
31.9
31.7
31.9
32.5
Viscosity
A
−2.921
−3.036
−3.121
−2.745
−3.031
−2.606
B
6826.5
7156.8
7213.1
6495.63
7108.6
6152.6
To
395.7
373.8
367.2
406.26
378.9
446
200 poise
1703
1715
1698
1694
1712
1700
400 poise
1632
1643
1628
1621
1641
1627
35000 poise
1310
1318
1308
1297
1317
1306
Gradient boat
internal
1240
1210
1220
1185
1200
1225
internal viscosity
146014.6
333210
217339.1
394643.6
423068.6
195918.1
T(35 kp) − T(liq)
70
108
88
112
117
81
[0055] Various modifications and variations can be made to the materials, methods, and articles described herein. Other aspects of the materials, methods, and articles described herein will be apparent from consideration of the specification and practice of the materials, methods, and articles disclosed herein. It is intended that the specification and examples be considered as exemplary. | Described herein are alkali-free, boroalumino silicate glasses exhibiting desirable physical and chemical properties for use as substrates in flat panel display devices, such as, active matrix liquid crystal displays (AMLCDs) and active matrix organic light emitting diode displays (AMOLEDs). In accordance with certain of its aspects, the glasses possess good dimensional stability as a function of temperature. The glasses comprise in mol percent on an oxide basis: 70-74.5 SiO2, 10.5-13.5 AL2O3, 0-2.5 B2O3, 3-7 MgO, 3-7 CaO, 0-4 SrO, 1.5-6 BaO, 0-0.3 SnO2, 0-03 CeO2, 0-0.5 As2O3, 0-0.5 Sb2O3, 0.01-0.08 Fe2O3 and F+Cl+Br RO/Al2O3 1.7 and 0.2 MgO/RO | 2 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 61/745,195, filed on Dec. 21, 2012, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is related to cost effective synthesis of 1-bromo-3,3,3-trifluoropropene. More specifically, the present invention is related to the synthesis of 1-bromo-3,3,3-trifluoropropene from the reaction of 3,3,3-trifluoropropyne and HBr.
BACKGROUND OF THE INVENTION
[0003] Chlorofluorocarbons (CFCs) are known and widely used in the industry as solvents, blowing agents, heat transfer fluid, aerosol propellants and other uses. But CFCs are also well-known to have ozone depletion potential (ODP) and are regulated by the Montreal Protocol. A suitable replacement material would have negligible or no ODP, as well as an acceptable global warming potential (GWP).
[0004] 1-Bromo-3,3,3-trifluoropropene, 2-bromo-3,3,3-trifluoropropene and 1,2-dibromo-3,3,3-trifluoropropene each have desirable ODP and GWP, and could potentially used as high efficiency fire extinguisher agents. For example, CN 102319498 A describes a dry powder fire extinguisher having 2-5 wt % of 2-bromo-3,3,3-trifluoropropene, the composition having high moisture-proof performance, high reburning resistance, and high fire extinguishing efficiency. Similarly, Zhang et al found a bromotrifluoropropene/zeolite mixture to be a highly efficient fire extinguisher ( Zhongguo Anquan Kexue Xuebao 2011, 21(5), 53; Process Safety and Enviromental Protection 2007, 85(B2), 147; Huozai Kexue (2010), 19(2), 60-67). 1-Bromo-3,3,3-trifluoropropene with an inert gas have many of the desirable properties of HALON 1301 fire extinguishing agents. The results show that the composites loaded with bromotrifluoropropene exhibited much better performance than that of common dry powders in putting out gasoline fires, requiring less powder, and having shorter fire extinguishing time.
[0005] One existing production process for 1-Bromo-3,3,3-trifluoropropene requires the reaction of 3,3,3-trifluoropropene with bromine, followed by dehydrobromination, to give the target compound. This process is very expensive, and not suitable for large quantity production.
[0006] Other production processes for bromotrifluoropropenes have been investigated. J. Chem. Soc. 1951, 2495 describes bromination of CF3CH═CH2 followed by alkaline treatment to give 2-bromo-3,3,3-trifluoropropene. J. Chem. Soc. 1952, 3490 describes hydrogen bromide (HBr) reaction with 3,3,3-trifluoropropyne at 0° C. or with AlBr 3 at −25° C. to give 1-bromo-3,3,3-trifluoropropene at high yield. Also, HBr reacted with 3,3,3-trifluoropropyne in a sealed cylinder with or without AlBr 3 yields 1-bromo-3,3,3-trifluoropropene in high yield (83-91% yield) when reacted at low temperatures ( J. Chem. Soc. 1952, 3490; J. Am. Chem. Soc. 1952, 650). 2-Bromo-3,3,3-trifluoropropene is an important intermediate for pharmaceutical and agrochemicals and was often used as the precursor of 3,3,3-trifluoroacetylenic anion and could dehydrobrominated with LDA or BuLi at 0° C. ( J. Org. Chem. 2009, 7559-61; J. Flu. Chem. 1996, 80, 145-7). Finally, Mori et al used 1,2-dibromo-3,3,3-trifluoropropene reacting with 20% aqueous NaOH to produce 2-bromo-3,3,3-trifluoropropene in 98% yield (JP 2001322955).
SUMMARY OF THE INVENTION
[0007] There remains a need for an improved process which may be used to efficiently produce bromotrifluoropropenes, and especially 1-bromo-3,3,3-trifluoropropene, in commercial quantities.
[0008] To this end, in accordance with one aspect of the present invention, a process of synthesizing bromotrifluoropropenes comprising mixing 3,3,3-trifluoropropyne with hydrogen bromide to make a first mixture, and subsequently contacting the first mixture with a catalyst at a temperature of at least 50° C. to yield at least one bromotrifluoropropene is provided.
[0009] Additionally, in accordance with a second aspect of the present invention, a process of synthesizing bromotrifluoropropenes comprising reacting 3,3,3-trifluoropropyne with hydrogen bromide without a catalyst at a temperature of at least 50° C. to yield at least one bromotrifluoropropene is provided.
DETAILED DESCRIPTION
[0010] In accordance with the present invention, it was found that 3,3,3-trifluoropropyne could react with HBr at high temperature under the influence of Lewis acid such as CuBr 2 , CuBr, ZnBr 2 , MgBr 2 , AlBr 3 , and other metal bromides (MBrx) to yield a product which contains a mixture of brominated olefins. Typically, the major product yielded was 1-bromo-3,3,3-trifluoropropene, but 2-bromo-3,3,3-trifluoropropene and 1,2-dibromo-3,3,3-trifluoropropene were also produced.
[0011] A variety of ionic solvents can be used for the reaction of 3,3,3-trifluoropropyne with HBr, for example, 1-alkyl-3-methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidinium and ammonium ions; however, an ionic solvent is not necessary. If an ionic solvent is used, 1-alkyl-3-methylimidazolium bromide is preferred, but a reaction having no such solvent is most preferred.
[0012] Catalysts can also be used. These include mineral acids such as H 2 SO 4 or Lewis acids such as metal salts, especially those of copper, aluminum and antimony (e.g. CuBr 2 , CuBr, and AlBr 3 ). Depending on the temperature of the reaction, the catalyst may not be necessary.
[0013] Reaction temperatures, for reactions at atmospheric pressure, were limited to 50-350° C., but the reaction might proceed at temperatures well above 350° C. To find the appropriate reaction temperature, a pre-mixed 3,3,3-trifluoropropyne and HBr was passed through the heated catalyst/solvent mixture and heating was continued until evidence of reaction was observed, for example, a measured release of heat or generation of volatiles.
[0014] Preferably, the molar ratio of HBr to 3,3,3-trifluoropropyne should be at least one, and can be higher; however, ratios in excess of 3 were not found to be particularly advantageous, and might increase the incidence of side reactions. Molar ratios in the range of 1.1 to 2.5 are particularly preferred.
[0015] In an example embodiment, HBr and 3,3,3-trifluoropropyne are mixed in a stainless cylinder and passed through a mixture of ionic liquid and catalyst or catalyst loaded on activated carbon at 50-350° C. Nitrogen or argon at a speed of 20 ml/m to 100 ml/m is used as a carrying gas. Reactants are controlled by a regulating valve at a rate of 10-50 ml/m. Product out of the reaction vessel is collected by a cooling trap at temperature of −20° C. to −78° C.
[0016] The following examples further illustrate the present invention, but should not be construed to limit the scope of the invention in any way.
EXAMPLES
Example 1
[0017] 3.52 g of CuBr was dissolved in 18 ml of 48% HBr acid at 0° C. To this solution was added 31.7 g of activated carbon (Shirasagi granular, G2 X 4/b-1) under argon. The mixture was briefly vacuumed and then settled under argon overnight. The solvent was removed under vacuum (<80° C.), then heated at 100° C. for 2 hours.
Example 2
[0018] 4.40 g of catalyst from Example 1 was heated in a 10 mm diameter Monel tube in the oven at 300° C. for 4 hours under nitrogen flow of 100 ml/m. Then, the oven was cooled to 250° C., nitrogen flow decreased to 20 ml/m, and 13.0 g of TFP and 15.0 g of HBr mixture in a cylinder was passed through the tube at 250° C. The product of 26.1 g clear liquid was collected in −78° C. trap. NMR analysis showed the presence of 9.47% Cis-1-bromo-3,3,3-trifluoropropene (−61.0 ppm, dd, J=7.6, 19.6 Hz), 64.79% trans-1-bromo-3,3,3-trifluoropropene (−64.7 ppm, dd, J=6.1, 20.1 Hz), 15.40% cis-1,2-dibromo-3,3,3-trifluoropropene (−66.5 ppm, d, J=19.8 Hz,), 10.33% 2-bromo-3,3,3-trifluoropropene (−69.4 ppm, d, J=19.6 Hz).
Example 3
[0019] The CuBr catalyst from Example 2 was reused. The oven was heated to 100° C., and 4.30 g of TFP and 8.10 g of HBr mixture in a cylinder was passed through the tube at 100° C. with nitrogen flow at 20 ml/m. The product of 5.2 g orange liquid was collected in a −78° C. trap. NMR and GC analysis showed that the liquid comprised 23.0% of 3,3,3-trifluoropropyne, 10.60% of cis-1-bromo-3,3,3-trifluoropropene, 56.77% of trans-1-bromo-3,3,3-trifluoropropene, 1.13% of 1,2-dibromo-3,3,3-trifluoropropene, 3.24% of 2-bromo-3,3,3-trifluoropropene, as well as some unidentified products. | In accordance with the present invention, processes for producing bromofluoropropenes in commercial quantities by reacting 3,3,3-trifluoropropyne with hydrogen bromide at elevated temperatures are provided. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not Applicable
REFERENCE TO SEQUENCE LISTING
[0002] Not Applicable
BACKGROUND OF THE DISCOVERY
[0003] The discovery relates to the field of using of a natural plant product for human body recovering.
[0004] As a result of many years of observations and then by specific experiments it was discovered that the apple pips (seeds), taken internally, can influence on some parts and systems of a human body.
[0005] It is well-known and described in world science and popular literature that apples are very beneficial for the human body due to their rejuvenating and restorative effects. It is also known that skin of the apples is more effective than the apple's flesh due to its higher concentration of a pectin. The pectin also supports high turgor—an internal pressure—into living cells of the plants and living bodies.
[0006] However, the elicited facts show that the rejuvenating effects of apple pips, taken internally, exceed very significantly healthy properties of the apples.
[0007] Any information about the influence of the apple pips (seeds), taken internally, on living human body was found neither in literature, nor in the patents.
[0008] There is only some information that a composition of some remedies for external application (creams, lotions) contains the apple pips (it was not found any information about the science researches or the patents in this field).
[0009] Therefore, it was elicited by this discovery for the first time in science and practice, that apple pips, taken internally, create the series of the effects which rejuvenate and restore of living bodies, and also improve and support noticeable outward aesthetics of some parts of human body by these effects.
[0010] This discovery was registered by author—Arnold Gilerson, New York, N.Y.—as U.S. Provisional Patent Application 60/899,501 of Feb. 5, 2007 with title:
[0011] “DISCOVERY OF THE ABILITY OF THE PEELED APPLE PIPS (SEEDS), TAKEN INSIDE, TO AFFECT VERY MIGHTLY ON A HUMAN ORGANISM, DELAYING A FORTHCOMING THE FACTORS WHICH CONNECTED WITH ITS AGEING”.
BRIEF SUMMARY OF THE INVENTION
[0012] On a base of many years of observations and facts (over 15 years) then reconfirmed by information about other people, it was discovered for the first time in world science and practice:
[0013] The peeled apple pips (seeds), taken internally, generate in the human organism several powerful rejuvenescent and recovering effects that exceed the well-known healthy properties of apples (or their skin).
[0014] It was observed that many years' use of apple pips (taken internally):
keeps health in good state, promotes a significant rejuvenation of the body, a preservation of energy and agility; influences positively on the body's parts connected with an activism of the melanocytes—hair color, skin's pigmentation; influences positively on the body's parts (hair, skin, nails) connected with an activism of the keratinocytes—hair follicles and a decrease (as a result) of a tendency for baldness; appearance, growth and overall state of the nails; skin's state and others.
[0019] It was discovered that the most immediate changes (occurring in one to two weeks) are:
the restoration of one's original hair color, a noticeable decrease of the facial wrinkles.
[0022] This discovery opens new the widest fields for new researches and new discoveries explaining the phenomenon of rejuvenation and conservation of vital body's ability, possible influence of apple pips substances on immune, cardiovascular, reproductive and other systems of the body.
DESCRIPTION
Brief Summary of the Facts, Experiments and Possible Explanations
[0023] The influence of apple pips on the restoration one's original hair color was noticed by the author when gray hair first began to appear on the temples and the center of the head (his colleagues by a job and friends of the same age or younger, began to have gray hair and get bald many years earlier).
[0024] It was observed that sometimes hair color oscillated between the early stages of graying and getting dark again due to some unknown causes.
[0025] Soon it was determined that the restoration of original hair color was connected with the author's habit to eat apple pips following consumption of apple.
[0026] This was 15-16 years ago and then these facts were confirmed via many observations. If the author did not consume apples and their pips during one or two months, his gray hair increased. But after a renewal in apple pip consumption, hair color was restored in several days.
[0027] As a result, it is the premise of the author to state that his delayed balding and graying can be explained by his apple pips eating habit from a relatively young age (aged approximately 25-30).
[0028] In Russia, (prior to the author's resettlement to the United States in 1997) the apples consumed were of Russian and European varieties. Among these were:
[0029] Anis, Antonovka, Grushovka moskovskaia, Ranet Krudnera, Slavianka, Jonatan and others.
[0030] After moving to the United States, American brands were used for the last 10 years. Among these were:
[0031] Golden Delicious, Cortlandt, Fuji, Red Delicious, Granny Smith, McIntosh, Gala, Macoun, Honeycrisp and others.
[0032] The following observations showed that apple pips also decrease the wrinkles on women and men's faces. This effect manifests itself relatively quickly, approximately in one to two weeks.
[0000] This was confirmed via personal experimentation many times.
[0033] Periodical influence of apple pips on the body for a prolonged period results in rejuvenating effects and the preservation of many of the organism's functions including energy, agility, mobility. Many people are incredibly surprised to learn the author's true age based on his physical appearance (relatively wrinkle-free face, hair color, no baldness) and external and internal state of his body (activity, agility, good health, no need to regularly take any prescriptions or medicines). Often they assume he is approximately 15-20 years younger.
[0034] The physical appearance of three persons also confirms this conclusion (the author's wife, daughter and grandson, who, following the author's example also consume apple pips). They repeatedly informed the author that the individuals they interacted with often did not believe their true age, generally believing them to be several years younger.
[0035] Recently, the role of apple pips and their influence in heart activity was observed: A reduced pulse in the morning (48-50), possibly connected with prescribed medication, during a long period without eating apple pips (6-7 weeks), became more stable after resuming their consumption, increasing to 52-58 pulse beats.
[0036] An effect on the skin pigment was observed—various spots of vitiligo on the face and arms became almost imperceptible after regular internal consumption of apple pips. This may be caused by the substances in apple pips affecting the activity of the melanocytes. These melanocytes are responsible for production of melanin (a pigment in hair, skin, and eyes), which determines hair color and skin pigmentation.
[0037] It was observed that (in several people) regular consumption of apple pips promote quick growth of the nails, maintain a magnificent appearance, excalation dry cuticles, and ensures nice form, color and luster. This may be caused by the substances in apple pips affecting the activity of the keratinocytes. These keratinocytes are responsible for the production of keratin (“keratin is an extremely strong protein—a major component in skin, hair, nails, and other keratin-containing parts of the body”).
[0038] Therefore, it is possible to assume that the chemicals of apple pips actively affect the melanocytes (which give melanin for color of hair and skin) and on the keratinocytes (which form keratin for hair, skin epidermis, nails) and on hair follicle keratinocytes. This serves to explain the delay of baldness.
[0039] Side effects were not noticed during many years of regular consumption of apple pips in various quantities.
[0040] Later it was discovered that these effects also have place with other persons who are taking internally apple pips.
[0041] The author received additional information about several elderly men and women who have a habit of eating apples together with the pips—they have good health and delayed canities and baldness. Some of them noticed periodical restoration of original hair color (unaware of the aforementioned explanation).
[0042] The detail information about positive effects of using peeled apple pips are cited in Table 1.
[0000]
TABLE 1
Confirmations of the efficacy of apple pips' influence on the human body.
Persons who take apple pips internally
Age
Term of eating
in
apples together
Positive effects
Pers.
Sex
2007
Place
with pips
Periodicity
I. Connected with an activism of the melanocytes
1.1.
The restoration
of one's
original hair
color
1.1.1.
A
M
82
Kazan,
All years from
After eating
(au-
Russia;
youth (a habit)
the apples
thor)
New York,
with some pauses
USA
(sometimes,
(after 1997)
many months
Observations: During last 15 years was observed gray hair increases after some intervals
in eating apple pips, and canities decreases after resumption eating pips.
Results: Bigger part of hair has dark color
1.1.2.
F
M
83
Kazan,
Many
After eating
Russia
years
the apple (or
together)
Observations: Often gray hair increased and became dark again (the causes were unknown).
Results: Bigger part of hair has dark color
1.1.3.
W
F
80
New York,
Approx.
After eating
USA
5 years
the apples
Results: White (very gray) hair became almost dark.
1.1.4.
R
F
82
Moscow
Many
Together
Russia
years
with eating
the apples
(or after)
Results: She does not have gray hair
1.1.5.
N
M
77
New York,
Many
Together
USA
years
with eating
the apples
Observations: Many years there are not any changes in quantity of gray hair
Results: Approx. a half of hair are dark.
1.2.1.
The pigmentation's
W
F
80
New York,
Approx. 5
After
changes of skin's
USA
years
eating
spots (vitiligo) on
the
a face and arms.
apples
Observation: More regularly eating apple pips last two years.
Results: The spots of vitiligo became almost imperceptible
II Connected with increasing of internal cell's pressure (turgor)
2.1.
A decrease of the
wrinkles on the
men and women's
faces
2.1.1.
A
M
82
New York
Many
After eating
years
the apples
2.1.2.
W
F
80
New York
Beginning of
After eating
eating apple pips
one apple
~5 years ago
every day
Observations: In one week the wrinkles decreased on her face (her friends asked her if
she made a cosmetic operation).
Results: A face's state gets better after eating apple pips during 2-3 days and
keeps 2-3 days.
2.1.3.
C
M
75
New York
~One year ago
Together with
eating apple
Observations: The wrinkles were decreasing on the face
Results: No any noticeable wrinkles on his face.
III Connected with an activism of the keratinocytes.
3.1.
The decrease a ten-
dency for baldness -
an influence on
hair follicle
keratinocytes
3.1.1.
A
M
82
Kazan,
See
See
New York
p.1.1.1.
p.1.1.1.
Observations: Hair's quantity was decreasing very slowly
Results: No noticeable baldness.
3.1.2.
F
M
83
Kazan,
See
See
Russia
p.1.1.2.
p.1.1.2.
Observations: Hair's quantity was decreasing very slowly.
Results: No noticeable baldness.
3.1.3.
N
M
77
New York
See
See
p.1.1.5.
p.1.1.5.
Observations: During 5 last years hair's quantity decreasing very slowly (early -
unknown for author).
Results: A little baldness is no increasing during some last years.
3.2.
Permanent magnifi-
cent look of nails,
quick nail's growth,
a lack of dry
cuticles, nice form,
color and luster -
an influence on
nails and skin
keratinocytes
3.2.1.
W
F
80
New York
See p.1.1.3.
See p.1.1.3.
Observations: One year ago it was observed quick growth of the nails and their magnificent
look.
Results: The magnificent look and quick growth are keeping.
3.2.2.
D
F
49
New York
6 years
Sometimes
after eating
the apples
Observations: The same.
Results: The same
3.2.3.
GS
M
17
New York
3 years
After eating
the apples
Observations: The same
Results: The same
3.2.4.
A
M
82
New York
See p.1.1.1.
See p.1.1.1.
Observations: The same
Results: The same
IV Rejuvenation effects of the body
4.1.
Preservation of
A
M
82
Kazan,
See
See
energy and agility,
New York
p.1.1.1.
p.1.1.1.
good health
Observations: Many years is in good mobility and activity. It is not a necessary
in any medicines regularly (an amazing all friends and doctors).
Results: Two years ago main test for the elderly - “maximum breathing capacity”
showed that vital state is equivalent an age 63. Own age feelings fit these estimates.
4.2.
The physical
appearance are
younger than true
age
4.2.1.
A
M
82
Kazan,
See
See
New York
p.1.1.1.
p.1.1.1.
Observations: Relatively wrinkle-free face, good hair color, no baldness. Many individuals
interacted with often do not believe in true age (they qualify as 18-20 years younger).
Result: Own feeling and some symptoms of body's state fit younger age.
4.2.2.
W
F
80
Kazan,
See
See
New York
p.1.1.3.
p.1.1.3
Observations: Many individuals interacted with often do not believe in true age.
Result: Own feelings and some symptoms of body's state fit younger age.
4.2.3.
D
F
49
New York
See p.3.2.2.
See p.3.2.2.
Observation: The same.
Result: The same.
4.2.4.
GS
M
17
New York
See p.3.2.3.
See p.3.2.3.
Observation: The same.
Result: The same.
DETAILED DESCRIPTION OF APPLYING METHODS
1. The Possible Method of the Elaboration of New Fast Acting Effective Product (Taken Internally) for the Restoration of One's Original Hair Color
[0043] 1.1. The Method Used by the Author (Initial Products, Quantity, Time Intervals).
[0044] Ingestion of pips from one apple (one apple has 10 pips or less) and then from 2-3 apples (up to 20-25) every day—as a rule, it was after eating one apple—the newly grayed hair darkened in one to two days. Continued ingestion of pips during several days intensifies the darkening of hair and preserves them in that state.
[0045] An omission of pips from the diet for several weeks causes an increase of gray hair. If the pip consumption is resumed once more, the process of hair color restoration will resume as well. The hair on other parts of body become darker as well, particularly evident near the wrist.
[0046] It is therefore possible to suppose (via author's experience) that regular consumption of apple pips at the approximate origin graying, will effectively postpone it for many years.
[0047] It was observed (about 3-4 years ago) that the different kinds of apple have a different efficiency for restoring hair color—“Golden Delicious” apples are better then others.
[0048] 1.2. The Possible Method of an Elaboration for the Manufactory New Effective Product.
[0049] It is expediently more thorough detections 2-3 apple kinds, the pips of which give maximum efficacy for hair color restoration.
[0000] The research can be made by comparative laboratory analyses of chemical composition, enzymatic and other substances of “strong” and “weak” apple kinds (for example, Golden Delicious and Red Delicious), and then by determining the differences in their effect of the hormones and activity of the melanocytes in the follicles which define canities (hair graying). Other researches may be required as well.
[0050] After selecting the most effective apple type, it is necessary to acquire the tests for hair color restoration (with the men and women's groups):
in beginning of graying in 8-12 months after graying in 2-3 years after graying in 5-6 years after graying
The experiment will have to be conducted as it was explicated in 1.1 (may be with the necessary corrections).
[0055] It is necessary to remember that the pips were consumed (as a rule) after eating one apple. Therefore, it is necessary to conduct the tests in two versions: a) after eating one apple and b) without eating an apple.
[0056] Through this research any and all possible side effects, provided they are present, will be determined.
[0057] If all tests prove to be in compliance with the data, a new fast acting product can be produced shortly thereafter (because there are the machines for pip's peeling and pulverizing)
[0058] 1.3. The Convenient Version for Sale.
[0059] If it is determined that the apple pips are more effective with an apple, one can use a convenient version for sale.
[0000] Each portion of pips can be mixed with some natural apple product, just about as one apple for one dose of the pips. It can be, for example, 100 gram of an apple sauce.
2. The Elaboration of New Fast Acting Effective Product (Taken Internally) to Decrease Wrinkles
[0060] 2.1. The Used Method.
[0061] The apple pips used of 1 or 2-3 apples (10-15-25 pips), after eating one apple. After 4-5 taking pips (during one week), the wrinkles were decreasing noticeably on the face an elderly woman (her friends asked her if she made a cosmetic operation). That wrinkles decreasing was continuing during 4-5 days. After next 2-3 takings, noticeable effect was evincing in 1-2 days.
[0062] 2.2. The Possible Method for Manufacturing of a New Product
[0063] First check-up can be made easily in accordance with 2.1.
[0064] The particular researches and practical experiments and also marketing research must show a practicability of creation one product by p.p.1 and 2 or it is better to have two different products.
[0065] The experiences showed that the restoration and preservation of hair color need more long preliminary and regular uses of product. The effect of wrinkles decrease evinces sooner with using more portions of the product (in 1-2 days). But both effects evince in both events.
[0066] Any side effects were not noticed during many years regular uses of apple pips (up to 25-30 pips for one dose).
3. The Possible Organization of Works for Further Researches of Discovered Rejuvenating and Recovering Effects Connected with Influence Apple Pips on the Human Body and for Creation New Rejuvenating Remedies and Drugs
[0067] 3.1 The Discovery Significant Positive Affects which are Connecting with Using Per Os Apple Pips, on Activity of the Melanocytes and Keratinocytes Determines Next Possible Pathways of the Researches:
[0068] Hair Color
[0000] Elaboration of the remedies for:
delaying of canities delaying and treatment of an albinism and other abnormal manifestations connecting with hair pigmentation
[0071] Hair State
[0000] Elaboration of the remedies for:
delaying of baldness treatment alopecia and other hair diseases against dandruff
[0075] Skin Pigmentation
[0000] Elaboration of the remedies:
for treatment vitiligo against the freckles for treatment other diseases connected with skin pigmentation—albinism, melasma and others
[0079] Skin Diseases
[0000] The researches and elaboration of the remedies for treatment such serious illnesses as psorias, melanomas and others.
[0080] Nails State
[0000] Elaboration of the remedies for:
supporting nice appearance of the nails treatment different diseases finger and toes nails.
[0083] Elaboration of the remedies for treatment other diseases of hair, skin, nails, eyes, mouth and other parts of body, connected with activity of the melanocytes and keratinocytes.
[0084] 3.2. The Researches by p.1. 2. have to Elicit the Main Active Substances, Containing into Apple Pips, that Influence Rejuvenation and Recovering Processes.
[0085] In new researches:
it can be verified an influence increase of concentration those active substances to more fast development of positive effects; it is possibly that it will be discovered natural or synthesized products or catalysts for increasing positive effects (the author discovered one of them for hair color restoration).
[0088] 3.3. New Perspective Directions are Opening for the Researches of the Influences Apple Pips on the Body's State:
[0089] Influences on:
cardiovascular system immune system reproductive system and others.
[0093] Undoubtedly, there are many other factors affecting to recovering and rejuvenation of human organism by apple pips substances. It is the widest field of the researches.
[0094] A realization these special, laboratory and clinical researches with using new created products, can open new significant recovering effects.
[0095] It also needs to take into consideration that all new products will possess by all well-known useful qualities of pectin—inclusive products with their maximum efficacy, and with upholding high turgor in the cells of the body. | It was discovered the ability of peeled apple pips (seeds), taken internally:
to affect very significantly a human organism, delaying the onset of factors associated with ageing; to promote a rejuvenation of the body, a preservation of energy and agility; to improve a state of body's parts connected with activism of the melanocytes and keratinocytes, including the restoration of one's original hair color, a noticeable decrease of facial wrinkles, a decrease of a tendency for baldness and others; to cure some illnesses. | 0 |
BACKGROUND
[0001] The present disclosure relates generally relates to the treatment of patients having treatable medical conditions using weak (i.e., low-intensity) low-frequency electromagnetic fields.
[0002] The term “arrhythmia” (i.e., irregular heartbeat) encompasses any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. A heartbeat that is too fast is called tachycardia and a heart beat that is too slow is called bradycardia. Although many arrhythmias are not life-threatening, some can cause cardiac arrest.
[0003] Atrial fibrillation is the most common cardiac arrhythmia. In atrial fibrillation, the normal regular electrical impulses generated by the sinoatrial (SA) node are overwhelmed by disorganized electrical impulses usually originating in the roots of the pulmonary veins, leading to irregular conduction of impulses to the ventricles which generate the heartbeat. Atrial fibrillation may be treated with medications to either slow the heart rate to a normal range (“rate control”) or revert the heart rhythm back to normal (“rhythm control”). Synchronized electrical cardioversion can be used to convert atrial fibrillation to a normal heart rhythm. Synchronized electrical cardioversion uses metallic plates with conductive gel to deliver a therapeutic dose of electric current to the heart at a specific moment in the cardiac cycle. A synchronizing function (either manually operated or automatic) allows the cardioverter to deliver a reversion shock of a selected amount of electric current over a predefined number of milliseconds at the optimal moment in the cardiac cycle which corresponds to the R wave of the QRS complex on the electrocardiogram (ECG). Synchronized electrical cardioversion is used to treat atrial fibrillation, atrial flutter, and ventricular tachycardia, when a pulse is present.
[0004] In the past, the possibility of treating cardiac arrhythmias with the application of low-intensity, low-frequency electromagnetic fields has been proposed. In particular, the concept of using an electromagnetic field generator as a regulator of atrial fibrillation has been previously disclosed.
[0005] The heart is a precise oscillatory organ capable of generating uninterrupted rhythmical activity over a very long period. The SA node is the impulse-generating (pacemaker) tissue located in the right atrium of the heart, and thus is the generator of normal sinus rhythm. The pacemaker cells located in the SA node are specialized cardiac myocytes that generate the regular oscillatory action potentials that drive each contraction cycle. In muscle cells, an action potential is the first step in the chain of events leading to contraction. Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane. These channels are shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a threshold value. When the channels open, they allow an inward flow of sodium ions. The rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, and the sodium ion channels then rapidly inactivate. Potassium channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. The pacemaker function depends upon the interaction between the foregoing plasma membrane ion channels. For example, malfunction of potassium channels may cause life-threatening arrhythmias.
[0006] Atrial fibrillation is the single most important cause of ischaemic stroke in people more than 75 years of age. Atrial fibrillation (AF) is characterized by rapid and irregular activation of the atrium, for example, 400-500 pulses of the atrium muscular wall per minute in humans. The occurrence of AF increases with age, with a prevalence rising from 0.5% of people in their 50s to nearly 10% of the octogenarian population. Several cardiac disorders predispose to AF, including coronary artery disease, pericarditis, mitral valve disease, congenital heart disease, congestive heart failure (CHF), thyrotoxic heart disease and hypertension
[0007] Normally, the heart rate is finely attuned to the body's metabolic needs through physiological control of the cardiac pacemaker function of the SA node, which maintains a rate of about 60 - 90 beats per minute at rest and can fire as rapidly as 170-200 times per minute at peak exercise. During AF, atrial cells fire at rates of 400-500 times per minute.
[0008] It is now accepted that the effect of the magnetic field on an excitable cell's membrane works through influencing the kinetics of calcium ions. This happens in the neurons as well as in the cardiac myocytes (cardiac muscle cells), which generate the electrical impulses that control the heart rate. Field intensity and modulation frequency were shown to be important determinants in weak magnetic fields causing cellular Ca 2+ efflux. The Ca 2+ channel modifies other ion transporters, such as the potassium and sodium channels.
[0009] Studies on animal neurons showed that 86% of the magnetically sensitive cells were inhibited by a weak magnetic field and 14% were excited. Both effects resulted from the movements of Ca 2+ ions at the cell membrane (Azanza and del Moral, 1988). It is known that outward immigration of K + ions through channels opened by Ca 2+ fluctuations brings forth hyperpolarization of the cells wherever they exist. This is followed by efflux of the K + ions triggered by the inside shift of Ca 2+ , which may activate the cell action potential (Meech, 1978).
[0010] Thus magnetic fields induce movements of Ca 2+ ions across the cell membrane, which affects the shifts of K + ions through openings in their membrane channels. The cell may become either inhibited or excited, depending on its inherent properties and most probably also depending on the specific pattern of weak magnetic field (WMF) stimulation.
[0011] Among the diverse excitable cells within the heart are the highly specialized pacemaker cells (in the SA node and the AV node, which have spontaneous depolarization due to slow outward efflux of K + ions, until reaching the threshold of excitation). Atrial cells, and ventricular cells, all have different electrophysiological properties, yet all possess Ca 2+ channels (in addition to Na + and K + channels). But, in a pathological state, all may exhibit an automatic excitability of their own to fire rapidly or irregularly, causing cardiac arrhythmias. This is one mechanism of cardiac arrhythmia.
[0012] A weak electromagnetic field (as weak as is still capable of affecting the flux of Ca 2+ ions across the cell membranes) can ignite a self-propagated process of Ca 2+ , K + and Na + ion shifts. It depends on the modes of WMF stimulation (frequency, intensity and configuration) and/or an additional external intervention (such as the application of drugs), to determine if the cell will discharge following its excitation or will be further inhibited. It is known from in vitro experiments that weak magnetic fields (VWMF) can induce activation, reactivation and inhibition of the excitable cells. Weak magnetic fields can have a negative cronotropic effect on cardiac pacemaker cells and can be used continuously or intermittently to alleviate atrial fibrillation. The effect of WMF to promote calcium efflux from atrial and myocardial cells is of utmost importance in arresting the deterioration observed with patients suffering from atrial fibrillation.
[0013] Accordingly, there is a need for systems and methods for treating cardiac arrhythmias using weak electromagnetic fields.
SUMMARY
[0014] The subject matter disclosed herein is directed to a method and an apparatus for monitoring a patient's cardiovascular system and, upon detecting an arrhythmia, applying weak (i.e., 10 picotesla to 25 nanotesla) electromagnetic fields that induce effects to ameliorate the defective cardiac performance. The apparatus comprises an electromagnetic resynchronization (EMR) device, which may optionally be coupled to a defibrillator, which can be activated by the EMR device in the event that ventricular fibrillation is detected. As described below, the EMR device comprises an ECG monitoring system and an electromagnetic field generator.
[0015] In accordance with embodiments disclosed herein, the ECG monitor/analyzer is programmed to issue an activation signal in response to detection of a cardiac arrhythmia (e.g., atrial fibrillation and ventricular tachycardia); and the electromagnetic field generator is programmed to apply a pulsed low-intensity, low-frequency magnetic field to a patient's heart (including, in particular, the SA node) in response to the activation signal from the ECG monitor/analyzer. The activation signal is encoded to include information or a characteristic that indicates which cardiac arrhythmia has been detected by the ECG monitor/analyzer. It should be appreciated that the system and methodology disclosed herein may be adapted to treat cardiac arrhythmias other than atrial fibrillation and ventricular tachycardia.
[0016] The electromagnetic field generator can be programmed to generate a first pulsed low-intensity magnetic field having a peak intensity in a first peak intensity range and a frequency in a first frequency range in response to a first activation signal from the ECG monitor/analyzer indicating that an atrial fibrillation event is occurring. In addition, the electromagnetic field generator can be programmed to generate a second pulsed low-intensity magnetic field having a peak intensity in a second peak intensity range and a frequency in a second frequency range in response to a second activation signal from the ECG monitor/analyzer indicating that a ventricular tachycardia event is occurring. This principle of operation can be extrapolated to encompass the design of further alternative magnetic field generation protocols for other types or sub-types of arrhythmia. A set of protocols may have different (yet overlapping) pulsed magnetic field peak intensity ranges and different (yet overlapping) pulsed magnetic field frequency ranges.
[0017] In accordance with embodiments disclosed herein, the electromagnetic field generator comprises coils which are placed in proximity to the patient's heart. The magnetic field generator is programmed to produce a pulsed electromagnetic field, preferably synchronized with the cardiac cycle. The pulsed electromagnetic field will have a peak intensity and a frequency appropriate for resynchronizing pathological/non-synchronized cells (e.g., cardiac cells, cardiac myocytes), which peak intensity and frequency (as previously stated) may fall in respective ranges which are dependent on which cardiac arrhythmia has been detected.
[0018] In accordance with further embodiments, the magnetic wave generator can be programmed to produce, in succession, pulsed electromagnetic fields having different frequencies. The ECG monitor/analyzer would monitor the resulting ECG data and analyze which frequency produced the optimum response from the patient. The ability to scan the frequencies in the frequency range applicable to the cardiac arrhythmia which has been detected allows the system to determine an optimum frequency. The electromagnetic wave generator would then supply pulsed electric current to the coil array at this optimum frequency, maintaining this frequency for a longer period of time.
[0019] In addition, research has suggested that an alternating magnetic field may influence the mechanical vibration of the myocardium cell membranes, and thus might influence the conductivity of ions through the membrane. Influence means not only intensity (the number of ions going through) but the duration the channel is open. Thus as a non-limiting example, the EMR device may be triggered and gated to deliver energy during part of the ECG cycle; for example, only during the QRS period (about 80 millisecond, which would be only about two cycles of EMR pulsed current depending on the frequency.
[0020] The EMR device disclosed herein has the capability to resynchronize the cardiac cells by shortening the action potential duration via opening of potassium ion channels on the cell membranes. This EMR device has no effect on normal, synchronized cells. The EMR device works mostly on pathological/non-synchronized cells to gradually resynchronize all non-synchronized cells. Thus, compared with a defibrillator that provides a high-voltage, abrupt energy to cease the arrhythmia, the EMR device accomplishes the same, but with no effect on normal cells, thereby minimizing the overall damage to the human body. It is a resynchronization device intended for non-life-threatening cardiac arrhythmias. Therefore, it is not employed in cases of ventricular fibrillation. The EMR device can be a stand-alone device operated by the patient. It can be operated by a physician, in ambulances, physician's clinics, hospitals. It can also be implanted into the patient in a miniaturized configuration.
[0021] A mode of operation for the overall system may be as follows: Electrocardiographic monitoring is utilized to detect cardiac arrhythmia in a patient. Once cardiac arrhythmia has been detected, an ECG monitor/analyzer will signal/switch-on the electromagnetic field generator for several minutes (e.g., 10 to 60 minutes). The electromagnetic field generator will deliver a low-frequency (i.e., 2 to 60 Hertz) electromagnetic field having a peak magnetic field strength (in the volume of space occupied by the SA node of the patient's heart) in the range of 10 nanotesla to 900 picoteslas. The ECG monitor/analyzer will detect once the arrhythmia has ceased and signal the electromagnetic field generator to stop. If the arrhythmia has not ceased, the ECG monitor/analyzer will signal the electromagnetic field generator to change frequency (±5 Hz) for another session. If during the second therapeutic session, the arrhythmia still does not cease, the ECG monitor/analyzer will signal the patient to see his doctor or change the therapeutic routine.
[0022] The above-described EMR device can detect the arrhythmia as soon as it starts and then apply an electromagnetic field to the patient's chest without delay, not shocking him as a regular defibrillator does, but rather, by applying this unnoticed electromagnetic field, suppress the arrhythmia as soon as it is detected. The EMR device is comfortable, easy to operate, customizable, and financially affordable and can be used as a long-term (months) Holter monitor to follow up the patient. The system optionally (but preferably) includes a regular defibrillator in case the patient's heart experiences ventricular fibrillation (which is a life-threatening event). In that event, the ECG monitor/analyzer will send an activation signal to the defibrillator, which will initiate the delivery of an electric shock. It will not be necessary in most of the applications to attach the defibrillator pads to the patient, only in cases when the physician anticipates such an event occurring with a specific patient.
[0023] In addition, the system includes an ECG and event recorder, which will store all of the patient's ECGs and the initiation and cessation times for the application of the EMR or the defibrillator.
[0024] Other aspects and further details of the systems and methods for treating cardiac arrhythmias generally described above are disclosed below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a diagram showing the configuration of an apparatus treating cardiac arrhythmia in accordance with one embodiment.
[0026] FIG. 2 is a block diagram representing circuitry incorporated in a non-invasive electromagnetic resynchronization device in accordance with another embodiment.
[0027] Reference will hereinafter be made to the drawings in which similar elements in different drawings bear the same reference numerals.
DETAILED DESCRIPTION
[0028] FIG. 1 shows the configuration of an apparatus for treating cardiac arrhythmia in accordance with one embodiment. This apparatus comprises an electromagnetic resynchronization (EMR) device (to be described in detail hereinafter) and a defibrillator 18 . The EMR device, in turn, comprises an ECG monitoring system (items 8 , 10 and 14 in FIG. 1 ) and an electromagnetic field generator (items 2 , 4 , 6 , 12 , 22 ).
[0029] The ECG monitoring system comprises a plurality of regular ECG electrodes 14 , which are connected via electrode wires to an ECG amplifier, monitor and analyzer 8 . This unit has in it the hardware and software to amplify and digitize the ECG signal picked up from the patient's body, and apply algorithms to detect and identify the different arrhythmias (e.g., atrial fibrillation, atrial flutter, ventricular tachycardia). The raw ECG data, along with data representing the results of ECG analysis, as well as event data representing the interpreted arrhythmias are stored continuously in a digital data storage device 10 . This data is available for retrieval by a play back system to analyze a patient's ECG output. The ECG monitoring system can be programmed with the capability to determine the type of arrhythmia which is afflicting the patient.
[0030] The ECG amplifier, monitor and analyzer 8 will produce a logical output which is a function of the type of arrhythmia detected: +1 volt for atrial fibrillation or atrial flutter; 0 volt for ventricular tachycardia; and −1 volt for ventricular fibrillation. That logical output is input to a logic-level detection circuit 12 of the electromagnetic field generator. The logic-level detection circuit 12 detects the logic level of the incoming signal and outputs an activation signal to one of three devices in dependence on the detected logic level. If the logic level is +1 volt, the logic-level detection circuit 12 outputs an activation signal to an atrial fibrillation program generator 2 . If the logic level is 0 volt, the logic-level detection circuit 12 outputs an activation signal to a ventricular tachycardia program generator 4 . If the logic level is −1 volt, the logic-level detection circuit 12 outputs an activation signal to the defibrillator 18 .
[0031] In response to an activation signal from the logic-level detection circuit 12 , the atrial fibrillation program generator 2 sends pulses of electrical current to the coil or coil array 22 via OR gate 6 , which pulses cause the coil or coil array 22 to produce a low-intensity magnetic field having a peak intensity in a first peak intensity range and a frequency in a first frequency range, which ranges are selected based on results of clinical treatment of atrial fibrillation. The electromagnetic field produced should have a frequency in a range of 5 to 22 Hz (inclusive) and a peak strength or intensity in a range of 10 picotesla to 10 nanotesla (inclusive) at the target location inside the patient's heart.
[0032] In response to an activation signal from the logic-level detection circuit 12 , the ventricular tachycardia program generator 4 sends pulses of electrical current to the coil or coil array 22 via OR gate 6 , which pulses cause the coil or coil array 22 to produce a low-intensity magnetic field having a peak intensity in a second peak intensity range and a frequency in a second frequency range which ranges are selected based on results of clinical treatment of ventricular tachycardia. The electromagnetic field produced by the ventricular tachycardia program generator 4 preferably has a frequency in a range of 10 to 60 Hz (inclusive) and a peak strength or intensity in a range of 900 picotesla to 25 nanotesla (inclusive) at the target location inside the patient's heart.
[0033] In response to an activation signal from the logic-level detection circuit 12 , the defibrillator 18 will charge its capacitors to the appropriate pre-set voltage to deliver an electrical shock to the patient's heart via special electrodes incorporated in defibrillator pads 20 (shown attached to the patient in FIG. 1 ). When the defibrillator 18 is triggered, the system will produce an alarm signal (i.e., visual or audible) and a prerecorded voice message announcing that the patient is going to receive a defibrillator electrical shock. This system has also a manual operating button to be operated by skilled emergency teams to enable the delivery of an electrical shock if needed and the patient is unconscious. The success of a resuscitation from a sudden cardiac arrest depends on the time elapsed since the heart stopped pumping blood efficiently: more than 5 minutes means brain damage, more than 10 minutes means certain death. The regular defibrillator can save a patient's life if the resuscitation response time is short enough.
[0034] The system shown in FIG. 1 can be set-up and operated in the following manner (not necessarily in the order in which the steps are listed):
[0035] (1) The ECG electrodes 14 are attached to the patient's body.
[0036] (2) An EMR pad, incorporating a coil or coil array 22 , is attached to the patient's chest as shown in FIG. 1 .
[0037] (3) If needed, the defibrillator pads 20 are attached to the patient's body.
[0038] (4) An electrical cable from the ECG amplifier. monitor and analyzer 8 is connected to the ECG electrodes 14 so that the former can receive ECG signals from the patient.
[0039] (5) An electrical cable from the electromagnetic wave generator is connected to the coil or coil array 22 for delivery of pulsed electric current from one of the program generators 2 or 4 to the coil(s).
[0040] (6) If needed, an electrical cable from the defibrillator 18 is connected to the electrodes incorporated in pads 20 .
[0041] (7) Operation of the ECG monitor and analyzer 8 is started. The analyzer has a display screen. The operator checks whether the ECG signal being displayed and recorded is clear. As soon as the operator has started the unit, the ECG data is stored in the ECG and event storage device 10 .
[0042] (8) As explained in more detail below, the ECG monitor and analyzer 8 monitors the incoming ECG data and determines whether the ECG data indicates the occurrence of a cardiac event, such as atrial fibrillation, ventricular tachycardia or ventricular fibrillation. Upon determining that the patient is suffering from one of these conditions, the ECG monitor and analyzer 8 outputs a signal (+1 volt for atrial fibrillation, 0 volt for ventricular tachycardia, and −1 volt for ventricular fibrillation) to logic-level detection circuit 12 , which in turn will send a triggering pulse to the appropriate program generator (the atrial fibrillation program generator 2 or the ventricular tachycardia program generator 4 ) or to the defibrillator 18 .
[0043] (9) In response to an activation signal from the ECG monitor/analyzer 8 indicating that an atrial fibrillation event is occurring, the atrial fibrillation program generator 2 of the electromagnetic wave generator will generate a pulsed electric current that causes the coil or coil array 22 to generate a pulsed low-intensity magnetic field having a peak intensity in a first peak intensity range and a frequency in a first frequency range. In response to an activation signal from the ECG monitor/analyzer 8 indicating that a ventricular tachycardia event is occurring, the ventricular tachycardia program generator 2 of the electromagnetic wave generator will generate a pulsed electric current that causes the coil or coil array 22 to generate a pulsed low-intensity magnetic field having a peak intensity in a second peak intensity range and a frequency in a second frequency range. The first and second ranges, for each parameter, may overlap. In either case, the OR gate 6 will deliver the pulsed electric current to the coil or coil array 22 to initiate the beneficial effect of the applied electromagnetic field.
[0044] (10) The ECG monitor/analyzer 8 will detect once the arrhythmia has ceased and signal the electromagnetic field generator to stop. If the arrhythmia has not ceased, the ECG monitor/analyzer will signal the electromagnetic field generator to change frequency (±5 Hz) for another session. If during the second therapeutic session, the arrhythmia still does not cease, the ECG monitor/analyzer will signal the patient to see his doctor or change the therapeutic routine.
[0045] (11) in case that, following the initiation of the EMR activity, the patient's heart transitions into ventricular fibrillation, the defibrillator is instructed to deliver an electric shock.
[0046] The atrial fibrillation program generator 2 and ventricular tachycardia program generator 4 may comprise separate processors or a single processor that executes respective software modules. The ECG monitor and analyzer 8 may comprise a separate processor capable of executing commercially available programs designed to detect the occurrence of the cardiac conditions of interest. Alternatively, the program generators and the ECG monitor/analyzer may be embodied as one computer or processor that hosts the various ECG analysis and field generation programs.
[0047] The ECG and event storage device 10 (which may also comprise a separate processor) provides the ability to play back the ECG signals received and analyzed by the monitor/analyzer 8 . The ECG and event storage device 10 will also record the time and date each time the EMR device or the defibrillator is triggered and what information was sent to the logic-level detection circuit 12 .
[0048] FIG. 2 shows the circuitry of a battery-powered integrated EMR unit in accordance with an alternative embodiment, which unit can be programmed to perform all of the functions of the ECG monitor/analyzer and the electromagnetic field generator shown in FIG. 1 . This device can be used by humans as a non-invasive pacemaker to suppress arrhythmia. This EMR unit can be lightweight and wearable by a cardiac patient. In accordance with this alternative embodiment, the EMR unit can communicate with a separate defibrillator in the event that the EMR therapy induces ventricular fibrillation.
[0049] Referring to FIG. 2 , the integrated EMR unit comprises a microcontroller unit (MCU) 58 having an ND input coupled to at least one ECG electrode 14 attached to the chest of a patient. The microcontroller 58 may be programmed with ECG analysis software for detecting predetermined points on the ECG waveforms acquired by the ECG electrode 14 . The microcontroller 58 incorporates non-volatile memory (e.g., battery-powered memory, flash memory or other non-volatile memory technology) for storing also waveform/protocol parameters and other data received from a master or host computer. Such waveform/protocol parameters may include some or all of the following: gain, amplitude, frequency, waveshape, duration of treatment, time of treatment, number of times a treatment may be repeated, and other relevant functions, such as amplitude modulation, frequency modulation and phase modulation. These functions may be programmed to depend on the results of the ECG analysis. Alternatively, a microcomputer or microprocessor having similar functionality can be used.
[0050] The battery-powered unit shown in FIG. 2 further comprises an RS232C communications channel by means of which waveform parameters and treatment protocol data can be loaded into the microcontroller from a computer. The channel comprises serial communication RS232C isolated interface 66 and an RS232C 9-pin connector 68 .
[0051] The microcontroller 58 processes the loaded treatment parameters and outputs a digital signal representing a waveform having a desired frequency and shape for driving the coils 22 of the magnetic field transducer. A digital-to-analog (D/A) converter 60 converts the digital signals output by the microcontroller 58 into an analog signal having the desired frequency and waveshape. The microcontroller 58 also outputs a digital value representing a setting to a digital potentiometer 62 . The function of the digital potentiometer 62 is to adjust the level of the treatment signal, since the D/A converter 60 is always giving full amplitude. The output of the D/A converter 60 and the digital potentiometer 62 form the input signal to the amplifier assembly 64 , the output of which is the current applied to the coils 22 .
[0052] The microcontroller 58 outputs the digital waveform signals in accordance with the stored treatment protocol data. For example, the treatment protocol may comprise a single continuous treatment or a plurality of treatment cycles separated by quiescent intervals or rest periods.
[0053] Still referring to FIG. 2 , the microcontroller 58 is powered by a battery or batteries 44 . The voltage from the battery is supplied to the microcontroller 58 via a voltage stabilizer/on-off control circuit or chip 46 . The voltage supplied by the battery is stabilized by the voltage stabilizer. The on-off control portion of chip 46 receives a control signal from the microcontroller 58 . The treatment device can turn itself off by command from the microcontroller. The output of the analog chain (i.e., the D/A converter 60 , the digital potentiometer 62 and the amplifier assembly 64 ) is connected into an ND input of the microcontroller 58 to enable autotest of the proper operation of that subsystem. A Start-On pushbutton 50 is provided to turn the system on (after it is shut down). An Off pushbutton 52 is also provided for shutting down the system at any time. More precisely, the microcontroller 58 is programmed to send an Off command to chip 46 in response to pushbutton 52 being depressed. Optionally, the microcontroller can be programmed to take some other action in response to depression of pushbutton 52 , in which case the latter could serve as a function switch in certain situations.
[0054] Still referring to FIG. 2 , numeral 48 indicates a low-voltage sense circuit that outputs an analog signal proportional to the current battery voltage to an input of the microcontroller 58 . The microcontroller 58 incorporates an ND converter that converts the analog signal to a digital value. That digital value is compared to a stored threshold value. When the battery voltage falls to a level corresponding to the stored threshold value, the microcontroller causes the red LED 54 to blink, indicating that the battery needs to be replaced. The red LED 54 is turned on as long as the EMR device is activated. A green LED 56 is activated whenever the speaker is used and blinks when treatment is being performed. The green LED lights continuously for one minute after the end of treatment whenever number of available treatments remaining is either one or two.
[0055] The waveform parameters and treatment protocol data may be fed to the microcontroller 58 via the RS232C interface. Alternative communications channels can be employed. All parameters and protocol data are stored in a central computer and loaded into microcontroller 58 either directly or via a PC computer connected to the treatment device. The microcontroller 58 can store any desired waveform by receiving a series of values that can be repeatedly transmitted as an amplitude and time interval as selected by data transferred from the master computer. Alternatively, the microcontroller can have an internal algorithm to generate a waveform of the desired shape, amplitude and frequency to be supplied to the coils.
[0056] In accordance with one implementation, the ECG analysis software loaded into the microcontroller 58 analyzes the ECG data from the ECG electrode and when a cardiac arrhythmia event is detected, generates a command which enables software for generating the appropriate pulsed low-intensity magnetic field. More specifically, the microcontroller 58 can be programmed to generate: (a) a first pulsed low-intensity magnetic field having a peak intensity in a first peak intensity range and a frequency in a first frequency range in response to detection of an atrial fibrillation event; or (2) second pulsed low-intensity magnetic field having a peak intensity in a second peak intensity range and a frequency in a second frequency range in response to detection of a ventricular tachycardia event.
[0057] The most common cardiac arrhythmia, atrial fibrillation, occurs when the normal electrical impulses that are generated by the SA node are overwhelmed by disorganized electrical impulses in the atria. These disorganized impulses cause the muscles of the upper chambers of the heart to quiver (fibrillate) and this leads to the conduction of irregular impulses to the ventricles. On an ECG there are two major characteristics that identify atrial fibrillation: (1) No P-waves before the QRS on the ECG. This is because there are no coordinated atrial contractions. (2) The heart rate will be irregular. Irregular impulses that the ventricles are receiving cause the irregular heart rate. When the heart rate is extremely rapid, it may be difficult to determine if the rate is irregular, and the absence of P-waves will be the best indicator of atrial fibrillation.
[0058] Previous algorithms have relied upon tracking either the absence of a type of electrical activity in the heart known as the P-wave, or the variability in the timing of the contraction of the ventricle (which produces the tall spikes on an ECG tracing). While absence of P-wave fluctuations is the most telling barometer for atrial fibrillation, motion and noise artifacts can result in atrial fibrillation going undetected.
[0059] The system disclosed herein will use a commercially available diagnostic software module for detecting atrial fibrillation and atrial flutter. One known software program, written in MATLAB, can detect portions of a patient's electrocardiogram that have characteristics of atrial fibrillation or atrial flutter. This is achieved by using the RR-intervals of the ECG data. Atrial fibrillation detection can be based on statistical techniques, such as root mean squares of successive differences, turning points ratio and Shannon entropy. For atrial flutter detection, a time-frequency analysis of the patient data can be implemented.
[0060] Tachycardia/tachyarrhythmia is defined as a rhythm with a heart rate greater than 100 bpm. An unstable tachycardia exists when cardiac output is reduced to the point of causing serious signs and symptoms. Serious signs and symptoms commonly seen with unstable tachycardia are: chest pain, signs of shock, shortness of breath, altered mental status, weakness, fatigue, and syncope. The system disclosed herein will use a commercially available diagnostic software module for detecting tachycardia.
[0061] While apparatus for treating cardiac arrhythmias have been described with reference to various embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the teachings herein. In addition, many modifications may be made to adapt the teachings herein to a particular situation without departing from the scope thereof.
[0062] As used in the claims, the term “computer system” should be construed broadly to encompass a system having at least one computer or processor, and which may have multiple computers or processors that communicate through a network or bus. As used in the preceding sentence, the terms “computer” and “processor” both refer to devices comprising a processing unit (e.g., a central processing unit) and some form of memory (i.e., computer-readable medium) for storing a program which is readable by the processing unit.
[0063] The method claims set forth hereinafter should not be construed to require that the steps recited therein be performed in alphabetical order (alphabetical ordering in the claims is used solely for the purpose of referencing previously recited steps) or in the order in which they are recited. Nor should they be construed to exclude any portions of two or more steps being performed concurrently or alternatingly. | A method and an apparatus for the treatment of cardiac arrhythmias using a weak pulsed magnetic field. A transducer that emits electromagnetic radiation of a prescribed frequency and peak intensity is placed on the patient's chest and, as a result, the weak electromagnetic field can cause activation, reactivation, inhibition or remodeling of electrophysiological change in cardiac tissue in an irradiated heart. This treatment method has wide application for use in patients who experience cardiac arrhythmia. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser. No. 11/862,628, filed on Sep. 27, 2007, now U.S. Pat. No. 8,123,523, which is a Continuation-In-Part of U.S. application Ser. No. 11/189,193, filed on Jul. 26, 2005, now U.S. Pat. No. 7,422,433, and a Continuation-In-Part of U.S. application Ser. No. 11/682,927 filed on Mar. 7, 2007, now abandoned, all of which are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The disclosure relates generally to dental instruments and, more specifically, to prophy angles and adapters for use with prophy angles.
[0004] 2. Description of the Related Art
[0005] Dental prophylaxis angles, generally referred to as “prophy angles,” are commonly used dental instruments for providing rotation for dental tools such as brushes, prophy cups, or other receptacles used in cleaning/polishing teeth. Referring to FIGS. 1A and 1B , a prophy angle 10 can include an inner housing 16 having an outer housing 18 and a rotor 14 extending at approximately a 90° angle to the neck 18 , which increases the ability of a dentist to reach various surfaces of the teeth of a patient. A drive shaft or rotating member 12 can be located within the housing 16 and attached to a driven gear 20 in the head of the prophy angle. Prophy angles 10 are generally affixed to an adapter or hand piece (not shown), which connects the prophy angle to a drive source (not shown), thereby enabling a rotating motion of the rotating member 12 and driven gear 20 of the prophy angle and any affixed dental tool.
[0006] Prophy angles 10 are commonly manufactured from lightweight plastic to make them disposable, thereby increasing overall sterility in the dental environment. Being disposable, there is a desire to reduce the cost and/or complexity of assembly of the prophy angle 10 while, at the same time, maintaining the functionality and safety of the prophy angle 10 .
[0007] One technique to reduce cost is to limit the number of separate pieces in the assembly of the prophy angle 10 . For example, the prophy angle in FIG. 1B includes four separate pieces: (i) the rotating member 12 , (ii) the inner housing 16 , (iii) the outer housing 18 , (iv) and the rotor 14 . A reduced number of separate pieces requires less molds to form the separate pieces and less assembly of the pieces. However, by reducing the numbers of separate pieces, each individual and separate piece typically becomes more complex as each piece can take on more functions.
[0008] One of the issues preventing further reduction in the number of pieces in a disposable prophy angle 10 relates to the ability of the prophy angle 10 to maintain and restrain the position of the rotor 14 within the outer housing 16 . Since the rotor 14 both engages the rotating member 12 and rotates at a head speed, the position of the rotor 14 within the outer housing 16 is critical to maintain a proper engagement between the rotating member and the rotor 14 and to prevent the rotor 14 from being unbalanced during rotation. An improperly positioned and/or restrained rotor 14 can cause failure of the prophy angle 10 and/or causes damage to the adaptor, the dental professional and/or the patient. There is, therefore, a need for an improved prophy angle that reduces the number of pieces in the prophy angle yet while maintaining the positional stability of the rotor within the outer housing.
BRIEF SUMMARY OF THE INVENTION
[0009] Embodiments of the invention provide a novel and non-obvious dental prophy angle. The dental prophy angle includes a housing and a rotor. The housing defines a first bore and a second bore in communication with the first bore, and rotor is disposed within the second bore. The rotor includes a gearing system, and rotor includes a lock having a lock channel configured to receive a tip of a drive shaft. The housing includes a lock receiver for receiving the lock, and the lock receiver permits rotation of the lock within the lock receiver and restrains linear movement of the lock in a direction substantially parallel to a rotational axis of the rotor. The lock includes a upper portion and a lower portion, and the upper portion and the lower portion define the channel. A seal is positioned between the housing and the rotor, and the second bore is adapted to removably receive the drive shaft.
[0010] In another embodiment of the invention, a dental adapter for a prophy angle includes a nose, a body connected to the nose, a drive shaft extending from the nose, and a slidable sleeve extending over at least a portion of the drive shaft. The drive shaft includes a gear. In a retracted position of the slidable sleeve, the gear is revealed, and in an extended position of the slidable sleeve, the slidable sleeve at least partially covers the gear. The drive shaft is linear movable relative to the body along a line substantially parallel to a longitudinal axis of the drive shaft. A resilient member is connected to the drive shaft for biasing the drive shaft along the line. The drive shaft includes a tip extending from a distal end of the drive shaft, and the tip is adapted to engage a rotor of the prophy angle. The adapter includes a drive source connected to the drive shaft by a coupler.
[0011] In yet another embodiment of the invention, a dental tool includes a prophy angle and an adapter for receiving and driving the prophy angle. The prophy angle includes a housing and a rotor, and the adapter includes a body, a drive shaft for driving the rotor, a slidable sleeve, and a nose for receiving the prophy angle. The rotor includes a lock having a lock channel configured to receive a tip of a drive shaft. The engagement of the lock channel and the tip restrains movement of the rotor lock in a direction towards the drive shaft and restrains movement of the lock relative to the tip in a direction substantially parallel to a rotational axis of the rotor. In a retracted position of the slidable sleeve, a gear of the drive shaft is revealed, and in an extended position of the slidable sleeve, the slidable sleeve at least partially covers the gear. The rotor includes a rotor conduit having an inlet and an outlet, the housing includes a housing conduit having an inlet and an outlet, and the adapter includes a supply conduit having an outlet. The outlet of the housing conduit is connected to the inlet of the rotor conduit, and the outlet of the supply conduit is releaseably connected to the inlet of the housing conduit.
[0012] Additional aspects of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The aspects of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0013] The accompanying drawings, which are incorporated in and constitute part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the invention. The embodiments illustrated herein are presently preferred, it being understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown, wherein:
[0014] FIGS. 1A and 1B are, respectively, a perspective view and a side cross-sectional view of a prophy angle;
[0015] FIGS. 2A and 2B are, respectively, side and cross-sectional side views of the rotor;
[0016] FIG. 3 is a cross-sectional side view of a drive shaft engaging the rotor, in accordance with the inventive arrangements;
[0017] FIGS. 4A , 4 B, and 4 C are, respectively, cross-sectional side, rear, and top views of the housing;
[0018] FIGS. 5A and 5B are, respectively, exploded and assembled cross-sectional side views of a housing and a rotor in accordance with the inventive arrangements;
[0019] FIGS. 6A and 6B are, respectively, exploded and assembled cross-sectional views of a prophy angle and adapter in accordance with the inventive arrangements;
[0020] FIGS. 7A and 7B are cross-sectional side views of the adapter with a sleeve, respectively, in extended and retracted positions, in accordance with the inventive arrangements; and
[0021] FIG. 8 is a cross-sectional side view of a portion of the adapter and the drive shaft.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Referring to FIGS. 5A-5B and 6 A- 6 B, a prophy angle 100 and adaptor 400 are disclosed. The prophy angle 100 includes a rotor 200 positioned within a housing 110 . The prophy angle 100 is adapted to fit over a drive shaft 350 and engage the adaptor 400 , and in certain aspects, the drive shaft 350 is part of the adaptor 400 . In operation, the prophy angle 100 may be inserted onto and removed from the adaptor 400 so as to be considered disposable.
[0023] Referring to FIGS. 2A and 2B , the rotor 200 includes an attachment device 210 to which an attachment, such as a prophy cup (not shown), can be attached. Many types of attachment devices 210 are known as capable of connecting an attachment to a rotor 200 , and the rotor 200 is not limited as to a particular type of attachment device 210 so capable. For example, the attachment device 210 may be a button. Although the button is not limited as to a specific shape or orientation, the button 210 may include additional protrusions 215 to accommodate a specific prophy cup. Another example of an attachment device 210 is a prophy cup with a threaded post molded inside.
[0024] The rotor 200 may include a radially-extending flange 220 . In certain aspects of the rotor 200 , the radially-extending flange 220 is sized to extend beyond an opening within the housing 110 (see FIG. 5B ). The flange 220 of the rotor 200 may also be positioned over the opening to the second bore 114 . In so doing, the flange 220 reduces the incidence of debris from the prophy cup or other attachment from entering the interior of the housing 110 , which could potentially interfere with the subsequent operation of the prophy angle 100 .
[0025] The rotor 200 , while positioned within the second bore 114 (see FIGS. 5A and 5B ), creates a seal 280 between the rotor 200 and an inner surface 134 of the second bore 114 . Creating a seal between two surfaces is well known in the art, and any manner of creating a seal is acceptable for use with the prophy angle 100 . However, in certain aspects of the prophy angle 100 , one of the rotor 200 and the inner surface 134 of the second bore 114 includes an annular extension 282 and the other of the rotor 200 and the inner surface 134 includes an annular groove 182 . Upon the rotor 200 being positioned within the second bore 114 , the rotor 200 and/or the housing 110 deforms so as to permit the annular extension 282 to be inserted into the annular groove 182 and create the seal 280 . The seal 280 also acts to restrain linear movement of the rotor 200 relative to the housing 110 . Although not limited in this manner, upon the assembly of the rotor 200 with the housing 110 , a lubricant may be added to ease the positioning of the rotor 200 within the housing 110 and/or reduce friction upon the rotor 200 rotating within the housing 110 during operation.
[0026] The rotor 200 includes a gearing system 230 to drive the rotation of the rotor 200 within the housing 110 . Many types of gearing systems 230 are known capable of driving the rotation of the rotor 200 within the housing 110 , and the rotor 200 is not limited as to a particular type of gearing system 230 so capable. However, in certain aspects of the rotor 200 , the gearing system 230 includes one gear of a bevel gear set. As will be described in more detail below, the other gear 352 of the bevel gear set is attached to the drive shaft 350 (see FIG. 3 ) and is positionable within the housing 110 .
[0027] The rotor 200 also includes a lock 240 . The lock 240 interacts with a lock receiver 120 (see FIGS. 4A-4C ) of the housing 110 to restrain linear movement of the rotor 200 within the housing 110 yet allow rotation of the rotor 200 within the housing 110 . In particular, the lock receiver 120 can restrain linear movement in a direction substantially parallel to a rotational axis of the rotor 200 . In certain aspects of the lock 240 , the lock 240 has a partially-curved outer profile 242 . Also, portions of the lock 240 may have a substantially spherical profile 242 taken along a cross-section perpendicular to a longitudinal axis of the rotor 200 . In so doing, the lock 240 interacts with the lock receiver 120 of the housing 110 to allow rotation of the rotor 200 within the housing 110 .
[0028] The rotor 200 may also include a rotor conduit 260 having an inlet 265 and an outlet 270 , and the prophy angle 100 is not limited as to the particular use of the rotor conduit 260 . For example, the rotor conduit 260 may be used to transfer materials (e.g., dentifrice, water) to a working area of the prophy angle 100 . Alternatively, the rotor conduit 260 may be used as part of a system to provide suction to the working area of the prophy angle 100 .
[0029] Referring to FIG. 3 , in certain aspects of the rotor 200 , the lock 240 includes a recessed lock channel 250 for receiving a tip 355 extending from a distal end of a drive shaft 350 . Upon the drive shaft 350 being engaged within the lock 240 , the tip 355 is positioned within the lock channel 250 . While so positioned, engagement between the tip 355 and upper and lower portions 255 U, 255 L of the lock 240 can restrict movement of the lock 240 , respectively, in a downward direction and an upward direction. Moreover, a width of the lock channel 250 between the upper and lower portions 255 ,U 255 L can be dimensioned slightly greater than a diameter of the tip 355 to further restrict movement of the lock 240 relative to the tip 355 and vice versa.
[0030] Although the lock 240 is illustrated as having both an upper portion 255 U and a lower portion 255 L, the lock 240 is not limited in this manner. For example, the lock 240 may only include the lower portion 250 L, which would restrain movement of the lock 240 in the upward direction. The drive shaft 350 also restricts movement of the lock 240 in a direction towards the drive shaft 350 .
[0031] In certain aspects of the rotor 200 , however, the lock 240 includes both an upper portion 255 U and a lower portion 255 L. These two portions 255 U, 255 L, acting together, can restrain rotation of the drive shaft 350 about a specified axis of rotation and position the draft shaft 350 within the specified axis of rotation. The drive shaft 350 typically rotates at a high speed, and any imbalance of the drive shaft 350 can cause the drive shaft 350 to wobble during rotation, which can damage the drive shaft 350 and/or prophy angle 100 and/or cause poor engagement between the drive shaft 350 and the gearing system 230 . However, by constraining the distal end (i.e., the tip 355 ) of the drive shaft 350 with the upper and lower portions 255 U, 255 L of the lock 240 , this wobble, if present, can be reduced.
[0032] A further discussion of engagement of the rotor 200 and the drive shaft 350 and between the rotor and the housing 110 and the configurations thereof is found in related U.S. application Ser. No. 11/189,193, filed on Jul. 26, 2005, incorporated herein by reference in its entirety.
[0033] Referring to FIGS. 4A-4C and 5 A- 5 B, the housing 110 is illustrated. The housing 110 includes a first bore 112 and a second bore 114 . The first bore 112 extends along a longitudinal length of the of housing 110 and is configured to receive the drive shaft 350 (see FIG. 6B ). The second bore 114 communicates with and extends substantially perpendicular from the first bore 112 . The second bore 114 is also configured to receive the rotor 200 . Although not limited in this manner, the housing 110 can be constructed from a variety of available plastics having sufficient rigidity to apply pressure to a patient's teeth, while remaining flexible enough to receive the internal components of the prophy angle.
[0034] The first bore 112 may also be configured to receive the adapter 400 (see FIG. 6B ). Although not limited in this manner, the inner surface 116 of the first bore 112 may define a first shoulder 118 that limits movement of a portion of the adapter 400 past the shoulder 118 . The adapter 400 engaging the first shoulder 118 may also be used to specifically position the adapter 400 and, thus, the drive shaft 350 , within the housing 110 . Other features capable of specifically positioning the adapter 400 within the housing 110 are known and can be used with the present adapter 400 and housing 110 .
[0035] Positioned within the second bore 114 is a lock receiver 120 . The lock receiver 120 receives the lock 240 of the rotor 200 and acts to restrain linear movement of the rotor 200 within the housing 110 yet allow rotation of the rotor 200 within the housing 110 . In certain aspects, the lock receiver 120 includes a plurality of bearing arms 122 positioned within the second bore 114 . The bearing arms 122 may include an upper bearing surface 124 and also a recess 126 on a radially inward-facing surface of the bearing arm 122 . The recess 126 may have a profile configured to receive the lock 240 of the rotor 200 .
[0036] The housing 110 may also include a housing conduit 128 having an outlet 130 that releaseably connects with the inlet 265 of the rotor conduit 260 . The housing conduit 128 also includes an inlet 132 that is configured to be releaseably connected to the adapter 400 .
[0037] Referring specifically to FIGS. 5A and 5B , the prophy angle 100 is assembled by inserting the rotor 200 into the second bore 114 . Upon the rotor 200 being positioned within the second bore 114 of the housing 110 , the lock 140 of the rotor 200 is nested within the lock receiver 120 of the housing 110 . As previously described, upon the lock 140 being nested within the lock receiver 120 , movement of the rotor 200 out of the second bore 114 is restrained. Also, upon insertion of the rotor 200 within the second bore 114 , the seal 280 between the rotor 200 and the inner surface 134 of the second bore 114 engages, which can further restrain movement of the rotor 200 out of the second bore 114 . By restraining movement of the rotor 200 out of the second bore 114 , a user can handle/manipulate the prophy angle 100 with reduced fear that the prophy angle 100 will become unintentionally disassembled.
[0038] Referring to FIGS. 6A and 6B , the prophy angle 100 is shown being assembled with an adapter 400 , and FIGS. 7A and 7B illustrate the adaptor 400 . The adapter 400 , directly or indirectly, provides the rotational movement to the gearing system 230 of the rotor (see FIG. 3 ), and any adapter 400 so capable is acceptable for use with the prophy angle 100 . The adaptor 400 includes a body 410 and a nose 412 , and the nose 412 may be removably attachable to the body 410 . Alternatively, the nose 412 may be integral with the body 410 . The adapter 400 includes a shaft 418 that is connected to a drive shaft 350 via a coupler 435 . The adaptor 400 may also include a supply conduit 430 (see FIGS. 7A and 7B ) that is releaseably connectable to the inlet 132 of the housing conduit 128 .
[0039] An outer portion of the nose 412 may be shaped to mate with the prophy angle 10 . As is known in the art, many types of different types of prophy angles 100 exist that have different mating profiles, and the present adaptor 400 is not limited as to a particular shape of the nose 412 and as to a particular profile of prophy angle 100 with which the nose 412 can mate. However, in a current aspect of the adapter 400 , the nose 412 is a configured as a doriot-style adapter. Depending upon the type of prophy angle 100 , other type of connections devices include, but are not limited to, latch type, 3-ball chuck, attachment ring, push chuck, quick-connect collars, autochucks, E-type (i.e., ISO 3964), DIN 13940, ISO 1797, U-type, NSK type, and Midwest type.
[0040] The shaft 418 is rotated by the drive source 450 . As is known in the art, many different types of drive sources 450 exist and these different drive sources 450 have different configurations for coupling with a rotating member, such as the shaft 418 . In this regard, the present adapter 400 is not limited as to drive source 450 for the adapter 400 . For example, the drive source 450 may be connectable to the adapter 400 . Alternatively, the drive source 450 may be integrated with the adapter 400 . Also, examples of drive sources 450 include electrically-driven and pneumatically-driven motors. A further discussion on adapters 400 and connections between the shaft 418 and either the drive source 450 or between the shaft 418 and the drive shaft 350 (e.g., via the coupler 435 ) is found in related U.S. application Ser. No. 11/682,927 filed on May 7, 2007, incorporated herein by reference in its entirety.
[0041] As illustrated, the drive shaft 350 is a part of the adaptor 400 . However, the drive shaft 350 is not limited in this manner. For example, the drive shaft 350 may be a portion of the prophy angle 100 . In other aspects, the drive shaft 350 is removably attachable to a collet within the adaptor 400 . In so doing, the drive shaft 350 can be replaceable and/or cleaned.
[0042] The adaptor 400 may include a retention device 440 for maintaining a position of the prophy angle 100 on the adaptor 400 and any retention device 440 so capable is acceptable for use with the adaptor 400 . In certain aspects of the adaptor 400 , however, the retention device 440 is a locking pin 442 that is positionable within an opening 142 (see FIGS. 5A-5B ) in the housing 110 of the prophy angle 100 . The locking pin 442 may be resiliently biased such that after the locking pin 442 is depressed, to either allow the prophy angle 100 to be positioned over the adapter 400 or to remove the prophy angle 100 from the adapter 400 , the locking pin 442 returns to an extended position. Upon the locking pin 442 being positioned within the opening 142 , the locking pin 442 prevents removal of the prophy angle 100 from the adaptor 400 .
[0043] Referring to specifically to FIGS. 7A and 7B , a slidable sleeve 460 may be positioned over the drive shaft 350 . The slidable sleeve 460 moves from an extended position ( FIG. 7A ), which conceals the gear 352 of the drive shaft 350 , to an retracted position ( FIG. 7B ), which reveals the gear 352 of the drive shaft 350 . The slidable sleeve 460 is not limited in the manner in which the slidable sleeve 460 moves from the extended position to the retracted position and back again. However, in certain aspects, the slidable sleeve 460 engages a second shoulder 144 (see FIGS. 5A-5B ) of the housing 110 as the slidable sleeve 460 is inserted into the housing 110 , which causes the slidable sleeve 460 to retract relative to the gear 352 of the drive shaft 350 .
[0044] The slidable sleeve 460 may also be connected to a resilient member 464 , such as a spring, which is compressed upon the slidable sleeve 460 is retracted. Upon the slidable sleeve 460 being removed from the housing 110 , the resilient member 464 biases the slidable sleeve 460 into the extended position. In this manner, upon the adapter 400 being completely removed from the housing 110 , even unintentionally, the gear 352 of the drive shaft 350 is not exposed.
[0045] Referring to FIG. 8 , while attached to the adaptor 400 , the drive shaft 350 may be capable of being biased along a line substantially parallel to a longitudinal axis of the drive shaft 350 . Although any technique of enabling the drive shaft 350 to be biased is acceptable for use, similar to the slidable sleeve 460 , the drive shaft 350 may be connected to a second resilient member 468 , such as a spring.
[0046] Upon being inserted into the housing 110 , the drive shaft 350 engages the gearing system 230 , which biases the drive shaft 350 towards the adaptor 400 . The second resilient member 468 , in turn, pushes back against the drive shaft 350 , which ensures proper engagement of the gear 352 of the drive shaft with the gear system 230 of the rotor 200 . The ability of the drive shaft 350 to be biased along the line substantially parallel to the longitudinal axis of the drive shaft 350 gives the drive shaft 350 linear adjustability relative to the body 410 of the adaptor 400 , and this linear adjustability allows for variations in dimensions in the housing 110 , rotor 200 , drive shaft 350 and/or adaptor 400 . | A dental prophy angle includes a housing and a rotor. The dental prophy angle adapter can include a drive shaft with a tip. The drive shaft of the adapter can be coupled to a gear at the same end of the tip with the rotor of the prophy angle being configured to receive the tip. Further, a slidable sleeve can extend over a portion of the drift shaft so that the slidable sleeve becomes automatically retracted upon engaging a shoulder of the housing resulting in the gear of the drive shaft being revealed. | 0 |
RELATED APPLICATIONS
This application claim benefit of U.S. Patent Application Ser. No. 61/217,278, filed May 29, 2009, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to a corral and head gate assembly for use in a livestock trailer and more particularly to such an assembly that is quickly and easily installed or removed.
Livestock corrals are commonplace on farms, ranches and feed lots. Corral assemblies typically include a number of fences, panels or gates all interconnected to form various chutes, runways, capture or loading facilities for livestock. Such corral assemblies are generally permanent structures and are often found built adjacent to barns or other buildings.
It is not uncommon, however, for farmers and ranchers to have widespread fields, pasture land or even feed lots where it is impractical or overly expensive to have a permanent corral system. It is also impractical and unduly expensive to install permanent corral and livestock catching facilities on leased or rented pasture land where the livestock owner might have to leave the permanent corral system as a fixture to the real state upon termination of the lease. Another significant drawback to permanent corral and livestock capturing facilities is that animals have to either be loaded in a transport vehicle and hauled to the facility or otherwise forcibly driven to the permanent structure.
Livestock trailers come in a variety of dimensions ranging in width from five to eight feet and lengths from approximately 12 to approximately 40 feet long. Livestock trailers are very convenient to load and transport animals from and to remote locations. It is common practice to load livestock into transport trailers in fields or pasture land by assembling a temporary corral external the trailer into which the animals are driven, then captured and then loaded on to the trailer. Assembling even a temporary corral for loading livestock into a trailer, however, is time consuming and labor intensive. Moreover, if a single, or very few, animals are to be loaded, it can take substantial time to capture the animal, place it in the trailer and then haul it to a remote location. What is desirable is a portable livestock trailer which includes an internal corral system which allows easy loading, sorting, inspection or working of livestock. However, because livestock trailers are also used for hauling animals for relocation, and any other variety of purposes, a livestock trailer with a dedicated internal corral assembly may be impractical and too expensive for sporadic use. Accordingly, a corral assembly with a livestock catch system which could be quickly installed into a livestock trailer for use and then removed therefrom when not in use would solve several of the identified problems. Such a system would allow a conventional livestock trailer to be retrofit with a corral and livestock catch assembly. Moreover, it would allow the livestock trailer to be used for hauling and transporting animals when the corral and catch assembly is not needed. Finally, such an assembly would allow the user to have an easily transportable and versatile livestock corral for use in remote locations and would preclude the need for multiple fixed corral system.
SUMMARY OF THE INVENTION
The present invention is a new corral assembly and livestock catching device which is removably installed into a livestock trailer. The corral assembly comprises a substantially U-shaped system of cattle panels mounted on rollers. The corral assembly can easily be rolled in to a livestock trailer to form two animal working aisles and a protected internal aisle for the user. A conventional head gate or catch gate is installed on one side of the corral panel assembly and may be hinged for opening. One side of the catch gate can be removably fastened to the rear most portion of the livestock trailer for stability. In a second embodiment of the invention the conventional catch gate is replaced by a squeeze chute of common design which is mounted to one side of the corral assembly. When the corral assembly is in place either the catch gate or the squeeze chute assembly is located near the back of the trailer. Animals to be worked or loaded into the aisle alleyway opposite the catch gate or squeeze chute and are maneuvered toward the front of the trailer, around the bend of the U-shaped corral assembly and down the working aisle of the system. The operator remains in the central aisle and is protected from direct contact with the animals as they are moved about the alleyways. Any number of hinged swing gates can be provided to segregate animals as they are worked through the system. An animal to be worked is captured in the catch gate or squeeze chute assembly and can be directly released exterior the trailer after the work is completed. Because most livestock trailers are provided with side gates, the innovative corral assembly also works well for sorting livestock in to different groups by selectively releasing animals out the trailer side gates into independently corralled areas.
The innovative corral assembly is an unitary device which can be easily rolled into a livestock trailer. It is to be understood that several different sizes of corral assemblies may be provided for use in varying sized trailers. Because the system is unitary and on wheels or other rollers, it does not necessarily have to be attached to the interior of the livestock trailer when installed. It may be preferable, however, to have multiple bracing units that contact the ceiling or sides of the trailer without impeding the travel pathway of the animals. This will add stability to the system and decrease the likelihood of damage to the system by animals during use.
When the internal corral assembly is no longer needed, it is simply rolled out of the livestock trailer and stored until the next use. Installation and use of the assembly does not require any modification to existing livestock trailers and does not cause any damage or undue wear on the livestock trailers.
In one configuration of the inventive device, additional short panels may be used on the sides or the board portion of the corral assembly which can be easily removed to adjust the dimensions of the device.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an embodiment of the corral assembly installed in a trailer.
FIG. 2 is a perspective view of an embodiment of the corral assembly.
FIG. 3 is a partial perspective view of an embodiment of the corral assembly installed in a livestock trailer.
FIG. 4 is a partial perspective view of an embodiment of the corral assembly installed in a livestock trailer.
FIG. 5 is cross-sectional view of an embodiment of the corral assembly installed in a livestock trailer.
FIG. 6 is a partial perspective view of an embodiment of the corral assembly installed into a livestock trailer.
FIG. 7 is a cross-sectional view of an embodiment of the corral assembly installed in a livestock trailer.
FIG. 8 is a perspective view of an embodiment of the corral assembly partially installed in a livestock trailer.
FIG. 9 is a detail perspective view of an embodiment of the corral assembly.
DESCRIPTION OF THE INVENTION
Referring now generally to the drawings, a removable corral assembly is provided for use in a livestock trailer. The corral assembly can be adapted and fit into a livestock trailer having virtually any dimensions. The livestock trailer will have a forward portion connectable to a truck or other towing vehicle and a rearward open end in to which animals are loaded. A pair of opposed sides span between the forward and rearward end of the trailer.
Livestock trailers are generally configured in one of two manners, one for bumper hitch attachment and one for goose neck attachment. It is understood that the inventive device can be used in either type of trailer. Moreover, trailers vary in width between approximately five feet and approximately eight feet wide and can have a length from between approximately 10 feet and over 40 feet. Again, the inventive device can be sized for use in a trailer having any of these dimensions.
Referring now to FIG. 1 a removable corral assembly 102 is shown installed in a livestock trailer 100 . As will be seen more clearly in relation to later figures, corral assembly 102 comprises a first end 104 located adjacent to and across the open rear end 106 of the trailer 100 . In various embodiments of the corral assembly 102 , various gates and chutes are mounted on the first end 104 to control the flow of livestock through the trailer 100 . In the embodiment shown in FIG. 1 , a ramp 108 and gate 110 are provide to control the entry of livestock into the trailer 100 , and a head gate 112 to hold the livestock for processing and to control the release of the livestock from the trailer 100 . The gate 112 may also comprise a squeeze chute or other livestock control device. Other gates or control devices may be provided as are known in the art.
Referring now to FIG. 2 , a perspective view of the corral assembly 102 is shown with the trailer 100 removed from the figure. The dashed lines denote the rough inner volume of the trailer 100 and indicate the location of the corral assembly 102 within that volume when installed therein. The assembly 102 comprises a frame 200 on which other components of the system are supported. The frame 200 defines a central walkway 202 down which workers may move to handle the livestock in the trailer 100 . Frame 200 is comprised of various horizontal frame members 204 and vertical frame members 206 . Frame members 204 and 206 are preferably formed from metal of various kinds, though other materials such as wood may be used if sufficiently light and strong to provide the necessary support for the other components of the assembly 102 . Frame members 204 and 206 may be joined together by welding, bolting or other means of attachment of sufficient strength as are known to those of skill.
Panels 208 are supported by frame 200 and define the livestock path through the trailer 100 . In some embodiments of the corral assembly 102 , panels 208 are formed from rigid fencing material often referred to as livestock panels. Each panel 208 has a frame encompassing a field material. Two common configurations of such panels exist. One type of panel 208 is similar to a farm gate and has spaced apart vertical end poles with a plurality of horizontally spaced bars interposing the end poles, comprising the field material. A second common livestock panel 208 has a rigid rectangular frame with a woven wire comprising the field material. Such panels 208 are often referred to as hog panels. Other embodiments of the panels 208 may incorporate sheets of metal, wood or other suitable material for the field of the panel 208 . Panels 208 of either configuration are generally provided with panel mounts 210 on each end thereof to connect the panel 208 to the frame 200 . Panel mounts 210 are described in more detail in reference to a later figure.
At the first end 104 of the assembly, a gate frame 212 is provided for attaching the ramp 108 , gate 110 , and head gate 112 to the frame 200 . As mentioned above, other configurations of gates and ramps may be provide and attached to frame 200 by gate frame 212 .
In some embodiments of the corral assembly 102 , an end piece 214 is provided to further define a livestock path through the trailer. The end piece 214 comprises a plurality of panels 216 provided to prevent the livestock from getting turned around in the front corners of the trailer. The panels 216 are formed in the same manner and materials as panels 208 . In the embodiment shown in the figure, the end piece 214 comprises three panels 216 pivotally attached to each other at the edges thereof. The end piece 214 may be formed from separate panels place to prevent livestock access to the corners of the trailer 100 , or from more than 3 panels 216 , as may be required in some embodiments.
If the removable corral assembly is to have a fixed dimension for use in a trailer having specific dimensions, each panel 208 can be singular and continuous having no joints and no connectors. It is preferable, however, that multiple panels 208 are used to make up the corral assembly 102 . Further, short panels 218 can be provided which can be used to adjust the overall length or width of the assembly 102 or to use as swing gates to block the livestock path. Similarly, a plurality of swing gates may be provided along any of the panels 208 to span between the panel 208 and the side of the trailer. These swing gates allow animals to be segregated within the aisles for any variety of reasons. An end panel 220 is also provided to define the end of the walkway 202 .
When installed in to the livestock trailer 100 , this assembly 102 creates a substantially u-shaped livestock path 222 around the outside surface of the panels 208 , 218 and 220 and the inside surface of the trailer 100 and panels 216 . Central walkway 202 is formed between the panels 208 and 218 .
In other embodiments, stabilizer bars may optionally be positioned near the top of the frame 200 to span between the upper portion of the frame 200 and the roof or ceiling of the livestock trailer 100 . Additional stabilizer bars may be provided which span between the frame 200 and the sides of the livestock trailer 100 . The stabilizer bars, if provided, diminish the likelihood that livestock will move the assembly 102 within the trailer 100 causing damage to the assembly 102 , the trailer 100 , the worker or themselves.
Referring now to FIG. 3 , a detailed perspective view of the gate frame 212 is depicted. In the embodiment shown in the figure, the gate frame 212 comprises a base 300 . The base 300 is supported by tube member 302 . A plurality of vertical members 304 define the opening of gate frame 212 , and side walls 306 may be provided on one or more of the vertical members 304 to provide, extra strength and prevent inadvertent entry by livestock into the gap between the gate frame 212 and the opening 106 of trailer 100 . Top member 308 connects the top ends of members 304 to each other. In other embodiments of the corral assembly 102 the exact structure of the gate frame 212 may be varied and still be within the scope of the corral assembly disclosure.
In the embodiment of the invention shown in the figures, a catch gate 112 is removably attached to the gate frame 212 by pin hinges 310 mounted on vertical members 304 so that it will be substantially adjacent and aligned with the rear opening 106 of the livestock trailer when the corral assembly 102 is installed. The catch gate 112 will be of conventional manufacture and any number of catch gates are readily available in the marketplace. It is preferred that the catch gate 112 be removably fastened to the gate frame 212 and may be hinged so that it can be selectively opened to allow animals to exit the trailer 100 . This gate frame 212 provides strength and rigidity to the gate 112 and eliminates the need to fasten the gate 112 directly to the livestock trailer 100 . It is should be understood that the orientation and placement of the catch gate 112 can be reversed and attached to the other side of the corral assembly if desired.
An entire squeeze chute assembly, not shown in the figures, may be incorporated into the corral assembly. Similar to the catch gate 112 previously described, squeeze chutes are well known within in the industry and any number of readily available squeeze chutes can be adapted for use with this invention. It is to be generally understood, however, that such a squeeze chute will only properly work in a trailer which is wide enough to accommodate standard squeeze chutes which are usually at least 30 inches wide. Accordingly, in narrow trailers, the width of the central aisle 202 may have to be decreased to accommodate the squeeze chute on one side of the trailer and leave an aisle which is large enough to accommodate livestock on the opposite side of the trailer. This can be achieved by adjusting the panels 208 as described in reference to a later figure.
The opposite end of the gate frame 212 may be provided with a ramp 108 that is pivotally attached to the base 300 , and a swing gate 110 pivotally attached to vertical member 304 . Other configurations may be provided for gates and ramps on the two ends of the gate frame 212 as desired.
Referring now to FIG. 4 , a detailed cut-away view of a portion of the corral assembly 102 is depicted. For purposes of clarity, some elements of the corral assembly have been removed from this view, either in whole or in part.
Two rails 400 are provided for supporting and guiding the frame 200 as it is installed into a trailer 100 . The rails comprise a plate 402 on which the frame 200 rests, and a guide 404 attached to the plate 400 which maintains the position of the frame 200 on the rail 400 . The rails 400 are installed into the trailer 100 prior to the installation of the frame 200 . They are secured along the length of the floor of the trailer 100 , preferably by releaseable means such as bolts. The rails are spaced apart such that the bottom horizontal members 204 of frame 200 rest on the base 402 against the outer side of guide 404 . Once installed the bottom horizontal member 204 may be bolted to the rail 400 by bolt 406 to secure the frame 200 in place during use.
Panels 208 , in the embodiment shown in FIG. 4 , comprise panel members 408 which define the size and shape of panel 208 , and field material 410 which is attached to the panel members 408 to prevent livestock from stepping through or inserting their heads through the panels 208 . As discussed above, the field material 410 may be a wire or mesh panel, or may be sheet material of an appropriate type.
In the embodiment shown in FIG. 4 , panel mount 210 comprises a support pole 412 . In the embodiment shown in the figures, each support pole is positioned adjacent to a vertical frame member 206 . The lower end of support pole 412 comprises a pivot mount 414 . A base support 416 is pivotally attached at a first end to pivot mount 414 . Base support 416 is slidably retained in collar 418 which is itself secured to a bottom frame member 204 of frame 200 . A means for securing base support 416 within collar 418 , such as bolt 420 is provided to allow support 416 to be fixed at a certain position. By removing bolt 420 , sliding support member 416 to a desired position, and reinserting bolt 420 , the position of panels 208 may be adjusted as needed.
The upper end of support pole 412 is provided with a second pivot mount 422 fixedly attached thereto. A pivot mount 424 is also provided on the adjacent vertical frame member 206 . The pivot mount 424 is slidably retained on the vertical frame member 206 , and can be moved up and down and secured along frame member 206 as desired. A panel support member 426 is provided to connect pivot mount 422 to pivot mount 424 . The connections between panel support member 426 and mounts 422 and 424 respectively are pivotal allowing mount 424 to be moved up and down on frame member 206 to vary the distance between the top end of support pole 412 and frame 200 .
Panels 208 are attached to support poles 412 by hinges 428 . A single panel can be swung away from frame 200 like a gate by removing the pins from the hinges 428 on one end of the panel 208 . Similarly, short panels 218 may be used as a control gate within the livestock path 222 by removing the pins from the hinges 428 on one side of the panel 218 and swinging the panel across the livestock path 222 . In some embodiments, some panels 208 or 218 may have hinges on only one side, and are secured to the support pole 412 on the opposite side by a bolt-style gate latch for ease of opening and closing the panel during use.
The described means of attaching support pole 412 to the frame 200 allow the pole 412 , and the panels 208 attached to it, to be adjusted in and out from frame 200 , and also to be leaned in and out from the frame 200 . Support pole 412 pivots on mount 414 , so as mount 424 is moved up and down on frame member 206 , the support pole 412 pivot around mount 414 , leaning either away from or toward the frame 200 . Since panels 208 are attached to support poles 412 , this allows the panels 208 to be adjusted in a similar manner.
Referring now to FIG. 5 , a cross-sectional view of an embodiment of the corral assembly 102 is depicted. The elements of the structure that support the panels 208 can be seen in this figure, including support pole 412 , pivot mount 414 , support 416 , collar 418 , pivot mounts 422 and 424 and member 426 . The means for slidably retaining mount 424 on member 206 is depicted in this embodiment as screw 500 provided with a head receptive to hand adjustment. Also visible in this figure are bolts 502 for releasably securing the plates 402 of rails 400 to the floor of trailer 100 .
Referring now to FIG. 6 , a detailed cut-away view of a portion of the corral assembly 102 is depicted. For purposes of clarity, some elements of the corral assembly have been removed from this view, either in whole or in part. FIG. 412 depicts the area of the corral assembly 102 adjacent to the end panel 220 .
The end panel 220 is provided to span the end of frame 200 . Panel 220 is formed in the same manner as panels 208 described above. The panel 220 is mounted to vertical members 206 by hinges on one edge and is secured to the other vertical member 206 by a gate latch 600 . In the embodiment shown in the figures, the gate latch 600 is a bolt type gate latch, but other types of latches may be used as desired.
The vertical members 206 are provided with wheels 602 to support the frame 200 on the rails 400 and to allow the frame 200 to be inserted into and removed from the trailer 100 . The wheels 602 are attached to the vertical member 206 by brackets 604 , and are disposed so that the wheel 602 and the horizontal frame member 204 are disposed on opposite sides of guide 404 on rail 400 . The guide 404 maintains the wheel 602 and frame member 204 in the proper position as the frame 200 is inserted and removed from the trailer 100 . A plurality of wheels 602 or other rollers are mounted at the bottom of the frame 200 , at various locations along the length thereof. These wheels or rollers are large enough that the frame 200 is easily rolled into a livestock trailer 100 .
Referring now to FIG. 7 , a cross-sectional view of an embodiment of the corral assembly 102 is depicted adjacent to end panel 220 . The bolt 700 rotatably attaches wheel 602 to bracket 604 . The position of member 204 and wheel 602 on opposite sides of guide 404 on both rails 400 keep the frame 200 stable and appropriately supported as the frame 200 is inserted into or removed from trailer 100 .
Referring now to FIG. 8 , an perspective view of the corral assembly 102 is depicted as it is inserted into or removed from the trailer 100 . As the assembly 102 is removed from the trailer 100 , means for supporting the assembly 102 are provided at various points on the frame 200 and on gate frame 212 . In the embodiment shown in the figures, removable jacks 800 are provided to allow for level support of the frame 200 on varying terrain. As the frame 200 is removed from the trailer, the jacks 800 are installed on the frame 200 at the appropriate points and lowered until contact with the ground provides support for the weight of the frame 200 . Then the trailer is pulled away from the frame 200 until the next mount point for a jack 800 is outside the trailer 100 . The numbers of jacks 800 necessary to support the frame 200 vary depending on the length of frame 200 and the weight of the assembly 102 . Typically jacks 800 are provided on gate frame 212 .
Referring now to FIG. 9 , a detailed view of one of the jacks 800 is depicted. The jack 800 depicted in the figure is attached to the end of gate frame 212 . Tube 302 which is a part of gate frame 212 extends from the end of the gate frame 212 and acts as a receiver for insert 902 attached to jack 800 . Similarly to a receiver hitch, tube 302 and insert 902 are provided with holes for receiving pin 904 to secure jack 800 in place. Similarly, at other spots on frame 200 where it is desired to have a jack 800 , a tube similar to tube 302 is provided to receive an insert 902 attached to a jack 800 . Once the jack 800 is secured to the assembly 102 by means of the receiver hitch, then the foot 906 of jack 800 is lowered into contact with the ground sufficient to hold the weight of the assembly 800 .
The innovative device, when installed in a livestock trailer, works extremely well with portable corral systems formed of interlocking livestock panels. Such panels can be set up at the rear or open end of the trailer to form a corral, holding pen, or a driving lane which is used to manipulate livestock toward the trailer.
Livestock trailers often have a forward side door. The innovative corral assembly works well to segregate animals. A number of animals are driven into the trailer and captured in the aisles. The animals are separated using the swing gates. Once the animals have been segregated, they may be selectively released through side doors as appropriate. This works particularly well when sorting animals by size, age or condition.
Operation of the present invention is very simple. When the portable corral assembly is needed, the livestock trailer 100 is positioned near the corral assembly 102 with the end panel 220 oriented toward the front of the trailer 100 . The corral assembly 102 is then placed into the livestock trailer. Loading of the corral assembly 102 can be accomplished in any number of loading methods. It is asserted that two workers can easily load the corral assembly in to a livestock trailer. It is also possible to pick up the corral assembly using the front end loading assembly of a tractor and placing it into the livestock trailer. Other loading methods may become apparent. Because the corral assembly does not have to be fastened to the inside of the livestock trailer, it is ready for use. It is understood, however, that it may be desirable to provide and adjust stabilizing bars or otherwise fasten the corral assembly within the trailer to prevent unwanted movement during use. When the corral assembly is no longer needed, it is simply pulled out of the livestock trailer by force.
While the present invention is described herein with reference to the embodiments illustrated for particular applications, it should be understood that the invention is not limited thereto. Those having ordinary skill in the art and access to the teachings provided herein will recognize additional modifications, applications, and embodiments within the scope thereof and additional fields in which the present invention would be of significant utility. It is therefore intended that the scope of the present invention only be limited by the claims appended hereto. | A removable corral assembly for use in a livestock trailer which includes a plurality of interlocking livestock panels. The panels are in a substantial U-shape so when they are installed in the livestock trailer a left aisle and right aisle are formed with a middle or center aisle which is segregated. The worker stands in the center aisle and is protected from livestock being worked in the left and right aisles. A catch gate or squeeze chute may be associated with the corral assembly and positioned near the rear opening of the trailer in either the left or right aisle. Rollers, wheels or similar mechanisms are fastened to the panel assembly so that the corral can easily be rolled in to and out of a livestock trailer. Varying panel sizes may be used to adjust the overall dimensions of the corral assembly for installation in trailers having varying sizes. | 1 |
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