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This application is a continuation of application Ser. No. 08/289,615 filed Aug. 12, 1994, now abandoned, which is a continuation of application Ser. No. 07/987,732, filed Dec. 8, 1992, now abandoned.
FIELD OF THE INVENTION
The present invention relates to a process for preparing polymeric particles which is specially designed to be served as an opacifying agent in coating compositions such as water-borne paints, paper coating compositions and molding compositions which have white or light color shades. In more detailed description, this invention is concerned with the preparation and use of emulsion polymer particles which were made by multi-stage emulsion polymerization and generating a microvoid inside of a particle when dried.
BACKGROUND OF THE INVENTION
It is well-known in paint industry that the so-called plastic pigment has played an important role to reduce the cost of high quality water-borne paints without sacrificing performance by replacing part of titanium dioxide which has been mainly used as a white pigment. In general, the methods to increase the hiding power of paint film can be devided into two categories; one is based on the use of the open cell of microvoids and the other is based on the use of the closed cell of microvoids. The typical example of utilising microvoids of open cell type may be seen in the water-borne paints of low-cost and low quality, in which the pigment volume concentration of the paints are formulated above a critical pigment volume concentration by highly loading the so-called extender and hence the hiding power of the paint film are increased by the formation of interfaces between pigment and air instead of interfaces between pigment and binder. Regardless of the increased hiding efficiency this method suffers from inferior gloss and relatively poor resistances to water, soap solution and stain because of the presence of the connected large voids in the dried film.
In order to overcome the problems mentioned above, fine non-film forming emulsion polymer particles whose glass transition temperature is above 40° C. and particle size is below 1.0 micron, e.g., polystyrene latexes, are formulated into the water-borne paint to reduce the size and quantity of continuous voids and to improve water resistance and washability with the help of the coalescing solvent added to partly sinter the non-film forming particles. However, this method also suffers from the fact that the hiding power of the paint films can not be maximized because of the lack of ability to scatter light rays by the emulsion polymer particles which has almost same reflectivity as that of film-forming latex binder.
Recently a number of approaches to incorporating microvoids of closed cell type into paint films have been suggested. One of these is the use of organic solvent which was embodied in U.S. Pat. No. 3,669,729. More specifically, the patent discloses the use of non-solvent entrapped film-forming latex binders as the main binder for latex paints whose dried film would be cellular form upon evaporation of the non-solvent and hence has an increased hiding power. However, despite of the improvement of hiding power, this method also suffers from such drawbacks as the complication of the process, poor storage stability, poor reproducibility of hiding power and the less environmental friendliness. A similar method was proposed in U.S. Pat. No. 3,637,431, in which non-film forming emulsion polymers emulsified with the organic solvent, immiscible with aqueous phase, were used to provide microvoids into the dried film, but it also suffered from the problems afore mentioned.
In order to overcome such problems a new method was proposed in recent years, in which microvoid-containing polymer particles were made in seperate process and blended into water-based coatings resulting in achieving more reliable opacifying method. Kershaw et. al, in U.S. Pat. No. 3,891,577 disclose preparation of vesiculated polymers by emulsion polymerization of a liquid medium which is obtained by the so-called double emulsification method, that is, emulsifying a water in oil emulsion, for example, the unsaturated polyester dissolved in styrene monomer containing water dispersed therein into water medium to become a water in oil in water emulsion and thus, by polymerizing such emulsion, obtaining polymer beads having 1 to 25 microns of diameter and several tiny water droplets inside of each bead. Whereas this material can play a better role as an opacifying pigment than polystrene solid particles because it has a hiding power itself, it is difficult for this material to have a contribution as the so-called spacer between TiO 2 particles because this material is not able to be produced as submicron sized due to an inherent nature of emulsification method carried out by mechanical stirring, and also this material has a problem of settling during storage and in addition it can not afford to be applied in the field of glossy coating compositions.
In recent years in order to overcome the problems mentioned previously, a new preparation method has been developed where microvoid-containing polymer particles were prepared by sequentially emulsion polymerizing a core monomer system to be the alkali-swellable polymer core, polymerizing in the presence of the core polymer dispersion a shell monomer system, and neutralizing with ammonia or base so as to swell said core and form particles which, when dried, contain a single closed cell of void. The efficiency of the so-called core-shell emulsion polymerization may be depending on several factors such as monomer compositions of each stage of polymerization, glass transition temperature of the polymer, the kinds and concentration of surfactants, the kinds and concentration of initiators and polymerization temperature. For example, if the core polymer formed in the first stage is more hydrophilic than the shell polymer formed in the subsequent stage, the polymer particles finally obtained may have an inverse core-shell morphology or so-called confetti-like structure regardless of the order of monomer addition. To avoid the formation of undesirable particle morphology it has been suggested that a multi-stage emulsion polymerization process should be controlled in optimum way.
According to U.S. Pat. No. 427,836, after making a hydrophilio polymer containing carboxylic acid group, which can be expanding more than 2 times in volume when neutralizing with aqueous solution of volatile base, in first stage of emulsion polymerization, there has been used a method to form the shell on the surface of the hydrophilio core polymer with the polymeric material which is permeable to aqueous base solution by a thermal or redox emulsion polymerization process. In the said invention it was disclosed that the core polymer contains at least 5%, preferably at least 10%, by weight of acid monomers and the shell polymer contains less than 10%, preferably not over 5%, by weight of acid monomers, and that the ratio of core weight to the total weight is from 1:4 to 1:100. It was also disclosed that the shell polymer was not permeable to aqueous inorganic base at 20° C., and was not able to form a continuous film at room temperature even in the presence of small amount of coalescing agents because its Tg is considerably higher than 40° C.
To obtain this particular partiole morphology as designed, empolyed was multi-stage emulsion polymerization process where monomers were fed in a preemulsified form under the condition of minimum level of concentration of conventional emulsifier. Because the internal structure of emulsion polymer was controlled by the concentration of the emulsifier in this case, it is difficult to accomplish the polymerization stability and the supression of generation new crop of secondary particles simultaneously. Because the shell-forming monomers are used at least 4 times, preferably 8 times, as such as the core-forming monomers in order to get the concentric core-shell particle structure, the wall of the hollow polymer particles is inevitably thicker than it may be needed.
To solve this problem, in Korea Patent No. 25,024, it was suggested that the copolymerizable surfactant is used as emulsifier to get better water resistance, and that a monomer feed rate, the kinds of polymerizing initiator and the reaction temperature are carefully chosen so as to suppress the formation of abnormal particles during a shell-forming stage and to get a desired particle morphology reproducibly without sacrificing a polymerization stability. It was claimed in the said invention that the concentric core-shell structured latex particles are obtained with using relatively less amount of the shell monomer compared to the method proposed by Kowalski et.al, in U.S. Pat. No. 4,427,836, because it provides higher encapsulation efficiency of the shell polymer on the core particle through suppressing the formation of abnormal particles.
Although the said methods can be used to produce aqueous dispersion of composite latex particles which have the alkali-swellable polymer as core and more hydrophobic polymer as shell, those suffer from the fact that, during drying, particles are collapsed especially when the strength or thickness of polymer wall is not sufficient enough to withstand the contraction force generated by the evaporation of water and the restoration of the swellen core polymer. Such formation of abnormal collapsed particles decreases their hiding efficiency by reduction of the volume of internal void and also restricts paint formulation due to the increases of the oil absorption amount and the binder demand of particles because of unnecessary increase of surface area of particles resulted from a non-spherical particle geometry. To solve this problem, methods employed are to thicken the shell layer of particles by increasing the ratio of shell-forming monomer to core-forming monomer and to prevent the particle collapse by increasing the strength of wall incorporating a proper amount of crosslinking monomer in a mixture of shell-forming monomer, but those are not able to maximize the hiding efficiency per unit weight of particles by unnecessary increase of a wall thickness.
SUMMARY OF THE INVENTION
Thus the purpose of this invention is to provide the method to produce the composite emulsion polymer of alkaline-swelling polymer core/hydrophobic polymer shell which can endure the contraction force during drying with a minimum thickness. The reduction of a wall thickness of hollow polymer particles is technically important because it contributes to a cost-reduction by decreasing the amount of polymeric material used. According to conventional production methods, semibatch processes have been used, in which, after polymerizing core-forming monomers containing acid-mer and comonomers, shell-forming monomers fed with constant speed as itself or as preemulsified are polymerized in the presence of the core particles.
The composite latex particles produced by such a two-stage emulsion polymerization have a well-defined two-layer structure, like a well-done egg, having uniform chemical compositions. Glass transition temperature has been regarded as the only criterion for selecting a shell-forming polymer in the said method as measure of the softening temperature of polymer and hence there is used a mixture of shell monomers whose Tg is at least 40° C., preferably at least 80° C., to endure the contraction force generated during drying process at ambient temperature. However, in the present invention, the toughness index is also regarded, besides Tg, as the criterion for selecting such a shell-forming polymer. The term "toughness index" expressed numerically refers to how tensile stress of polymeric material responds to the imposed tensile strain, and, according to S. Wu in Journal of Applied Polymer Science Vol. 20, 327(1976), it is defined as a function of glass transition temperature (Tg) and brittle-ductile transition temperature (Tb) as follows: ##EQU1##
For example, if comparing polystyrene with polymethylmethacrylate, even though the glass transition temperature of the former is quite similar to that of the latter, specifically 100° C. and 105° C., respectively, the tough index of the former is quite lower than that of the latter, that is, 0.027 and 0.159, respectively, because the brittle-ductile transition temperature of the former is much higher than that of the latter, 90° C. and 45° C., respectively.
Therefore, because, although the glass transition temperature of two polymers are much the same, they are quite different in mechanical strength, the toughness index should be taken into consideration together with the the glass transition temperature when designing the structured latex as is the case in the present invention. Polymethylmethacrylate is more suitable than polystyrene as a uniform shell polymer of the core-shell structured latex particles because of having a higher toughness index. The toughness index is determined solely by a monomer composition in a homogeneous system like the polymer solution, whereas it is depending on not only a monomer composition but also the interior structure of particles in a heterogeneous system, e.g., latex polymers.
The important embodiment of this invention is to increase the toughness index of the shell polymer of the hollow polymer particles by making the structure of latex particles of being heterogeneous in order to enhance the mechanical properties of the homogeneous particles. As mentioned above in the case of core/shell polymers of discrete two-layer structure produced by conventional process, the collapse and deformation of particles during drying is governed by the mechanical properties of the homogeneous shell polymer. Therefore, the polymer particles composed of conventional radical polymers can be preserved from the deformation when the thickness of the polymer wall exceeds at least 20% of an entire particle diameter, whereas the polymer particles having a spectrum-like shell structure disclosed in the present invention can be preserved from the deformation even when the shell thickness is less than 20 percent of an entire particle diameter. The term "spectrum-like" structure defines that in which the change in molecular structure in the particle is one such as is represented by the gradual, consistent and even change observed in a spectrum.
In this invention, the core particles are prepared by the conventional emulsion polymerization, and then the emulsion polymer having the spectrum-like shell structure is produced using a feed method of gradually changing the composition of monomer mixture, that is, monomer mixture is fed into a reactor by gradually changing the composition of the shell-forming monomer mixture from the beginning to the end of the shell-forming stage. The similar instance in which the mechanical properties of the latex particles were improved by introducing the effect of particle structure using a feed method of the so-called "continual change in monomer composition" is reported in "Emulsion Polymers and Emulsion Polymerization, ACS Symposium Series 165, P. 371(1981)" by D. R. Bassett and K. L. Hoy. Hereto they found that the toughness index of 50/50 MMA/EA copolymer latexes can be varied drastically according to the particle morphology, for example, the toughness index of the homogeneous single staged latex was 0.9, but that of the heterogeneous one having hard core gradually changing to a soft exterior was 1.9. Though a spectrum-like morphology of single staged latexes was disclosed in U.S. Pat. No. 3,804,881 and in U.S. Pat. No. 4,039,500 to improve mechanical properties and film-forming ability, respectively, but nobody has yet applied it for designing two-staged or multi-staged latexes, especially for preparing hollow polymer particles. For easier and better understanding of the polymerization process disclosed in the present invention, the simplest example in which monomer A is copolymerized with B is described below.
In the conventional polymerization method, monomer mixture of A and B is supplied into a reactor from a monomer feed tank through a certain period with a predetermined feed rate, whereas in the polymerization method of this invention, the each monomer, A and B, stored in two separate tanks is simultaneously fed into a reactor and hence the composition of monomer mixture entering into the reactor is varying with time because the feed rate of each monomer is changed gradually and seperately. For instance, when the feed rate of monomer A is increased from 0 in the very early stage to 100 in the end of feeding and at the same time that of B is decreased from 100 to 0, specially structured latex particles having the copolymer abundant in B in the interior of particle and that rich in A in the surface of particle may be consequently produced. As aforesaid, by varying feed rates of each feed tank which is directly connected to a reactor, monomer compositions entering in the reactor can be controlled as desired. However, such gradual change of monomer composition can be more easily achieved by connecting the two feed tank in a row to the reactor and introducing monomer mixture in the near tank to the reactor simultaneously with the addition of the monomer mixture in the far tank to the near tank. During the simultaneous flows from the far tank to the near tank and from the near tank to the reactor there is continual variation in the compositional content of monomers in the near tank and consequently the composition of incoming monomer to the reactor is as follows:
C.sub.1 =C.sub.2.sup.0 -(C.sub.2.sup.0 -C.sub.1.sup.0) (1-α).sup.x
Where C 1 0 and C 2 0 is the initial monomer composition of the near and far feed tank, respectively, and α is the conversion ratio or the feed monomer ratio and x is the ratio of the monomer amounts in the two feed tanks. Accordingly, the simplest instance where each of two feed tanks is connected directly to the reactor and the feed rate of monomer A is increased from 0 to 100 and simultaneously that of monomer B is decreased from 100 to 0 can be more conveniently duplicated by means of the so-called "simultaneous monomer flows in a row" in which x is 1, α is 0.5, and C 1 0 is 100% of B monomer, C 2 0 is 100% of A monomer.
Though the feed method of continual change in monomer composition was described with simplest case, the variations in feed rate and in arrangements of feed tanks are practically innumerable. Hitherto it was explained assuming that the composition of polymer produced in the reactor should reflect the composition of monomer entering the reactor. In an important embodiment of the process of this invention, the polymerization system is at any instant kept under the monomer starved condition, by controlling the monomer feed rate and other polymerization conditions appropriately, which means there is no significant time delay between introduction of monomers to the reactor and essentially complete polymerization of the monomers and hence there is no cumulation of any specific monomer in the polymerization zone even when mixtures of monomers of quite different reactivity ratios and water solubilitie are employed. Therefore, in this invention, the polymerization rate and the monomer addition rate should be controlled so that the instantaneous conversion is at least 70 percent, preferably at least 65 percent at any time in the shell-forming stage.
Hereinafter another embodiment of this invention is described. When a specific monomer even if its toughness index is low must be used essentially for the cost-down or for an easier particle morphology control, this invention is applied usefully, too. For example, when styrene should be used as a shell-forming monomer, the wall of polymer produced should be thick because of poor mechanical strength of styrene whose toughness index is 0.027. But by using the process of this invention, the wall thickness may be reduced effectively by the introduction of suitable comonomer such as acrylonitrile or methylmethacrlate to make a spectrum-like shell polymer structure.
In this invention, in order to enhance the toughness index introduced is not only a heterogeneity of the particle structure with respect to the change in monomer composition but also a heterogeneity of crosslinking degree inside latex particles. Using the feed method of continual change in composition, the strength of shell polymer can be maximized by providing the concentration gradients of monomer composition as well as crosslinking degree in the shell layer. The crosslinkable monomers may be present in the both tanks or either in the near or in the far feed tank, more preferably in the far feed tank, the proportion thereof being in the range of 0.01 to 5.0%, preferably 0.05 to 1.0%, by weight, based on the total monomer weight of the shell. Examples of the crosslinkable monomers include divinyl benzene, allyl (meth)acrylate, tripropylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, ethylene glycol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, 1,3-butylene glycol di(meth)acrylate, and trimethylolpropane tri(meth)acrylate.
DETAILED DESCRIPTION
Hereinafter the present invention is explained in detail stage by stage of polymerization process.
In accordance with the present invention, the preparation of core-shell polymer particles which are useful for opacifying agents in coating compositions is composed of (1) producing ionic core polymer particles by copolymerizing acid monomers containing a carboxylic group with common monomers, (2) encapsulating the core polymer with the hard and rigid polymer sheath by polymerizing shell-forming monomers with the feeding method of continual change in the monomer compositions in the presence of the preformed core particles, and (3) neutralizing and expanding the produced core-shell composite polymer particles with base at elevated temperature, and generating inner void when dried.
The said core particles may be prepared in single polymerization stage or preferably prepared in plural stages containing a preparing stage of seed polymer and followed by the making of the shell to control more easily the particle size and its distribution of final latex and the void size and its distribution. Hence the first stage of emulsion polymerization in the process may be the preparation of a seed polymer, which may or may not contain as one component thereof any acid monomer but provides particles of minute size which form the nuclei on which the acid monomer mixture is polymerized in a sequential stage and which has an average particle diameter in the range of about 0.02 to about 0.5 micron, preperably 0.03 to 0.2 micron. Suitable acid monomers include acrylic acid, methacrylic acid, itaconic acid, crotonic acid, fumaric acid, aconitic acid, maleic acid or anhydride, monomethyl maleate, monomethyl fumarate, and monomethyl itaconate. An acid monomer or mixture of acid monomers is copolymerized with one or more of comonomers, the proportion of acid monomer being 0 to 10%, preferably 0 to 5%, by weight based on the total monomer weight. The ethylenically unsaturated monomers copolymerized with acid monomer include styrene, vinyltoluene, ethylene, butadiene, vinylacetate, vinyl chloride, vinylidene chloride, acrylonitrile, alkyl acrylate, and alkyl methacrylate. Any nonionic or anionic emulsifier may be used, either alone or together, in an amount of about 0.1 to 2.0%, by weight, based on the total monomer weight. Examples of the nonionic type of emulsifier include octyl phenoxy ethyl polyethoxyethanol and nonyl phenoxy ethyl polyethoxyethanol. Examples of anionic emulsifiers include sodiumlaurylsulfate, sodium dodecyl benzenesulfonate, sodium octyl phenoxy ethyl polyethoxyethyl sulfate, and sodium salt of sulfosuccinate derivatives.
As in common in emulsion polymerization, there is used a water soluble free radical initiator, such as alkali metal persulfates, ammonium persulfate, hydrogen peroxide and tertiarybutylhydroperoxide, or a mixture of such an initiator with a reducing agent, such as an alkali metal sulfite, hyposulfite or sodiumformaldehydesulfoxylate, to form a redox system. The amount of initiator may be from 0.1 to 2% by weight of the monomer, and the reaction temperature may be in such that the decomposition half-life time of the initiator used is from 30 to 300 minutes.
For instance, in the case of a ammonium persulfate, potassium sulfate or sodium persulfate, being used alone, the temperature is preferably in the range of 60° C. to 90° C., whereas in the case of a mixture of a sodium bisulfite or sodium formaldehyde sulfoxylate with the sulfate initiators, the temperature is preferably in the range of 30° C. to 60° C. As is common to emulsion polymerization, the criteria for the selection of initiator and reaction temperature are applied to the subsequent core-forming and shell forming stages as well.
After the seed polymer is formed, a subsequent stage is carried to form core polymers using hydrophilic monomers. The core polymer may contain as components thereof about 15 to 60% by weight of acid monomers, 39 to 85% by weight of monoethylenically unsaturated monomers, and about 0 to 2% by weight of a crosslinkable monomer. Examples of the respective monomers are mentioned above. The amount of the core monomer may be 2 to 40 weight % based on the total weight of the monomer mixture irrespective of the presence of a seed stage, and if the core is obtained from a seed polymer, it may be used about 4 to 20 times as much as the seed-forming monomer. The suitable rate of monomer addition may be in the range of 30 minutes to 3 hours, which should be determined by carefully considering its effects on the polymerization stability, the control of heat generated, and the behavior of particle growth. The amounts of emulsifier and initiator, and reaction temperature of the core-forming stage should be designed so as for the particle diameter of the polymer obtained to be in the range about 0.1 to 0.5 micron in unswellen state, that is, before any neutralization to raise pH to above 5.
The subsequent stage of forming a shell polymer on the core polymer particles will be effected in another reactor by transferring the core polymer stored in shelf or preferably in the same reactor where the formation of the core was accomplished. The mixture of monomers used in shell-forming stage consists of 95 to 100%, by weight, of one or more of monoethylenically unsaturated monomers and 0 to 5%, by weight, of acid monomers. As described above, glass transition temperature and toughness index should be regarded as the criteria for the monomer selection. Emulsifier and initiater are selected among those mentioned hereinbefore and the amount of emulsifier to be used should be controlled in the range of 0.01 to 2.0%, by weight, based on the monomer weight to accomplish a good polymerization stability as well as a desirable particle growth behavior at once. In an embodiment of this invention, whether the shell polymer is formed in a single stage or in a plurality of stages, at least one shell-forming stage should be performed with the monomers being fed in the manner of the so-called "continual change in composition" but preferably it is composed of a first shell-forming stage with a regular monomer feeding and a 2nd shell-forming stage with the continual change in feed composition. In such case, the process of neutralization necessary to prepare microvoid may be performed after the first-shell polymer is formed. The neutralization temperature should be selected by considering glass transition temperature of the first-shell polymer in order to get the maximum expansion of the entire particle along with shell layer, preferably being at 50°-100° C. For the operational convenience, it is more desirable to carry out the neutralization stage at a given polymerization temperature, without changing the temperature, and hence it should be considered its relation with polymerization temperature. Because, in the sequential emulsion polymerization composed of core--the first shell--neutralization--the second shell, the major roles of the first shell polymer are to prevent drastic increase of viscosity which may occur during the neutralization of core particles and to maintain the encapsulation efficiency of the second shell polymer, by providing polymer barrier, even after neutralization which generally decreases encapsulation efficiency because of forming much more hydrophillic surface by the dissociation of carboxyl group, the mixture of acrylic monomers of intermediate chemical properties may be used as the first shell monomers and the ratio of the core weight to the first shell weight is from 1:1 to 1:50, preferably 1:1 to 1:8. Because the major role of the second shell polymer is to prevent the deformation of particles during drying process, it is proposed in this invention that the emulsion polymerization should be carried out with feeding the mixture of monomers having the proper toughness index in the manner of the continual change in composition and that the ratio of the first shell polymer to the second shell polymer should be from 1:1 to 1:100, preferably 1:1 to 1:50.
In such feeding method, concentration of a certain monomer will vary linearly with time when the volume of monomer present in the two feed tanks is same, whereas, when it is not, it will vary non-linearly with time. For instance, if the ratio of the volume of monomer present in the far tank to that in the near tank is more than 1, the concentration curve may have a convex type curvature, whereas, if it is less than 1, it may have a concave type curvature when plotting the concentration vs. time. As described above, the criteria for selecting monomers to be used in the 2nd shell-forming stage include glass transition temperature and toughness index. Generally glass transition temperature is at least 30° C., perferably at least 50° C., and toughness index is at least 0.04, preferably at least 0.08. For example, in the case of using styrene as main monomer, alkyl(metha)acrylate or the like may be mixed in the range of 5 to 50% by weight to increase toughness index of polymer formed preferably. More specifically, the 2nd shell-forming stage may be designed so as to produce a polymer having glass transition temperature of 54° C. and toughness index of 0.09, when 100 parts of a 60/40 styrene /butylacrylate mixture is present in the near tank and 100 parts of styrene is present in the far tank.
In the case of introducing crosslinking monomer to increase the toughness of the 2nd shell, it may be added either equally to both feed tanks without having any concentration gradient or preferably to anyone of feed tanks to have the concentration gradient whether linear or not.
Base used in neutralization stage may be either volitile base such as ammonia and the tertiary amine, or alkali metal hydroxide such as sodium hydroxide and potassium hydroxide. When it is added, pH of emulsion polymeric dispersion is preferably in the range of 7 to 12 after neutraization. To help the base permeate into particles, organic solvent may be added either at neutralization, or before or after neutralization.
Solvent should have more chemical affinity to core polymer than to shell polymer and have a certain degree of water solubility. For instance, one or more of alcohols chosen among ethanol, propanol, hexanol, and TEXANOL (2,2,4-trimethyl-1,3-pentanediol mono(2-methylpropanoate)) may be used in the range of about 2-100% by weight based on the core polymer weight.
The particle diameter of the emulsion polymer prepared by the process in the present invention may be in the range of 0.1 to 2.0 micron, preferably 0.2-1.0 micron, and the diameter of void after dried may be in the range of 0.05 to 1.5 micron, preferably 0.1 to 0.8 micron. Because the collapse or deformation of particles during drying is not observed even when the ratio of wall thickness to the entire particle diameter is relatively low, the composite polymer particles prepared by the process in the present invention may more effectively and economically serve as an opacifying agent for latex paints and paper coatings than conventional counterparts. Therefore, when compared opacity of the films which have been made by drying of draw-downs of a blend of a film-forming acrylic latex with the alkali-swellen composite polymer latexes in a ratio of 7:3 by weight, it was found that the product produced by the process of the present invention was superior to conventional opaque polymers because of thinner wall and consequently of higher void volume concentration at the same solid content.
EXAMPLE 1
To a 1-liter 4-neck round-bottomed flask equipped with a paddle stirrer, thermometer, dropping funnel, nitrogen inlet and reflux condenser is added 400 g of deionized water, 0.5 g of sodium bicarbonate and 0.5 g of sodium dodecylbenzene sulfonate and then heated to 80° C. under a nitrogen atmosphere and followed by the addition of 0.45 g of sodium persulfate dissolved in 30 g of water. While the temperature is maintained at 80° C. a monomer emulsion consisting of 40 g of deionized water, 0.05 g of sodium dodecylbenzene sulfonate, 52 g of butyl acrylate, 66 g of methyl methacrylate and 1.4 g of methacrylic acid is added to the flask over an hour period. After the completion of the monomer feed, the dispersion is held at 80° C. for 1 hour and cooled to room temperature. Upon examination with a light scattering method, the average particle diameter of this dispersion is found to be 43 nm and its solid content is 19.7%.
To 1010 g of deionized water and 30 g of the acrylic seed polymer dispersion in a 2-liter 4-neck flask heated to 80° C., there is added 2.0 g of sodium persulfate dissolved in 50 g of water. While the temperature is maintained at 80° C., a monomer emulsion consisting of 115 g of deionized water, 0.5 g of sodium dodecylbenzene sulfonate, 190 g of methyl methacrylate, 105 g of methacrylic acid and 1.5 g of ethyleneglycol dimethacrylate is added to the flask over 2 hour period. After the completion of the monomer feed, the dispersion is held at 80° C. for an hour and then cooled to room temperature to obtain core polymer latex. The product has average particle diameter of 162 nm(light scatter) and 22.8% total solids.
720 g of deionized water and 160 g of the acrylic core polymer latex are charged into a 2-liter 4-neck flask and heated to at 80° C. and followed by the addition of 0.87 g of sodium persulfate dissolved in 25 g of water. A monomer emulsion consisting of 220 g of deionized water, 20 g of styrene, 83 g of methyl methaorylate, 42 g of butyl acrylate, 3.5 g of sodium dodecylbenzene sulfonate and 2.2 g of Triton X-100 (Rohm & Haas product) is added to the flask over 2 hour period at 80° C. After the completion of the monomer feed, the dispersion is held at 80° C. for 1 hour. The dispersion is neutraized to pH 11.0 with aqueous ammonia solution and held at 80° C. for 1 hour. The average particle diameters are 280 nm and 430 nm before and after the neutralization, respectively, and its solid content is 14.4%. 1.74 g of sodium persulfate dissolved in 20 g of water is added to the flask while maintaining temperature at 80° C.
There is charged to a near dropping funnel 45 g of butyl acrylate, 32 g of methyl methacrylate and 68 g of styrene and charged to a far dropping funnel 10 g of methyl methacrylate, 22 g of butyl acrylate and 113 g of styrene. The contents of the near funnel is fed into the flask at a rate of 2.2 cc/min while simultaneously introducing into the near funnel from the far funnel the contents of said far funnel at a rate of 1.1 cc/min for 90 minutes. After completion of the monomer feed, the dispersion is held at 80° C. for an hour and then cooled. At 55° C. during cooling down, 0.4 g of sodium formaldehyde sulfoxylate and 0.3 cc of t-buthy hydroperoxide(70%) dissolved in 10 g of water are added.
The dispersion have solid content of 28.9% and viscosity of 190 cps. Upon examination with a Transmission Electron Microscope the average particle diameter and the average microvoid diameter of the final dispersion polymer is found to be 484 nm and 340 nm, respectively.
EXAMPLE 2
160 g of the core polymer dispersion which was prepared with the same procedure described in Example 1 and 720 g of deionized water charged into a 2-liter flask were heated to 80° C. and then added 0.87 g of sodium persulfate dissolved in 25 g of water. While the temperature was maintained at 80° C., a monomer emulsion consisting of 220 g of deionized water, 15 g of styrene, 62 g of methyl methacrylate, 32 g of butyl acrylate, 3.0 g of sodium dodecylbenzene sulfonate and 1.90 g of triton X-100 was added to the flask over 2 hour period. An hour after the completion of the monomer addition, the dispersion was neutralized to pH 11.0 with aqueous ammonius solution and was stirred for an additional hour at 80° C., and then 1.52 g of sodium persulfate dissolved in 20 g of water was added. There was charged to a near dropping funnel 34 g of butyl a crylate, 24 g of methyl methaorylate, 51 g of styrene and 1.2 g of ethyleneglycol dimethoacrylate and charged to a far dropping funnel 23 g of butyl acrylate, 8 g of methyl methacrylate, 85 g of styrene and 0.6 g of ethyleneglycol dimethacrylate. The contents of the near funnel was fed into the flask at a rate of 2.2 cc/min while simultaneously introducing into the near funnel from the far funnel the contents of said far funnel at a rate of 1.1 cc/min. The rest of the process was same as in Example 1. The product has a solid content of 25.0%, viscosity of 195 cps, an average particle diameter of 460 nm, and an average void diameter of 349 nm.
EXAMPLE 3
The procedure described in Example 2 was followed. The example differs from Example 2 in that the mixture of 8 g of n-butanol and 8 g of n-hexanol was added during neutralization. The final emulsion product had a solid content of 24.7% and viscosity of 360 cps. An average particle diameter was 461 nm and an average void diameter was 353 nm.
EXAMPLE 4
The procedure described in Example 2 was followed until the neutralization stage. The example differs in the composition and weight ratio of the monomer mixture present in each feed tank during the 2nd shell-forming stage, 23 g of butyl acrylate, 16 g methacrylate, 34 g of styrene and 0.6 g of divinyl benzene were charged in a near dropping funnel and 21.3 g of butyl acrylate, 10.7 g of methyl methacrylate, 113 g of styrene and 1.2 g of divinyl benzene were charged in a far dropping funnel. The contents of the near funnel was fed into the flask at a rate of 2.2 cc/min while simultaneously introducing the contents of the far funnel from the far funnel into the near funnel at a rate of 0.73 cc/min. The rest of the process was same as in Example 1. The emulsion product had 24.9% total solids and 230 cps viscosity. The average particle diameter was 456 nm and the average void diameter was 345 nm.
EXAMPLE 5
The procedure described in Example 2 was followed until the nutralization stage. The example differs in the composition and weight ration of the monomer mixture present in each feed tank during the 2nd shell-forming stage 34.3 g of butyl acrylate, 18.7 g of methyl methacrylate, 92 g of styrene and 1.5 g of divinyl benzene were charged in a near dropping funnel and 10 g of butyl acrylate, 8 g of methyl methacrylate, 55 g of styrene and 0.3 g of divinyl benzene were charged in a far dropping funnel. The contents of the near funnel was fed into the flask at a rate of 2.2 cc/min while simultaneously introducing the contents of the far funnel from the far funnel into the near funnel at a rate of 1.46 cc/min. The rest of the process was same as in Example 1. The emulsion product had a globular shape, and 24.8% total solids and 260 cps viscosity. The average particle diameter was 460 nm.
COMPARATIVE EXAMPLE 1
For the purpose of comparision with Example 1, the procedure described in Example 1 was followed. This example differs from Example 1 in that single feed tank was employed during second-shell formation. The monomer mixture consisting of 67 g of butyl acrylate, 42 g of methyl methacrylate and 181 g of styrene was added to a flask at a rate of 2.2 cc/min for 90 minutes. The final emulsion product has a solid content of 29.6%, viscosity of 445 cps, and average particle diameter of 490 nm. It was observed under electron microscope that most particles were collapsed.
COMPARATIVE EXAMPLE 2
In order to compare with example 2, the same monomer composition as in Example 2 was used during second-shell formation. In this example, a single feed tank was used. The monomer mixture cosisting of 50 g of butyl acrylate, 32 g of methyl methacrylate, 136 g of styrene and 1.8 g of ethyleneglycol dimethacrylate was injected to a flask at a rate of 2.2 cc/min. The final emulsion product has 24.8% total solids, 441 nm average particle diameter and viscosity of 270 cps. It was ovserved that most particles were collapsed.
COMPARATIVE EXAMPLE 3
This comparative example was performed to compare it with Example 4. The monomer mixture consisting of 44.3 g of butyl acrylate, 26.7 g of methyl methacrylate, 147 g of styrene and 1.8 g of divinyl benzene was gradually supplied to a flask at the same time feed rate as in Example 4. The product has a solid content of 24.7%, viscosity of 220 cps, an average particle diameter of 460 nm. Most particles were found to be collapsed.
COMPARATIVE EXAMPLE 4
The same recipe and procedure were used as in Comparative Example 3, only 219.8 g of styrene monomer being used as a 2nd-shell forming monomer. The final emulsion product has 24.9% total solids, average particle diameter of 465 nm and 380 cps viscosity. Most of particles were in a deformed shape.
COMPARATIVE EXAMPLE 5
The styrene was used as a second shell-forming monomer as is the case in Comparative Example 4. This example differs from Comparative Example 4 in that an amount of styrene used is increased three times and deionized water is added for prepaing latex of same solid content. The final emulsion polymer has an average particle diameter of 526 nm, 24,8% total solids, and viscosity of 106 cps. Deformation of particles was not observed under electron microscope.
APPLICATION EXAMPLE 1
In order for compare opacifying efficiencies of the swollen core/shell polymer dispersions prepared in Example 1 to 5 and Comparative Example 1 to 5, a blend of each of the said core/shell polymer dispersion and a commercially available film-forming latex(H5250-Korea Chemical Co.) was made (30% core/shell polymer based on a solid weight) and was drawn down over an opacity chart with a Bird applicator. The wet films of thickness of 3 mil were dried at ambient temperature. The Kubelka-Munk scattering coefficients (S) were measured by the method of K, Nyi, Australian OCCA Proceedings and News, Nov. 1982, P. 4-13. Table 1 reports the results of varying the monomer composition and feeding method of the second shell stage on the film opacity for core/shell particles prepared using the processes of Example 1 to 5 and Comparative Example 1 to 5.
TABLE 1______________________________________ Compo- sitional Film gradient Opacity*.sup.4)Monomer Composition*.sup.1) (order)*.sup.2) (S/mil)______________________________________Example1 BA/MMA/ST*.sup.3) = 1 0.38 37/23/1002 BA/MMA/ST/EGDMA = 1 0.46 28/18/75/1 28/18/75/13 BA/MMA/ST/EGDMA = 1 0.44 28/18/75/1 28/18/75/14 BA/MMA/ST/DBV = 2 0.44 24/15/81/15 BA/MMA/ST/DBV = 1/2 0.42 24/15/81/1Compara-tiveExample1 BA/MMA/ST = 0 0.27 37/23/1002 BA/MMA/ST/EGDMA = 0 0.29 28/18/75/13 BA/MMA/ST/DBV = 0 0.27 24/15/81/14 ST = 121 0 0.215 ST = 363 0 0.19______________________________________ .sup.1) Parts by weight based on 100 parts of solid polymer after the firstshellforming stage. .sup.2) The first order means a linear change in concentration. The secon order indicates a convextype change, one halves a concavetype change, and a zeroth no change in compositional content. .sup.3) BA: Butylacrylate, MMA: Methyl methacrylate, ST: Styrene, DVB: Divinyl benzene EGDMA: Ethylene glycol dimethacrylate .sup.4) KubelkaMunk scattering coefficient per unit film of thickness 1 mil
APPLICATION EXAMPLE 2
For a practical comparision of opacifying effectiveness, typical white-colored latex paints were prepared according to the following paint formulation, in which part of TiO 2 was replaced by the core/shell polymer particles. The paints were adjusted to have viscosity of 80±5 KU, pigment volume concentration (PVC) of 72.5%, and solid volume ratio (SVR) of 33%.
______________________________________ Parts byRaw Materials Weight______________________________________Deionized water 17.0Sequestering agent: 10% Aq. soln of sodium 3.0hexamethaphosphatePinment dispersant: Orothan 731 (Rohn and Hass Co.) 0.1Pigment wetting agent: Trition CF-10 (ROHM AND 0.3HAAS CO.)Preservative: Floxal XL-2 (ICI CO.) 0.2Antifoamer: Nopoco-NXZ (SANOPCO CO.) 0.2Thickner: 3% Aq. soln of Natrosol (HERCULES CO.) 12.3PH adjuster: 20% ammonia 0.2Freeze-thaw stabilizer: Ethylene glycol 2.0Pigment:Talc 325 8.0Calcium carbonate 1000 13.0Titanium dioxide 10.0Alsilate W 14.0______________________________________
The above ingredients were ground at high speed for 30 minutes and let down at slower speed with the addition of the following ingredients.
TABLE I______________________________________Coalesoing agent: Texanol 0.3Binder: H5250 (Korea Chemical Co.) 14.2A Swollen Core/Shell Polymer Dispersion 6.0______________________________________
The paints were applied on an opacity chart (The Lenete Co., Form 2B) using a Bird applicator with wet film thicknesses of 4 mil and 6 mil and dried at least one day at room temperature. The contrast ratios of paints were measured by the method KSM 5345. The results were given in Table II.
______________________________________ Contrast Ratio 4 mil 6 mil______________________________________Example1 0.942 0.9702 0.946 0.9733 0.946 0.9774 0.941 0.9715 0.943 0.973ComparativeExample1 0.932 0.9612 0.933 0.9613 0.929 0.9644 0.926 0.9595 0.928 0.954______________________________________ | The present invention relates to a process for preparing polymeric particles which is specially designed to be served as an opacifying agent in coating compositions such as water-borne paints, paper coating compositions and molding compositions which have white or light color shades. In more detailed description, this invention is concerned with the process for making an aqueous dispersion of core-shell emulsion polymer particles comprising (1) preparing the core by polymerizing carboxylic acid monomers with other monoethylenically unsaturated monomers, (2) encapsulating said core with a rigid polymer shell by polymerizing shell-forming monomers, in the presence of said core particles, which are fed in such manner that compositional contents of monomers entering to a polymerization zone is changing gradually thoughout the period of monomer feeding, and (3) neutralizing with base so as to swell said core and form particles which, when dried, contain at least one void. | 2 |
[0001] This application claims benefit of provisional application No. 60/371,882, filed Apr. 11, 2002, the entire disclosure of which is considered to be part of the disclosure of this application and is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Respiratory infections, particularly upper respiratory tract infections are very common and cause substantial suffering and hundreds of millions of dollars of economic loss every year.
[0003] The majority of the pathogens contributing to upper respiratory tract infections are spread through air and through touching of the infected surfaces and then touching one's eyes or nose.
[0004] The nasopharynx, the nasal passages, and the sinus cavities all play an important role in filtering and housing majority of these pathogens.
[0005] Prior to this invention, as of the date of writing of this application, no effective, easy to use, and widely accepted cure, treatment, remedy, and particularly no prevention had been found for the upper respiratory tract infections.
[0006] Human body is equipped with organs, such as the tonsils and the nervous system, that give early warnings about the invasion of the respiratory tract's lining by pathogens. This early warning mechanism is part of the effective method of preventing respiratory infections, presented in this patent application.
SUMMARY OF THE INVENTION
[0007] The inventor has experienced that if the early warnings given by the various organs of the body, such as tonsils and the nervous system, are heeded and acted upon by taking an action to render the pathogen(s) causing the symptoms ineffective, the cold or flue will never fully develop and thus the major undesirable symptoms and the accompanying economic losses can be prevented.
[0008] The inventor has further experienced that the pathogens responsible for the common upper respiratory tract infections, i.e. common “cold and flue”, seem to be most vulnerable when they have been newly activated and/or they have newly invaded the body. This is the corner stone of this invention. That is, if the pathogen is attacked shortly after it invades the body it can easily be rendered ineffective.
[0009] Thus, based on the above two experiences, a method is presented here for prevention of various respiratory infections which can be caused by one or more pathogens (bacteria, viruses, and fungi) including, but not limited to, those causing the various forms of upper respiratory tract infection (common cold), influenza, bronchitis, laryngitis, etc. in human being, by using a non-toxic, easily accessible to public “effective formula” to attack the newly activated or the newly invading pathogen and rendering it ineffective. If the infection has already fully taken effect, the present method helps reduce the symptoms of the infection (illness) and its duration by preventing occurrence of secondary infections. This method may also be applied to other mammals.
DETAILED DESCRIPTION OF THE INVENTION
[0010] Through experience, I have observed that the minor discomforts (symptoms) such as minor throat irritation (ache, itching, scratchiness), minor headache, minor chills or feeling abnormally hot without any physical efforts, minor eye irritations, during the cold season, in a normal, otherwise healthy person, are all directly related to the onset of one of the multiple kinds of the upper respiratory tract infections (“cold” or “flue”). Again I have experienced that these symptoms, however minor, must be taken seriously, especially during the cold season. I theorize that these symptoms, in an otherwise healthy person, indicate the onset of activation and/or invasion of the pathogens. These pathogens either already exist in the body of the person feeling the symptoms, or they are newly invading it.
[0011] Once even if one of the above symptoms is felt, the person must right away (experience showed “right away” safely can extend about one hour) implement (undertake) the method of this invention. Doing so will render the responsible pathogen(s) ineffective and thus prevent a full upper respiratory tract infection with its quite painful, uncomfortable, and costly consequences. That is the inventor has experienced that the pathogens responsible for “cold and flue” seem to be most vulnerable when they have been newly activated and/or they have newly invaded the body. This is the corner stone of this invention. This implies, if the pathogen is attacked shortly after it invades the body it can easily be rendered ineffective.
[0012] The method of this invention was found to be fully effective in every case that it was tried based on the guidelines presented here. For a few examples please refer to the examples section below. It was observed experimentally that, if the method presented here is not implemented shortly after the initial feeling of any of the above symptoms, the infection takes effect and develops into a major sickness with full set of symptoms.
[0013] The method presented here is implemented by using (without limiting the scope of this invention) one type of oral rinse (mouthwash) that is available in pharmacies without prescription of a doctor. This type of mouthwash typically has an ingredient list of: Active Ingredients—Thymol 0.064%, Eucalyptol 0.092%, Methyl Salicylate 0.060%, and Menthol 0.042%; Inactive Ingredients—Water, Alcohol 26.9%, Benzoic Acid, Poloxamer 407 and Caramel.
[0014] Right after initially feeling one or more of the above symptoms, about three tea spoons (15 milliliters) of the above liquid oral rinse (mouthwash) is poured into the mouth and by tilting the head backward it is guided to the throat area. Then gargling is started. The gargling should continue for approximately 40 seconds. During these 40 seconds the gargling should be stopped at least three times, and each time the vapors of the oral rinse from the throat area should be passed (gently forced) along with the exhaled air thorough the nasopharynx and the nasal passages to outside. Also while the air is inhaled, some of the vapor from the oral rinse is naturally passed along with the inhaled air through the larynx, over the vocal cords, and through trachea to the lungs. Also during this 40 seconds the mouthwash fluid should be swished around the mouth several times to thoroughly disinfect the mouth. At the end of the 40 seconds the mouthwash should be emptied out from the mouth. Then the mouth should be rinsed with water so that none or minimal amount of the mouthwash remains in the mouth. If one or both of the nasal passages are congested and thus they do not conduct air easily, then this method should be repeated when the passages open up or become less congested.
[0015] Upon feeling any of the minor symptoms discussed above, the gargling method just described should be done at least four times: morning, noon, evening, and night. This minimum frequency is for when no other infected people, such as family members, coworkers, classmates, etc., with developed symptoms are around. If such people also exist, or if a major upper respiratory tract infection epidemic is going on, then this gargling method should be repeated approximately every two hours from right after getting up, to bed time.
[0016] During the “cold and flue” eason, even if no symptoms exist, as a precaution and as a preventive mechanism, the method described above should be undertaken with frequency reduced to two times, once in the morning right after rising, and once before sleeping at night. Also, during the cold and flue season, within one hour of a meeting with people, the gargling method described above should be done.
[0017] It should be noted that the 15 ml of mouthwash and 40 seconds duration of gargling are the amount and duration suitable for a healthy adult of medium weight. The amount and duration vary with the age and weight of the person using the method of this invention, as well as with other factors such as tolerance for the “effective formula”. These various amounts and durations need to be determined through research and they need to be tabulated for various ages, weights, and other factors.
[0018] Also it should be noted that in case the respiratory infection has already entered its developed stages, then the method of this invention still is helpful by preventing and or minimizing the secondary infections. Thus, the person who has developed the full symptoms of the common cold or influenza, should implement the more frequent (that is every two hours) gargling method described above.
[0019] Detailed research is necessary to come up with a better “effective formula” than the example given in this application (i.e. the oral rinse), in terms of suitability for age, health, handicap, or other factors such as tolerance for taste, odor, etc. I theorize that such better formulae are quite possible. They can be in various forms: different oral rinse, vapors, sprays, injections, tablets, etc., which each could be suitable for a given category of end users such as human beings (children, adults, young, old, male, female) and other mammals.
[0020] Also research is necessary to reduce the side effects of the “effective formulae”. In the case of the oral rinse, the side effects, although not harmful and quite tolerable, never the less did exist and included bad taste, odor, burning sensation of throat, and the pharynx and the nasopharynx.
[0021] It should be noted that the method of this invention should not be used as a substitution for other established helpful procedures for good health and prevention of respiratory infections. These other procedures include: often washing hands thoroughly with soap and water; washing face, nose, eyes; not touching dirty hands to the eyes, nose, ears, mouth, and face; resting well, eating well, and exercising. Rather, the method presented here should be used in conjunction with these other good health procedures.
[0022] Finally, although the above discussion has been primarily regarding the common upper respiratory tract infections, I theorize that the above discussion holds true regarding most, if not all, other types of respiratory infections. Also the method presented here is applicable to other mammals as well, with a suitable “effective formula” administered on a regular periodic basis during the epidemic breakouts and/or during the season for a particular respiratory infection.
EXAMPLES
Example 1
[0023] A 44 years old male had experienced minor throat irritation. The method of this invention was applied as described in this application. The symptoms went away and no “cold or flue” developed.
Example 2
[0024] A 77 years old male had experienced some “early warning symptoms” as described in this application, he utilized the method of this invention. Again no cold or flue developed.
Example 3
[0025] An 11 years old female had experienced some of the minor symptoms described here, she implemented the method of this invention, again as a result no cold or flue developed.
Example 4
[0026] A couple both had similar minor symptoms as described in this patent application. The husband did follow the guidelines for implementing the method of this invention, and the wife didn't. The husband did not develop any cold or flue, while the wife developed a major case of influenza.
Example 5
[0027] A five years old male was experiencing some of the minor symptoms described above, he was helped to implement the method of this invention, he did not develop a cold or flue. | A method is presented for prevention of various respiratory infections which can be caused by one or more pathogens (bacteria, viruses, and fungi) including, but not limited to, those causing the various forms of upper respiratory tract infection (common cold), influenza, bronchitis, laryngitis, etc. in human being, by using a non-toxic, easily accessible to public “effective formula” to attack the newly activated or the newly invading pathogen and rendering it ineffective. If the infection has already fully taken effect, the present method helps reduce the symptoms of the infection (illness) and its duration by preventing occurrence of secondary infections. This method may also be applied to other mammals. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to an improved spiked-drum type fruit harvester.
The high cost of hand harvesting and difficulty of engaging suitable labor at critical times of harvest are serious problems for the fruit grower. The general purpose of this invention is to provide an improved harvesting device that will reduce labor cost and improve the economics and quality of the harvest. This is accomplished by oscillating the spikes or rods of the fruit harvester in a manner to achieve uniform acceleration and displacement to the fruiting canopy, thereby effecting efficient fruit removal. Although designed for brambles, it is envisioned that the improved shaker will have application to other small fruits such as blueberries and grapes.
Among the known types of mechanical harvesters for small fruit the spiked-drum shaker is preferred, because the spikes or rods gently enter the fruiting canopy as the harvester moves along the row. Oscillation of the spikes frees the ripe fruit from the entire canopy with minimal damage to the fruit or vine. The spiked-drum shaker is adaptable to continuous operation of the harvester along the row and to different configurations of the fruiting canopy.
Uniform acceleration of the spikes is a particularly desirable feature of the spiked-drum shaker. This results in uniform displacement of the fruiting canopy, and the force of oscillation may then be adjusted to the minimum amount required to remove the fruit with minimal damage to the vines. Uniformity of shaking action allows for better selectivity in removing mature fruit and leaving immature on the vine.
Heretofore it has not been possible to achieve uniform acceleration of the spikes in the same plane as the rotation of the drum as the harvester moves along the row.
Christie et al., U.S. Pat. No. 3,325,984 (June 20, 1967), describe a spiked-drum shaker oscillated by a directeccentric drive that gives uniform acceleration of the spike but oscillates in a motion perpendicular to the rotation of the drum.
Oscillation in the same plane as the rotation of the drum is provided by Perties with an eccentric cam, U.S. Pat. No. 3,255,578 (June 14, 1966), and by Weygandt et al. with weighted eccentrices, U.S. Pat. No. 3,245,211 (Apr. 12, 1966), but these methods produce substantial differences in acceleration at different points on the spike.
SUMMARY OF THE INVENTION
We have now found that a spiked-drum shaker, designed so that the point of oscillation is located at a distance from the point of rotation, is effective in providing more uniform acceleration along the spikes than previously described shakers.
It is an object of this invention to provide an improved spiked-drum shaker that oscillates in the same plane as the rotation of the drum as the harvester moves along the row, and with substantially uniform acceleration along the spikes.
It is a further object of the invention to provide an improved spiked-drum shaker with means to control the force required to cause rotation of the drum.
It is a further object of this invention to provide a shaker capable of adjustment so that the proper force may be applied to remove substantially all fruit of a predetermined degree of ripeness.
It is a further object of the invention to provide a unique shaking action that effects positive displacement in one direction and variable displacement in the opposite direction.
It is a further object of the invention to provide a mechanical harvester that is mechanically simple, easily maintained, and economically efficient.
Other objects and advantages of this invention will become obvious from examination of the drawings and the ensuing detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The various aspects of this invention will be more fully understood when the specification is read in conjunction with the accompanying drawings, wherein:
FIG. 1 is a side view of the improved spiked-drum shaker. FIG. 2 is an end view of the shaker. FIG. 3 is a top view of the shaker.
FIG. 4 is a detailed schematic drawing of the friction pad to control rotation of the drum.
FIGS. 5 and 6 are schematic diagrams of a ratchet to control rotation of the drum.
FIG. 7 shows a schematic diagram of the displacement or acceleration of the spikes in the improved shaker compared to the inertia drive and cam drive shaker.
FIGS. 8, 9, and 10 show application of the new shaker to various trellis configurations.
FIG. 11 shows a multiple drum side by side configuration, which is the preferred embodiment of the invention.
FIG. 12 shows a multiple drum diagonally opposite configuration.
DETAILED DESCRIPTION OF THE INVENTION
This shaker is designed to operate within the framework of a mechanical harvester, which comprises a ground-traversing carriage, means for supporting and powering the shakers, and means mounted beneath the shaker to collect the fruit shaken from the plants. A typical harvester is described by Christie et al. (supra).
The shaker can be easily positioned to accommodate a variety of cultural training practices including the "V" trellis, "T" trellis, and vertical or conventional trellis, as shown in FIGS. 8, 9, and 10. It is anticipated that the spiked-drum shaker would be mounted in a mechanical harvester so that it can be moved continuously along the fruiting canopy while harvesting.
The main components of the preferred configuration of the shaker are illustrated in FIGS. 1, 2, and 3. These comprise a stationary frame 1, oscillating arms 2, a set of eccentric drive means 3, a series of rod or spike panels 4, and a drag or ratchet mechanism 5.
The rigid frame is securely attached to the harvester frame and provides support for a driving means such as a hydraulic motor 7 for the eccentric drive mechanism. The rigid frame also provides support for the oscillating arms by multiple bearings 8 at the oscillating points. The oscillating arms have bearings 9 at the rotating points that support the rod panels and allow them to rotate through the fruiting canopy.
Each rod panel comprises flexible rods or spikes 10 constructed of nylon or other suitable material radially spaced at equal angles and securely fastened to rigid disks 11. Each disk is securely fastened to a rigid tube 12, which has a shaft 13 on each end that is supported by the bearings on the oscillating arms.
The shaker is oscillated by a set of eccentric drives joined by connecting rods 27 to the oscillating arms at pin 28. Power from the hydraulic motor is supplied to the eccentric drives by a conventional drive consisting of chains, sprockets, and drive shafts. Each spiked drum is driven in opposite direction to the other to provide for a balanced shaking action. The frequency of oscillation can be easily controlled by conventional means, such as varying the flow of fluid to the hydraulic motor. The length of shaker stroke can be varied by changing the throw on the crank. It is obvious that optimum frequency of oscillation would vary depending upon the particular fruit to be harvested and the configuration of the fruiting canopy. Oscillation of the shaker of the present invention may be varied from about 2 to 15 hz, with a preferred frequency of about 8 hz.
The details of the drag mechanism are shown in FIG. 4 (drag disk). For each drag mechanism, a smooth drag disk 14 is securely fastened to the rod support shaft 13. A friction pad 15 affixed to a pad support plate 16, which is positioned by the pad support rod 17 and guide rod 18, is pressed against the drag disk to create friction to resist rotation of the rods.
The force generated to resist rotation is adjustable by means of a spring 19 and force-adjusting bolt 20 operating in support tubes 21.
Force on the friction pad is set so that oscillation of the rods transmits sufficient energy to the vines or canes to remove fruit but allows rotation of the rods through the fruiting canopy as the harvester moves continuously along the row.
If the force to remove the fruit exceeds the force that allows the rods to freely rotate through the canopy, a ratchet mechanism illustrated in FIGS. 5 and 6 is an alternative to the drag mechanism. As shown, the ratchet wheel 22 is mounted on the rod support shaft and allows clockwise rotation around point 9 as the harvester moves forward.
No counterclockwise rotation is allowed around point 9. Force to hold the ratchet wheel is applied by a force-adjusting bolt 24 acting upon the ratchet spring 23 and pawl 26, which rests upon a pivot 25.
Since the rotation point is between the oscillating point and the tips of the rod, rearward movement of the oscillating frame will cause a positive displacement of the rods because of the restricted rotation about point 9. Movement in the forward direction will cause a variable displacement of the rods, depending on the force of the ratchet spring against the pawl. The greater the force on the panel, the greater is the force imparted by the rods in the forward direction; but there is more resistance to rotation of the rods through the fruiting canopy.
A clutch 29 is used to support the ratchet wheel on the rod support shaft and acts as a safety device during the positive displacement of the rods. The clutch is set at a force/slip level high enough to transmit sufficient energy for fruit removal, but it prevents damage if the rods engage a rigid object such as a trellis support member.
As illustrated in FIG. 7, this invention imparts shaking forces and accelerations parallel along the row with a direct eccentric drive. The displacement and acceleration of the shaking rods are more uniform than with inertia or cam-drive on conventional spiked-drum shakers. As an example, comparing the displacement of rods on a 30" diameter spiked wheel, a 1" displacement of the rod at the tip yields 0.63", 0.27", and 0.15" at 11" from the tip for the direct drive, inertia drive, and cam drive, respectively. This action allows the direct drive shaker to transfer more uniform force and acceleration to the fruiting canopy than do the inertia or cam-driven shakers. The direct eccentric drive shaker has fewer moving parts than either the inertia or cam-driven shaker.
It is desirable to mount multiple drums on a mechanical harvester to increase efficiency in fruit removal and to minimize vibration of the harvester frame. Other drive mechanisms will also be obvious to those skilled in this area. FIGS. 11 and 12 illustrate examples of different arrangements of drums and drive mechanisms. The preferred configuration is shown in FIG. 11, since this configuration permits it to be easily adapted to a variety of trellis systems.
It is apparent that as a harvester equipped with spiked drum shakers traverses a canopy, preferably straddling the fruiting vines or canes, the rods or spikes will contact each bush at the side thereof. The spiked drum is not rotated by direct means and may either rotate with the movement of the harvester or be held against rotation. The rods may be swung by the branches so as to project into the canopy. This results in minimum injury to the branches but allows the rods to contact each branch. The oscillating motion of the rods is thereby transferred to substantial portions of the canopy at different elevations. This permits shaking of all portions of the canopy and efficient removal of the fruit therefrom, and collection by a collector means located under the spiked-drum shaker.
In many canopy configurations, particularly with brambles, it is desirable to shake in a horizontal direction or opposite to the principal orientation of the vines. This may be accomplished with the direct eccentric drive shaker described in this invention.
While the preferred embodiment of this invention has been illustrated, it is understood that changes in construction and configuration may be made without departing from the spirit of the invention, which is defined by the claims. | An improved shaking mechanism for small fruits is described. The shaker comprises panels of radially spaced flexible rods which are oscillated by a positive displacement, direct drive that gives more uniform acceleration and displacement along the length of the rods than do conventional inertia and cam-drive shakers. Shaker design is mechanically simple and reliable. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates to novel bisazo compounds and electrophotographic photoconductors comprising the bisazo compounds, and more particularly to novel bisazo compounds and an electrophotographic photoconductor comprising, on an electroconductive support material, a photoconductive layer containing any of the novel bisazo compounds.
Conventionally, a variety of inorganic and organic electrophotographic photoconductors are known. As inorganic photoconductors for use in electrophotography, there are known types, in which the photoconductive material is, for instance, selenium, cadmium sulfide, or zinc oxide. In an electrophotographic process, a photoconductor is first exposed to corona charges in the dark so as to electrically charge the surface of the photoconductor uniformly. The thus uniformly charged photoconductor is then exposed to original light images and the portions exposed to the original light images selectively become electroconductive, so that electric charges dissipate from the exposed portions of the photoconductor, whereby latent electrostatic images corresponding to the original light images are formed on the surface of the photoconductor. The latent electrostatic images are then developed by the so-called toner which comprises a colorant, such as a dye or a pigment, and a binder agent made, for instance, of a polymeric material; thus, visible developed images can be obtained on the photoconductor. It is necessary that photoconductors for use in electrophotography have at least the following fundamental properties: (1) chargeable to a predetermined potential in the dark; (2) minimum electric charge dissipation in the dark; and (3) quick dissipation of electric charges upon exposure to light.
While the above-mentioned inorganic electrophotographic photoconductors have many advantages over other conventional electrophotographic photoconductors, at the same time they have several shortcomings from the viewpoint of practical use.
For instance, a selenium photoconductor, which is widely used at present, meets the above-mentioned three conditions (1) through (3) fairly well, but it has the shortcomings that it is difficult to work it into the form of a belt due to its poor flexibility, and it is so vulnerable to mechanical shocks that it must be handled with the utmost care. Other inorganic electrophotographic photoconductors have similar shortcomings to those of the selenium photoconductor.
Recently, electrophotographic photoconductors, employing a variety of organic photoconductive materials have been investigated, developed in order to eliminate the shortcomings of the inorganic electrophotographic photoconductors and some of them are in fact employed for practical use. Representative examples of such organic electrophotographic photoconductors are an electrophotographic photoconductor having a photoconductive layer comprising poly-N-vinylcarbazole and 2,4,7-trinitro-fluorene-9-one (U.S. Pat. No. 3,484,237); a photoconductor having a photoconductive layer comprising poly-N-vinylcarbazole which is sensitized by a pyrylium salt type coloring material (Japanese Patent Publication No. 48-25658); a photoconductor having a photoconductive layer comprising as the main component an organic pigment (Japanese Laid-Open patent application No. 47-37543); and a photoconductor having a photoconductive layer which contains as the main component an eutectic crytaline complex consisting of a dye and a resin (Japanese Laid-Open patent application No. 47-10735).
Although the above-mentioned organic electrophotographic photoconductors have many advantages over other conventional inorganic electrophotographic photoconductors, in particular, with respect to the mechanical strength and flexibility, they still have several shortcomings from the viewpoint of practical use. In particular, they are relatively low in electrophotographic photosensitivity.
Further, there is known an electrophotographic photoconductor comprising, on an electrically conductive support material, a photoconductive layer which contains an azo compound. An example of such electrophotographic photoconductor is disclosed in Japanese Patent Publication Ser. No. 44-16474, in which a monoazo compound is employed in the photoconductive layer. Another example is an electrophotographic photoconductor employing a benzidine-type bisazo compound, which is disclosed in Japanese Laid-open patent application Ser. No. 47-37543. A further example is an electrophotographic photoconductor employing a bisazo compound having a stilbene skelton, which is disclosed in Japanese Laid-open patent application Ser. No. 53-133445. The above azo compounds are in fact useful materials for the photoconductive layers of electrophotographic photoconductors. However, they also have several shortcomings from the viewpoint of practical use, particularly in terms of photosensitivity and flexibility.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide novel bisazo compounds and an electrophotographic photoconductor comprising, on an electroconductive support material, a photoconductive layer comprising any of the novel bisazo compound, which electrophotographic photoconductors has high photosensitivity and high flexibility.
The bisazo compound according to the present invention are represented by the following general formula: ##STR3## where n is an integer of 2 or 3, and when n=2, substituent A is ##STR4## and when n=3, the substituent A is the above (a), (b) or (c), wherein R 1 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; X is an unsubstituted or substituted cyclic hydrocarbon group, or an unsubstituted or substituted heterocyclic group; Y is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, or ##STR5## (in which R 4 is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted styryl group; R 5 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; or R 4 and R 5 can form a ring in combination with carbon atoms bonded to R 4 and R 5 ); R 2 is an unsubstituted or substituted hydrocarbon group; R 3 is an alkyl group or a carboxyl group or an ester group thereof; and Ar is an unsubstituted or substituted cyclic hydrocarbon group.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings,
FIG. 1 is an infrared spectrum of a tetrazonium salt prepared in Example 1-1.
FIG. 2 is an infrared spectrum of a bisazo compound No. 1-1 prepared in Example 1-1.
FIG. 3 is an infrared spectrum of a bisazo compound No. 1-66 prepared in Example 1-15.
FIG. 4 is an infrared spectrum of a tetrazonium salt prepared in Example 2-1.
FIG. 5 is an infrared spectrum of a bisazo compound No. 2-1 prepared in Example 2-1.
FIG. 6 is an infrared spectrum of a bisazo compound No. 2-66 prepared in Example 1-19.
FIG. 7 is a schematic illustration in explanation of the structure of an electrophotographic photoconductor according to the present invention.
FIG. 8 is a schematic illustration in explanation of the structure of another electrophotographic photoconductor according to the present invention.
FIG. 9 is a schematic illustration in explanation of the structure of a further electrophotographic photoconductor according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As mentioned previously, the bisazo compounds according to the present invention are those having the structural formula: ##STR6## where n is an integer of 2 or 3, and when n=2, substituent A is ##STR7## and when n=3, the substituent A is the above (a), (b) or (c), wherein R 1 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; X is an unsubstituted or substituted cyclic hydrocarbon group, or an unsubstituted or substituted heterocyclic group; Y is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, or ##STR8## (in which R 4 is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted styryl group; R 5 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; or R 4 and R 5 can form a ring in combination with carbon atoms bonded to R 4 and R 5 ); R 2 is an unsubstituted or substituted hydrocarbon group; R 3 is an alkyl group or a carboxyl group or an ester group thereof; and Ar is an unsubstituted or substituted cyclic hydrocarbon group.
An electrophotographic photoconductor according to the present invention contains any of the bisazo compounds of the above formula in the photoconductive layer thereof.
In the above formula, specific examples of the cyclic hydrocarbon group represented by X are a benzene ring and a naphthalene ring. Specific examples of the heterocyclic group represented by X are an indole ring, a carbazole ring and a benzofuran ring. Specific examples of the cyclic hydrocarbon ring represented by Y and R 4 are a phenyl group, a naphthyl group, an anthryl group and a pyrenyl group. Specific examples of the heterocyclic group represented by Y and R 4 are a pyridyl group, a thienyl group, a furyl group, an indolyl group, a benzofuranyl group, a carbazolyl group and a dibenzofuranyl group. An example of the ring formed by R 4 and R 5 in combination with carbon atoms is a fluorene ring. Specific examples of the hydrocarbon group represented by R 2 are an alkyl group, such as a methyl group, an ethyl group and a butyl group, a propyl group; and an unsubstituted or substituted aryl group, such as a phenyl group. Examples of a substituent of the hydrocarbon group represented by R 2 are an alkyl group, such as a methyl group, an ethyl group, a propyl group and a butyl group; an alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group and butoxy group; a halogen, such as chlorine and bromine; a hydroxyl group; and a nitro group. Examples of a substituent of the phenyl group represented by R 1 and examples of a substituent of the cyclic hydrocarbon group and the heterocyclic group represented by X are a halogen, such as chlorine and bromine. Specific examples of a substituent of the cyclic hydrocarbon group and the heterocyclic group represented by Y or R 4 , and specific examples of a substituent of the ring formed by R 4 and R 5 are an alkyl group, such as a methyl group, an ethyl group, a propyl group and a butyl group; an alkoxy group, such as a methoxy group, an ethoxy group, a propoxy group; a halogen, such as chlorine and bromine; a dialkyl amino group, such as a dimethylamino group and a diethylamino group; a diaralkylamino group, such as a dibenzylamino group; a halomethyl group, such as a trifluoromethyl group; a nitro group; a cyano group; a carboxyl group and an ester group thereof; a hydroxyl group; and a sulfonic group, such as --SO 3 Na. Specific examples of the cyclic hydrocarbon group represented by Ar are a phenyl group and a naphthyl group. Substituents of Ar are, for example, an alkyl group, such as a methyl group, an ethyl group, a propyl group and a butyl group; an alkoxy group, such as a methoxy group, a propoxy group and a butoxy group; a nitro group; a halogen, such as chlorine and bromine; a cyano group; and a dialkylamino group, such as a dimethylamino group and a diethylamino group.
Specific examples of the bisazo compounds of the above formula are shown below only by showing the structure of the substituent A in the following general formula of the bisazo compounds according to the present invention: ##STR9## where n=2 or 3.
The prefixes 1- and 2- of the numbers of the following bisazo compounds respectively indicate the bisazo compounds in which n is 2, and the bisazo compounds in which n is 3.
______________________________________BisazoCompoundNo. A______________________________________1-1 2-1 ##STR10##1-2 2-2 ##STR11##1-3 2-3 ##STR12##1-4 2-4 ##STR13##1-5 2-5 ##STR14##1-6 2-6 ##STR15##1-7 2-7 ##STR16##1-8 2-8 ##STR17##1-9 2-9 ##STR18##1-10 2-10 ##STR19##1-11 2-11 ##STR20##1-12 2-12 ##STR21##1-13 2-13 ##STR22##1-14 2-14 ##STR23##1-15 2-15 ##STR24##1-16 2-16 ##STR25##1-17 2-17 ##STR26##1-18 2-18 ##STR27##1-19 2-19 ##STR28##1-20 2-20 ##STR29##1-21 2-21 ##STR30##1-22 2-22 ##STR31##1-23 2-23 ##STR32##1-24 2-24 ##STR33##1-25 2-25 ##STR34##1-26 2-26 ##STR35##1-27 2-27 ##STR36##1-28 2-28 ##STR37##1-29 2-29 ##STR38##1-30 2-30 ##STR39##1-31 2-31 ##STR40##1-32 2-32 ##STR41##1-33 2-33 ##STR42##1-34 2-34 ##STR43##1-35 2-35 ##STR44##1-36 2-36 ##STR45##1-37 2-37 ##STR46##1-38 2-38 ##STR47##1-39 2-39 ##STR48##1-40 2-40 ##STR49##1-41 2-41 ##STR50##1-42 2-42 ##STR51##1-43 2-43 ##STR52##1-44 2-44 ##STR53##1-45 2-45 ##STR54##1-46 2-46 ##STR55##1-47 2-47 ##STR56##1-48 2-48 ##STR57##1-49 2-49 ##STR58##1-50 2-50 ##STR59##1-51 2-51 ##STR60##1-52 2-52 ##STR61##1-53 2-53 ##STR62##1-54 2-54 ##STR63## 1-55 2-55 ##STR64##1-56 2-56 ##STR65##1-57 2-57 ##STR66##1-58 2-58 ##STR67##1-59 2-59 ##STR68##1-60 2-60 ##STR69##1-61 2-61 ##STR70##1-62 2-62 ##STR71##1-63 2-63 ##STR72##1-64 2-64 ##STR73##1-65 2-65 ##STR74##1-66 2-66 ##STR75##1-67 2-67 ##STR76##1-68 2-68 ##STR77##1-69 2-69 ##STR78##1-70 2-70 ##STR79##1-71 2-71 ##STR80##1-72 2-72 ##STR81##1-73 2-73 ##STR82##1-74 2-74 ##STR83##1-75 2-75 ##STR84##1-76 2-76 ##STR85##1-77 2-77 ##STR86##1-78 2-78 ##STR87##1-79 2-79 ##STR88##1-80 2-80 ##STR89##1-81 2-81 ##STR90##1-82 2-82 ##STR91##1-83 2-83 ##STR92##1-84 2-84 ##STR93##1-85 2-85 ##STR94##1-86 2-86 ##STR95##1-87 2-87 ##STR96##1-88 2-88 ##STR97##1-89 2-89 ##STR98##1-90 2-90 ##STR99##1-91 2-91 ##STR100##1-92 2-92 ##STR101##1-93 2-93 ##STR102##1-94 2-94 ##STR103##1-95 2-95 ##STR104##1-96 2-96 ##STR105##1-97 2-97 ##STR106##1-98 2-98 ##STR107##1-99 2-99 ##STR108##1-100 2-100 ##STR109##1-101 2-101 ##STR110##1-102 2-102 ##STR111##1-103 2-103 ##STR112##1-104 2-104 ##STR113##1-105 2-105 ##STR114##1-106 2-106 ##STR115##1-107 2-107 ##STR116##1-108 2-108 ##STR117##1-109 2-109 ##STR118##1-110 2-110 ##STR119##1-111 2-111 ##STR120##1-112 2-112 ##STR121##1-113 2-113 ##STR122##1-114 2-114 ##STR123##1-115 2-115 ##STR124##1-116 2-116 ##STR125##1-117 2-117 ##STR126##1-118 2-118 ##STR127##1-119 2-119 ##STR128##1-120 2-120 ##STR129##1-121 2-121 ##STR130##1-122 2-122 ##STR131##1-123 2-123 ##STR132##1-124 2-124 ##STR133##1-125 2-125 ##STR134##1-126 2-126 ##STR135##1-127 2-127 ##STR136##1-128 2-128 ##STR137##1-129 2-129 ##STR138##1-130 2-130 ##STR139##1-131 2-131 ##STR140##1-132 2-132 ##STR141##1-133 2-133 ##STR142##1-134 2-134 ##STR143##1-135 2-135 ##STR144##1-136 2-136 ##STR145##1-137 2-137 ##STR146##1-138 2-138 ##STR147##1-139 2-139 ##STR148##1-140 2-140 ##STR149##1-141 2-141 ##STR150##1-142 2-142 ##STR151##1-143 2-143 ##STR152##1-144 2-144 ##STR153##1-145 2-145 ##STR154##1-146 ##STR155##1-147 ##STR156##1-148 ##STR157##1-149 ##STR158##1-150 ##STR159##______________________________________
The above bisazo compounds of the formula (I) can be prepared by reacting a tetrazonium salt of the following formula (II) with any of the following couplers of the formulae (III)-a through (III)-d, provided that the coupler of the formula (III)-d is not employed when the bisazo compounds with n=3 is prepared. ##STR160## where Z is an anionic functional group, and n is an integer of 2 or 3. ##STR161## wherein R 1 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; X is an unsubstituted or substituted cyclic hydrocarbon group, or an unsubstituted or substituted heterocyclic group; Y is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, or ##STR162## (in which R 4 is an unsubstituted or substituted cyclic hydrocarbon group, an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted styryl group; R 5 is hydrogen, an alkyl group, an unsubstituted or substituted phenyl group; or R 4 and R 5 can form a ring in combination with carbon atoms bonded to R 4 and R 5 ); R 2 is an unsubstituted or substituted hydrocarbon group; R 3 is an alkyl group or a carboxyl group or an ester group thereof; and Ar is an unsubstituted or substituted cyclic hydrocarbon group.
More specifically, a bisazo compound of the following formula can be prepared as follows, ##STR163## which bisazo compound corresponds to a bisazo compound of the above described general formula (I) in which n=2 and the substituent A is the same as that defined in the general formula (I).
A tetrazonium salt for use in preparing the above bisazo compound is prepared by reducing, for example, 1,4-bis(4-nitrophenyl)-1,3-butadiene to obtain 1,4-bis(4-aminophenyl)-1,3-butadiene and by subjecting the thus obtained 1,4-bis(4-aminophenyl)-1,3-butadiene to diazotization.
More specifically, 1,4-bis(4-nitrophenyl)-1,3-butadiene can be prepared by the so-called Wittig-Horner reaction in which 4-nitrocinnamaldehyde is made to react with diethyl 4-nitrobenzylphosphonate. The 1,4-bis(4-nitrophenyl)-1,3-butadiene is then reduced to prepare 1,4-bis(4-aminophenyl)-1,3-butadiene, in an organic solvent, such as N,N-dimethylformamide, in the presence of a reducing agent, such as a mixture of iron and hydrochloric acid. This reduction reaction terminates within a period of 30 minutes to 2 hours when the reaction temperature is in the range of 70° C. to 120° C.
Diazotization of the thus prepared 1,4-bis(4-aminophenyl)-1,3-butadiene is conducted as follows:
1,4-bis(4-aminophenyl)-1,3-butadiene is added to a dilute inorganic acid, such as dilute hydrochloric acid or dilute sulfuric acid. To this mixture is added an aqueous solution of sodium nitrite, while maintaining the temperature of the reaction mixture in the range of -10° C. to 10° C. This diazotization reaction terminates within 30 minutes to 3 hours. It is preferable that the diazonium compound of 1,4-bis(4-aminophenyl)-1,3-butadiene be separated in the form of a tetrazonium salt by adding, for example, fluoboric acid to the reaction mixture, to precipitate the tetrazonium salt. The tetrazonium salt is then separated from the reaction mixture by filtration. To the thus obtained tetrazonium salt is added one of the above-described coupling components in an amount of 1 to 10 moles, preferably in an amount of 2 to 5 moles, with respect to one mole of the tetrazonium salt, so as to allow a coupling reaction. In practice, this coupling reaction is accomplished by dissolving both the tetrazonium salt and the coupling component in an organic solvent, such as N,N-dimethylformamide or dimethyl sulfoxide and then adding dropwise an alkaline aqueous solution, such as an aqueous solution of sodium acetate, to the reaction mixture, while maintaining the reaction mixture at temperatures between approximately -10° C. to 10° C. Thus, a novel bisazo compound of the formula (I)-1 according to the present invention can be obtained.
The invention will now be described in more detail by referring to the following examples:
EXAMPLE 1-1
(1) Preparation of Diazonium Salt
13.0 g of 1,4-bis(4-aminophenyl)-1,3-butadiene was added to a dilute sulfuruc acid prepared by mixing 200 ml of water and 17 ml of concentrated sulfuric acid. The mixture was stirred at 60° C. for 30 minutes and was then cooled rapidly to 0° C. To the mixture, there was added dropwise with stirring, over a period of 40 minutes, an aqueous solution of sodium nitrite prepared by dissolving 8.40 g of sodium nitrite in 30 ml of water, while maintaining the reaction mixture at temperatures ranging from 0° C. to 1° C. The reaction mixture was further stirred in the same temperature range for 30 minutes.
Unreacted materials, which were small in amount, were removed from the reaction mixture by filtration. To the filtrate was then added 60 ml of a 42% fluoboric acid. Orange crystals separated, which were collected on a suction funnel and washed with a small amount of methanol and dried, whereby the desired tetrazonium difluoroborate was obtained in the form of orange needle-like crystals. The yield was 19.7 g (82.0%). The decomposition point of the thus obtained tetrazonium salt was 115° C. An infrared spectrum of the tetrazonium salt taken by use of a KBr tablet indicated an infrared absorption at 2,200 cm -1 characteristic of the --N═N-- bonds in the tetrazonium salt. This infrared spectrum is shown in FIG. 1.
(2) Preparation of Diazo Compound No. 1-1
2.77 g of 2-hydroxy-3-naphthoic acid anilide (a coupling component) was dissolved in 340 ml of N,N-dimethylformamide. To this solution, 2.17 g of the tetrazonium salt prepared in the above (1) was added. To the mixture, an aqueous solution of sodium acetate prepared by dissolving 1.64 g of sodium acetate in 18 ml of water was added dropwise over a period of 50 minutes, while the temperature of the reaction mixture was maintained at 20° C. to 26° C. After the dropwise addition of the sodium acetate aqueous solution, the reaction mixture was stirred at room temperature for 3 hours. Precipitates were formed. The precipitates were collected by filtration and were then washed with N,N-dimethylformamide three times, using 350 ml thereof at each time. The precipitates were then washed with water two times, using 350 ml thereof at each time. The thus purified precipitates were then dried under reduced pressure, with application of heat thereto, whereby a bisazo compound No. 1-1 shown in Table 3 was obtained. The yield was 3.53 g (90.0%).
The elemental analysis of the bisazo compound indicated as follows:
______________________________________ Calculated Found______________________________________% C 76.50 76.33% H 4.63 4.53% N 10.71 10.55______________________________________
An infrared spectrum of this bisazo compound, taken by use of a KBr tablet, which is shown in FIG. 2, indicated an infrared absorption at 1680 cm -1 characteristic of the secondary amide.
EXAMPLES 1-2˜1-14
Example 1-1 was repeated except that the coupling component employed in Example 1-1 was replaced by the coupling components listed in Table 1, whereby bisazo compounds Nos. 1-29, 1-3, 1-2, 1-7, 1-4, 1-5, 1-6, 1-8, 1-19, 1-15, 1-13, 1-14 and 1-21 were prepared, which bisazo compounds are listed in Table 3.
TABLE 1__________________________________________________________________________Compound CompoundNo. Coupling Component No. Coupling Component__________________________________________________________________________1-29 ##STR164## 1-3 ##STR165##1-2 ##STR166## 1-7 ##STR167##1-4 ##STR168## 1-5 ##STR169##1-6 ##STR170## 1-8 ##STR171##1-19 ##STR172## 1-15 ##STR173##1-13 ##STR174## 1-14 ##STR175##1-21 ##STR176##__________________________________________________________________________
EXAMPLE 1-15
1.48 g of 2-hydroxy-3-phenylcarbamoyl-11H-benzo[a] carbazole (coupling component) was dissolved in 140 ml of N,N-dimethylformamide. To this solution, 0.87 g of the tetrazonium salt prepared in Example 1-1 was added. To the mixture, a sodium acetate aqueous solution prepared by dissolving 0.69 g of sodium acetate in 7 ml of water was added dropwise over a period of 30 minutes, while the temperature of the reaction mixture was maintained at 20° C. to 25° C. Thereafter, the reaction mixture was stirred at room temperature for 3 hours. The product precipitated was then separated by filtration and was washed with N,N-dimethylformamide three times, using 200 ml thereof at each time, and was then washed with water two times, using 200 ml thereof at each time. The product was dried by application of heat thereto under reduced pressure, whereby bisazo compound No. 1-66 shown in Table 3 was obtained. The yield was 1.67 g (86.5%). An infrared spectrum of this bisazo compound, taken by use of a KBr tablet, is shown in FIG. 3.
EXAMPLES 1-16˜1-26
Example 1-15 was repeated except that the coupling component employed in Example 1-15 was replaced by the coupling components listed in Table 2, whereby bisazo compounds Nos. 1-68, 1-67, 1-44, 1-45, 1-41, 1-42, 1-43, 1-50, 1-47, 1-48 and 1-52 were prepared, which bisazo compounds are listed in Table 3.
TABLE 2__________________________________________________________________________Com- Com-pound poundNo. Coupling Component No. Coupling Component__________________________________________________________________________1-68##STR177## 1-67 ##STR178##1-44##STR179## 1-45 ##STR180##1-41##STR181## 1-42 ##STR182##1-43##STR183## 1-50 ##STR184##1-47##STR185## 1-48 ##STR186##1-52##STR187##__________________________________________________________________________
TABLE 3__________________________________________________________________________ In- fra- red Spec- tra cm.sup.-1 Elemental (KBre Cal- Meth-Com- cu- od)pound lated Found νC =No. Structure Formula of Bisazo Compounds (%) (%) O__________________________________________________________________________1-1##STR188## C H N 76.33 4.53 10.55 76.50 4.63 168011-29##STR189## C H N 73.70 4.53 9.90 73.91 4.78 16701-3##STR190## C H N 73.81 4.63 9.92 73.91 4.78 16751-2##STR191## C H N 76.53 4.79 10.18 76.82 4.97 168041-7##STR192## C H N 76.71 4.79 10.29 76.82 4.97 168041-4##STR193## C H N 70.21 3.97 9.68 70.32 4.02 16801-5##STR194## C H N 68.42 3.82 12.60 68.63 3.92 168011-6##STR195## C H N 68.40 3.93 12.51 68.63 3.92 168011-8##STR196## C H N 73.98 4.90 9.40 74.29 5.09 16751-19##STR197## C H N 71.43 4.90 9.18 71.66 4.91 16701-15##STR198## C H N 70.69 4.31 9.29 70.81 4.35 16801-13##STR199## C H N 70.80 4.31 9.50 70.81 4.35 16801-14##STR200## C H N 76.90 5.21 9.76 77.11 5.28 16801-21##STR201## C H N 66.31 4.20 8.39 66.58 4.36 16751-66##STR202## C H N 77.22 4.21 11.54 77.31 4.40 167041-68##STR203## C H N 75.01 4.51 10.86 75.12 4.54 167051-67##STR204## C H N 75.19 4.68 10.39 75.40 4.80 167061-44##STR205## C H N 75.01 4.55 10.89 75.12 4.54 167051-45##STR206## C H N 74.98 4.45 10.72 75.12 4.54 167051-41##STR207## C H N 77.31 4.49 11.09 77.55 4.69 167511-42##STR208## C H N 77.25 4.48 11.11 77.55 4.69 167511-43##STR209## C H N 77.43 4.48 11.16 77.55 4.69 167511-50##STR210## C H N 70.60 3.72 13.18 70.71 3.84 168001-47##STR211## C H N 72.09 3.91 10.82 72.15 3.91 167561-48##STR212## C H N 71.97 3.80 10.61 72.15 3.91 168061-52##STR213## C H N 77.71 4.92 10.90 77.77 4.95 16700__________________________________________________________________________ Note: Decomposition Point: 250° C. or more
A bisazo compound of the following formula ##STR214## which corresponds to a bisazo compound of the previously described general formula (I) in which n=3 and the substituent A is the same as that defined in the general formula (I), can be prepared in the same manner as in the case of the bisazo compound with n=2.
A tetrazonium salt for use in preparing the above bisazo compound can be prepared by reducing, for example, 1,6-bis(4-nitrophenyl)-1,3,5-hexatriene to obtain 1,6-bis(4-aminophenyl)-1,3,5-hexatriene and by subjecting the thus obtained 1,6-bis(4-aminophenyl)-1,3,5-hexatriene to diazotization.
More specifically, 1,6-bis(4-aminophenyl)-1,3,5-hexatriene can be obtained by reducing 1,6-bis(4-nitrophenyl)-1,3,5-hexatriene in an organic solvent, such as N,N-dimethyl-formamide, in the presence of a reducing agent, such as a mixture of iron and hydrochloric acid, which 1,6-bis(4-nitrophenyl)-1,3,5-hexatriene can be prepared by the so-called Wittig-Horner reaction in which 5-(4-nitro-phenyl)-2,4-pentadienal is made to react with diethyl 4-nitrobenzyl-phosphonate. This reduction reaction terminates within a period of 30 minutes to 2 hours when the reaction temperature is maintained in the range of 70° C. to 120° C.
Diazotization of the thus prepared 1,6-bis(4-aminophenyl)-1,3,5-hexatriene is conducted as follows:
1,6-bis(4-aminophenyl)-1,3,5-hexatriene is added to a dilute inorganic acid, such as dilute hydrochloric acid or dilute sulfuric acid. To this mixture is added an aqueous solution of sodium nitrite, while maintaining the temperature of the reaction mixture in the range of -10° C. to 10° C. This diazotization reaction terminates in 30 minutes to 3 hours. It is preferable that the diazonium compound of 1,6-bis(4-aminophenyl)-1,3,5-hexatriene be separated in the form of a tetrazonium salt by adding, for example, fluoboric acid to the reaction mixture in order to precipitate the terazonium salt. The tetrazonium salt is then separated from the reaction mixture by filtration. To the thus obtained tetrazonium salt is added one of the previously described coupling components in an amount of 1 to 10 moles, preferably in an amount of 2 to 5 moles, with respect to one mole of the tetrazonium salt, so as to allow a coupling reaction. In practice, this coupling reaction is accomplished by dissolving both the tetrazonium salt and the coupling component in an organic solvent, such as N,N-dimethylformamide or dimethyl sulfoxide and then adding thereto dropwise an alkaline aqueous solution, such as an aqueous solution of sodium acetate, while maintaining the reaction mixture at temperatures between approximately -10° C. to 10° C. This reaction terminates within a period of 5 minutes to 30 minutes. Thus, a bisazo compound of the formula (I)-2 according to the present invention can be obtained.
Preparation of the bisazo compounds of the formula (I)-2 according to the present invention will now be described in more detail by referring to the following examples:
EXAMPLE 2-1
(1) Preparation of Diazonium Salt
14.0 g of 1,6-bis(4-aminophenyl)-1,3,5-hexatriene was added to a dilute sulfuric acid prepared by mixing 200 ml of water and 18 ml of concentrated sulfuric acid. The mixture was stirred at 60° C. for 30 minutes and was then cooled rapidly to -1° C. To the mixture, there was added dropwise with stirring, over a period of 50 minutes, an aqueous solution of sodium nitrite prepared by dissolving 8.10 g of sodium nitrite in 25 ml of water, while maintaining the reaction mixture at temperatures ranging from -1° C. to -2° C. The reaction mixture was further stirred at the same temperatures for 10 minutes.
Unreacted materials, which were small in amount, were removed from the reaction mixture by filtration. To the filtrate was then added 60 ml of a 42% fluoboric acid. Red crystals separated, which were collected on a suction funnel and washed with a small amount of methanol and dried, whereby the desired tetrazonium difluoroborate was obtained in the form of red needle-like crystals. The yield was 20.6 g (84.0%).
The decomposition point of the thus obtained tetrazonium salt was 113° C. An infrared spectrum of the tetrazonium salt taken by use of a KBr tablet indicated an infrared absorption at 2,200 cm -1 which is characteristic of the --N═N-- bonds in the tetrazonium salt. This infrared spectrum is shown in FIG. 4.
(2) Preparation of Diazo Compound No. 2-1
1.11 g of 2-hydroxy-3-naphthoic acid anilide (a coupling component) was dissolved in 140 ml of N,N-dimethylformamide. To this solution, 0.97 g of the tetrazonium salt prepared in the above (1) was added. To the mixture, an aqueous solution of sodium acetate prepared by dissolving 0.69 g of sodium acetate in 7 ml of water was added dropwise over a period of 40 minutes, while the temperature of the reaction mixture was maintained at 22° C. to 26° C. After the dropwise addition of the sodium acetate aqueous solution, the reaction mixture was stirred at room temperature for 3 hours. Precipitates were formed, which were collected by filtration and were then washed with N,N-dimethylformamide three times, using 350 ml thereof at each time. The precipitates were then washed with water two times, using 200 ml thereof at each time. The thus purified precipitates were then dried under reduced pressure, with application of heat thereto, whereby a bisazo compound No. 2-1 shown in Table 6 was obtained. The yield was 1.35 g (83.3%).
An infrared spectrum of this bisazo compound, taken by use of a KBr tablet, indicated an infrared absorption at 1680 cm -1 characteristic of the secondary amide, which infrared spectrum is shown in FIG. 5.
EXAMPLES 2-2˜2-18
Example 2-1 was repeated except that the coupling component employed in Example 2-1 was replaced by the coupling components listed in Table 4, whereby bisazo compounds Nos. 2-29, 2-3, 2-2, 2-7, 2-4, 2-5, 2-6, 2-8, 2-19, 2-15, 2-13, 2-14, 2-16, 2-37, 2-38, 2-36 and 2-69 were prepared, which bisazo compounds are listed in Table 6.
TABLE 4__________________________________________________________________________Com- Com-pound poundNo. Coupling Component No. Coupling Component__________________________________________________________________________2-29##STR215## 2-3 ##STR216##2-2##STR217## 2-7 ##STR218##2-4##STR219## 2-5 ##STR220##2-6##STR221## 2-8 ##STR222##2-19##STR223## 2-15 ##STR224##2-13##STR225## 2-14 ##STR226##2-16##STR227## 2-37 ##STR228##2-38##STR229## 2-36 ##STR230##2-69##STR231##__________________________________________________________________________
EXAMPLE 2-19
1.48 g of 2-hydroxy-3-phenylcarbamoyl-11H-benzo[a]carbazole (coupling component) was dissolved in 140 ml of N,N-dimethylformamide. To this solution, 0.92 g of the tetrazonium salt prepared in Example 2-1 was added. To the mixture, a sodium acetate aqueous solution prepared by dissolving 0.69 g of sodium acetate in 7 ml of water was added dropwise over a period of 5 minutes, while the temperature of the reaction mixture was maintained at 26° C. to 30° C. The reaction mixture was stirred at room temperature for 3 hours. Thereafter, the product precipitated was separated by filtration and was washed with N,N-dimethylformamide 4 times, using 200 ml thereof at each time, and was then washed with water 2 times, using 200 ml thereof at each time. The product was dried by application of heat thereto under reduced pressure, whereby a bisazo compound No. 2-66 shown in Table 6 was obtained. The yield was 1.65 g (83.3%). An infrared spectrum of this bisazo compound, taken by use of a KBr tablet, is shown in FIG. 6.
EXAMPLES 2-20˜2-36
Example 2-19 was repeated except that the coupling component employed in Example 2-19 was replaced by the coupling components listed in Table 5, whereby bisazo compounds Nos. 2-68, 2-67, 2-44, 2-45, 2-41, 2-42, 2-43, 2-49, 2-50, 2-51, 2-46, 2-47, 2-48, 2-52, 2-56, 2-53 and 2-55 were prepared, which bisazo compounds are listed in Table 6.
TABLE 5__________________________________________________________________________Com- Com-pound poundNo. Coupling Component No. Coupling Component__________________________________________________________________________2-68##STR232## 2-67 ##STR233##2-44##STR234## 2-45 ##STR235##2-41##STR236## 2-42 ##STR237##2-43##STR238## 2-49 ##STR239##2-50##STR240## 2-51 ##STR241##2-46##STR242## 2-47 ##STR243##2-48##STR244## 2-52 ##STR245##2-56##STR246## 2-53 ##STR247##2-55##STR248##__________________________________________________________________________
TABLE 6 (Decom- Elemental Value Infrared Com- posi- Cal- Spectra cm.sup.-1 pound tion culated Found (KBr Method) No. Structure Formula of Bisazo Compounds Point) (%) (%) νC = O 2-1 ##STR249## (311° C.) CHN 76.89 4.6110.14 77.01 4.7310.37 1680 2-29 ##STR250## (307° C.) CHN 74.21 4.67 9.59 74.46 4.87 9.65 1675 2-3 ##STR251## (311° C.) CHN 74.57 4.78 9.42 74.46 4.87 9.65 1675 2-2 ##STR252## (306° C.) CHN 77.05 4.85 9.78 77.30 5.0610.02 1680 2-7 ##STR253## (312° C.) CHN 77.05 4.96 9.86 77.30 5.0610.02 1680 2-4 ##STR254## (333° C.) CHN 71.05 3.89 9.46 70.97 4.13 9.55 1680 2-5 ##STR255## (318° C.) CHN 68.95 3.8012.19 69.32 4.0412.44 1680 2-6 ##STR256## (336° C.) CHN69.09 3.8212.20 69.32 4.0412.44 1690 2-8 ##STR257## (320° C.) CHN 74.57 5.16 9.23 74.81 5.17 9.35 1675 2-19 ##STR258## (328° C.) CHN 72.01 4.78 8.91 72.23 4.99 9.03 1675 2-15 ##STR259## (321° C.) CHN 71.57 4.20 9.23 71.43 4.45 9.26 1680 2-13 ##STR260## (324° C.) CHN 71.66 4.20 9.09 71.43 4.45 9.26 1680 2-14 ##STR261## (316° C.) CHN 77.39 5.10 9.55 77.57 5.36 9.69 1680 2-16 ##STR262## (313° C.) CHN 68.78 4.21 8.79 69.00 4.30 8.94 1675 2-37 ##STR263## (319° C.) CHN 65.10 4.01 8.22 65.06 4.05 8.43 1675 2-38 ##STR264## (309° C.) CHN 79.02 4.71 8.86 79.29 4.95 8.95 1670 2-36 ##STR265## (321° C.) CHN 75.20 4.30 7.80 75.41 4.42 8.00 1680 2-69 ##STR266## (324° C.) CHN 77.50 4.24 8.46 77.55 4.28 8.48 1675 2-66 ##STR267## (336° C.) CHN 77.51 4.4011.24 77.71 4.4911.33 1675 2-68 ##STR268## (304° C.) CHN 75.56 4.4610.51 75.55 4.6210.68 1670 2-67 ##STR269## (314° C.) CHN 75.52 4.6410.29 75.81 4.8810.40 1670 2-44 ##STR270## (316° C.) CHN 75.28 4.5010.43 75.55 4.6210.68 1675 2-45 ##STR271## (334° C.) CHN 75.54 4.4310.42 75.55 4.6210.68 1680 2-41 ##STR272## (312° C.) CHN 77.66 4.5910.94 77.92 4.7711.02 1680 2-42 ##STR273## (335° C.) CHN 77.83 4.6010.75 77.92 4.7711.02 1680 2-43 ##STR274## (318° C.) CHN 78.02 4.6810.84 77.92 4.7711.02 1680 2-49 ##STR275## (334° C.) CHN 70.95 3.7112.72 71.23 3.9312.98 1680 2-50 ##STR276## (341° C.) CHN 71.04 3.7012.71 71.23 3.9312.98 1680 2-51 ##STR277## (353° C.) CHN 71.11 3.7212.73 71.23 3.9312.98 1690 2-46 ##STR278## (338° C.) CHN 72.85 3.8610.38 72.64 4.0110.59 1680 2-47 ##STR279## (338° C.) CHN 72.66 3.8210.40 72.64 4.0110.59 1680 2-48 ##STR280## (337° C.) CHN 72.57 3.8010.31 72.64 4.0110.59 1675 2-52 ##STR281## (312° C.) CHN 78.24 4.8210.42 78.13 5.0210.72 1675 2-56 ##STR282## (337° C.) CHN 77.95 4.9110.54 78.13 5.0210.72 1675 2-53 ##STR283## (307° C.) CHN 75.55 4.6210.35 75.81 4.8810.40 1670 2-55 ##STR284## (318° C.) CHN 75.63 4.7510.28 75.81 4.8810.40 1670
Electrophotographic photoconductors according to the present invention will now be explained, which contain any of the above-described novel bisazo compounds in the photoconductive layers thereof.
Those photoconductors can be classified into three types in accordance with their structures as shown in FIGS. 7 to 9.
Referring to FIG. 7, there is shown an electrophotographic photoconductor comprising, on an electroconductive support material 1, a photoconductive layer 2a which comprises a bisazo compound 4 dispersed in a resinous binder material 3. In this electrophotographic photoconductor, the bisazo compound 4 works as a photoconductive material.
For the preparation of the photoconductor as shown in FIG. 7, the bisazo compound is ground to small particles with a diameter not greater than 5 μm, preferably not greater than 2 μm, by a ball mill or by other conventional grinding means, and the bisazo compound particles are dispersed in a solution of a binder agent. The bisazo compound dispersion is applied to the electroconductive support material by a conventional method, for instance, by use of a doctor blade or wire bar, and is then dried.
The thickness of the photoconductive layer 2a is in the range of approximately 3 μm to 50 μm, preferably in the range of 5 μm to 20 μm.
In the photoconductor as shown in FIG. 7, the photoconductive layer 2a contains 30 to 70 percent by weight of a bisazo compound, preferably about 50 percent by weight of the same.
In this photoconductor, it is preferable that the bisazo compound particles be present in contact with each other continuously through the photoconductive layer 2a, from the outer surface of the photoconductive layer 2a to the surface of the electroconductive support material 1, because the bisazo compound works as a photoconductive material, by which bisazo compound charge carriers necessary for the light-decay of the photoconductor are formed and through which bisazo compound the charge carriers are transported across the photoconductive layer 2a. In this sense, the greater the content of the bisazo compound in the photoconductive layer 2a, the better the photoconductor in terms of its photoconductive properties. However, in view of the required strength and photosensitivity of the photoconductor, it is most preferable that the photoconductive layer 2a contain approximately 50 percent by weight of the bisazo compound.
Referring to FIG. 8, there is shown another electrophotographic photoconductor according to the present invention, which comprises, on the electroconductive support material 1, a photoconductive layer 2b which comprises the bisazo compound 4 and a charge transporting medium 5 which is a mixture of a charge transporting material and a resinous binder material.
For the preparation of the photoconductor as shown in FIG. 8, the bisazo compound is ground to small particles with a diameter not greater than 5 μm, preferably not greater than 2 μm. The finely ground bisazo compound is dispersed in a solution of a charge transporting material and a binder agent. The content of the bisazo compound in the photoconductive layer 2a is 50 percent by weight or less, while the content of the charge transporting material is in the range of about 10 to 95 percent by weight, preferably in the range of about 30 to 90 percent by weight. The dispersion is applied to the electroconductive support material 1 and is then dried.
The thickness of the photoconductive layer 2b in FIG. 8 is in the range of approximately 3 μm to 50 μm, preferably in the range of 5 μm to 20 μm.
In the photoconductor as shown in FIG. 8, the charge transporting material constitutes a charge transporting medium in combination with the binder material and, when necessary, a plasticizer is added thereto, while the bisazo compound works as the charge carrier producing material. In this photoconductor, the charge carriers which are required for the light-decay of the photoconductor are produced by the bisazo compound, while the produced charge carriers are transported through the charge transporting medium.
Furthermore, in the photoconductor in FIG. 8, it is required that the absorption wavelength range of the charge transporting medium and that of the employed bisazo compound not overlap. More specifically, when visible light is employed for electrostatic latent image formation, it is required that the charge transporting medium be transparent with respect to visible light, allowing visible light to be transmitted without absorption thereof, in order that enough visible light reach the surface of the bisazo compound and cause the bisazo compound to produce charge carriers efficiently.
In any case, it is a fundamental requirement that the absorption wavelength range of the charge transporting medium and that of the employed bisazo compound not overlap in the particular absorption wavelength range corresponding to the desired photosensitive range of the photoconductor.
Referring to FIG. 9, there is shown a further electrophotographic photoconductor according to the present invention, which is a modification of the photoconductor shown in FIG. 8. In this photoconductor, a photoconductive layer 2c comprises a charge carrier producing layer 6 consisting essentially of the bisazo compound 4, and a charge transporting layer 7.
For the preparation of the photoconductor as shown in FIG. 9, the bisazo compound is deposited in a vacuum on an electroconductive support material 1, or the bisazo compound is ground to small particles with a diameter not greater than 5 μm, preferably not greater than 2 μm, and is then dispersed in a solvent, when necessary, with addition of a binder agent thereto, and the dispersion is applied to the electroconductive support material 1 and is then dried. When necessary, the surface of the bisazo compound layer which is the charge carrier producing layer 6 is polished or its thickness is adjusted to an appropriate thickness by buffing the bisazo compound layer or by other conventional methods. Thereafter, a solution of a charge transporting material and a binder agent is applied to the bisazo compound layer and is then dried. Thus, a layered photoconductor as shown in FIG. 9 can be prepared.
In the photoconductor as shown in FIG. 9, the thickness of the charge carrier producing layer 6 is 5 μm or less, preferably 3 μm or less, while the thickness of the charge transporting layer 7 is in the range of approximately 3 μm to 50 μm, preferably in the range of 5 μm to 20 μm.
In the photoconductor as shown in FIG. 9, the content of the charge transporting material in the charge transporting layer 7 is in the range of about 10 to 95 percent by weight, preferably in the range of about 30 to 90 percent by weight.
In the photoconductor as shown in FIG. 9, light that passes through the charge transporting layer 7 reaches the charge carrier producing layer 6, in which charge carrier producing layer 6 charge carriers are produced by the bisazo compound 4. The charge transporting layer 7 receives the thus produced charge carriers injected thereto and transports the same. Therefore, the photoconductor as shown in FIG. 9 is the same as that shown in FIG. 8 in the sense that charge carriers required for the light-decay of the photoconductor are generated by the bisazo compound 4 and the charge carriers are transported through the charge transporting medium.
When preparing the photoconductors in FIGS. 7 through 9, a plasticizer can be employed together with a binder agent.
As the electroconductive support material for use in the photoconductors according to the present invention, a metal plate or metal foil, for example, an aluminum plate or aluminum foil; a metal-evaporated plastic film, for example, an aluminum-evaporated plastic film; or a paper treated so as to be electroconductive, can be employed.
As the binder materials for use in the present invention, the following resins can be employed: condensation resins, such as polyamide, polyurethane, polyester resin, epoxy resin, polyketone, polycarbonate; vinyl polymers, such as polyvinylketone, polystyrene, poly-N-vinylcarbazole, polyacrylamide resins, and other electrically insulating and adhesive resins.
As the plasticizers for use in the present invention, halogenated paraffin, polybiphenyl chloride, dimethylnaphthalene and dibutyl phthalate can be employed.
As the charge transporting materials for use in the present invention, the following polymers and monomers can be employed: Vinyl polymers, such as poly-N-vinylcarbazole, halogenated poly-N-vinylcarbazole, polyvinyl pyrene, polyvinyl indoloquinoxaline, polyvinyl dibenzothiophene, polyvinyl anthracene, polyvinyl acridine; condensation resins, such as pyrene-formaldehyde resin, bromopyreneformaldehyde resin, ethylcarbazole-formaldehyde resin, chloroethylcarbazole-formaldehyde resin; monomers, such as fluorenone, 2-nitro-9-fluorenone, 2,7-dinitro-9-fluorenone, 2,4,7-trinitro-9-fluorenone, 2,4,5,7-tetranitro-9-fluorenone, 4H-indeno[1,2-b]thiophene-4-one, 2-nitro-4H-indeno[1,2-b]thiophene-4-one, 2,6,8-trinitro-4H-indeno[1,2-b]thiophene-4-one, 8H-indeno[2,1-b]thiophene-8-one, 2-nitro-8H-indeno[2,1-b]thiophene-8-one, 2-bromo-6,8-dinitro-4H-indeno[1,2-b]thiophene, 6,8-dinitro-4H-indeno[1,2-b]thiophene, 2-nitro-dibenzothiophene, 2,8-dinitrodibenzothiophene, 3-nitro-dibenzothiophene-5-oxide, 3,7-dinitro-dibenzothiophene-5-oxide, 1,3,7-trinitrodibenzothiophene-5,5-dioxide, 3-nitro-dibenzothiophene-5,5-dioxide, 3,7-dinitro-dibenzothiophene-5,5-dioxide, 4-dicyanomethylene-4H-indeno[1,2-b]thiophene, 6,8-dinitro-4-dicyanomethylene-4H-indeno[1,2-b]thiophene, 1,3,7,9-tetranitrobenzo[c]cinnoline-6-oxide, 2,4,10-trinitrobenzo[c]cinnoline-6-oxide, 2,4,8-trinitrobenzo[c]cinnoline-6-oxide, 2,4,8-trinitrothioxanthone, 2,4,7-trinitro-9,10-phenanthrenequinone, 1,4-naphthoquinonebenzo[a]anthracene-7,12-dione, 2,4,7-trinitro-9-dicyano-methylene fluorene, tetrachlorophthalic anhydride, 1-bromopyrene, 1-methylpyrene, 1-ethylpyrene, 1-acetylpyrene, carbazole, N-ethylcarbazole, N-β-chloroethylcarbazole, N-β-hydroxyethylcarbazole, 2-phenylindole, 2-phenylnaphthalene, 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole, 2,5-bis(4-diethylaminophenyl)-1,3,4-triazole, 1-phenyl-3-(4-diethylaminostyryl)-5-(4-diethylaminophenyl)-pyrazoline, 2-phenyl-4-(4-diethylaminophenyl)-5-phenyloxazole, triphenylamine, tris(4-diethylaminophenyl)methane, 8,6-bis(dibenzylamino)-9-ethylcarbazole, 4,4'-bis(dibenzylamino)diphenylmethane, 4,4'-bis(dibenzylamino)diphenyl ether, 1,1-bis(4-dibenzylaminophenyl)propane, 2(α-naphthyl)-5-(4-diethylaminophenyl)-1,3,4-oxadiazole, 2-styryl-5-(3-N-ethylcarbazolyl)-1,3,4-oxadiazole, 2-(4-methoxyphenyl)-5-(3-N-ethylcarbazolyl)-1,3,4-oxadiazole, 2-(4-diethylaminophenyl)-5-(3-N-ethylcarbazolyl)-1,3,4-oxadiazole, 9-(4-diethylaminostyryl)anthracene, 9-(4-dimethylaminostyryl)anthracene, α-(9-anthryl)-β-(3-N-ethylcarbazolyl)ethylene, 5-methyl-2-(4-diethylaminostyryl)benzoxazole, 9-(4-dimethylamino-benzylidene)fluorenone, N-ethyl-3-(9-fluorenylidene)carbazole, 2,6-bis(4-diethylaminostyryl)pyridine, methylphenylhydrazono-3-methylidene-9-ethylcarbazole, methylphenylhydrazono-4-methylidene-N,N-diethylaniline, 4-N,N-diphenylaminostilbene, and α-phenyl-4'-N,N-diphenylaminostilbene.
These charge transporting materials can be employed alone or in combination with two or more charge transporting materials.
In the photoconductors according to the present invention, an adhesive layer or a barrier layer can be interposed between the electroconductive support material and the photoconductive layer when necessary. The materials suitable for preparing the adhesive layer or barrier layer are polyamide, nitrocellulose and aluminum oxide. It is preferable that the thickness of the adhesive layer or barrier layer be 1 μm or less.
Copying by use of the photoconductors according to the present invention can be performed by the process comprising the steps of electrically charging the surface of the photoconductive layer, and exposing the charged surface to a light image to form a latent electrostatic image thereof on the surface, and developing the latent image with developer. When necessary, the developed image is transferred to paper or other materials and is then fixed thereto.
EXAMPLE 1-27
This is an example of an electrophotographic photoconductor according to the present invention, in which the aforementioned bisazo compound No. 1-66 in Table 3 was employed.
A mixture of 1 part by weight of a polyester resin (Trade Name: Polyester Adhesive 49000 made by Du Pont), 1 part by weight of the bisazo compound No. 1-66, and 26 parts by weight of tetrahydrofuran was ground in a ball mill. This dispersion was coated on an aluminum-evaporated polyester film by a doctor blade and was then dried at 100° C. for 10 minutes, so that a photoconductive layer with a thickness of 7 μm was formed on the aluminum-evaporated polyester film, forming an electrophotographic photoconductor of the type as shown in FIG. 7.
The surface of the photoconductive layer of the electrophotographic photoconductor was charged positively in the dark under application of +6 KV of corona charge for 20 seconds by a commercially available electrostatic copying sheet testing apparatus and was then allowed to stand in the dark for 20 seconds without applying any charge thereto, and the surface potential Vpo (V) of the photoconductor was measured. The photoconductor was then illuminated by a tungsten lamp in such a manner that the illuminance on the illuminated surface of the photoconductor was 20 lux, and the exposure E 1/2 (lux.sec) required to reduce the initial surface potential Vpo (V) to 1/2 the initial surface potential Vpo (V) was measured. The result showed that Vpo was 110 V and E 1/2 was 11.2 lux.sec.
EXAMPLE 1-28
A mixture of 2 parts by weight of the bisazo compound No. 1-1, and 98 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge carrier producing layer with a thickness of 1 μm was formed on the aluminum-evaporated polyester film.
Further, 2 parts by weight of 9-(4-diethylaminostyryl)anthracene, 2 parts by weight of a polycarbonate resin (Trade Name: Panlite L made by Teijin Limited) and 16 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 11 μm was formed on the charge carrier producing layer, whereby a layered type electrophotographic photoconductor as shown in FIG. 9 was prepared.
The surface of the photoconductive layer of the photoconductor was charged negatively in the dark under application of -6 KV of corona charge for 20 seconds by a commercially available electrostatic copying sheet testing apparatus and was then allowed to stand in the dark for 20 seconds without applying any charge thereto, and the surface potential Vpo (V) of the photoconductor was measured. The photoconductor was then illuminated by a tungsten lamp in such a manner that the illuminance on the illuminated surface of the photoconductor was 20 lux, and the exposure E 1/2 (lux.sec) required to reduce the initial surface potential Vpo (V) to 1/2 the initial surface potential Vpo (V) was measured. The results showed that Vpo was -895 V and E 1/2 was 7.2 lux.sec.
EXAMPLE 1-29˜1-33
Example 1-28 was repeated except that the bisazo compound No. 1-1 employed in Example 1-28 was replaced by the bisazo compounds listed in the following Table 7, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-28. The results are shown in Table 7.
TABLE 7______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-29 1-15 -1120 5.21-30 1-66 -1060 7.41-31 1-68 -970 4.91-32 1-79 -1230 9.51-33 1-137 -1000 11.2______________________________________
EXAMPLE 1-34
A mixture of 1 part by weight of the bisazo compound No. 1-1 and 66 parts by weight of a polyester resin tetrahydrofuran solution containing 0.5 wt.% of a polyester resin (Vylon 200 made by Toyobo Company, Ltd.) was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at 80° C. for 2 minutes, so that a charge carrier producing layer with a thickness of 0.7 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of 1,1-bis(4-dibenzylaminophenyl)propane, 2 parts by weight of a polycarbonate resin (Trade Name: Panlite K-1300 made by Teijin Limited) and 16 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 13 μm was formed on the charge carrier producing layer, whereby a layered type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as that in Example 1-28. The result showed that Vpo was -1020 V and E 1/2 was 11.0 lux.sec.
EXAMPLE 1-35˜1-39
Example 1-34 was repeated except that the bisazo compound No. 1-1 employed in Example 1-34 was replaced by the bisazo compounds listed in the following table 8, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-34. The results are shown in Table 8.
TABLE 8______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-35 1-7 -1150 9.51-36 1-66 -1200 12.01-37 1-67 -1020 11.01-38 1-95 -1310 10.91-39 1-137 -990 13.0______________________________________
EXAMPLE 1-40
A mixture of 2 parts by weight of the bisazo compound No. 1-1 and 70 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge carrier producing layer with a thickness of 1.5 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of 1-phenyl-3-(4-diethylaminostyryl)-5-(4-diethylaminophenyl)pyrazoline, 3 parts by weight of polystyrene (Trade Name: Toporex made by Mitsui Toatsu Chemicals, Inc.) and 17 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 16 μm was formed on the charge carrier producing layer, whereby a layered-type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as that in Example 1-28. The result showed that Vpo was -630 V and E 1/2 was 2.9 lux.sec.
EXAMPLE 1-41˜1-45
Example 1-40 was repeated except that the bisazo compound No. 1-1 employed in Example 1-40 was replaced by the bisazo compounds listed in the following table 9, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-34. The results are also shown in Table 9.
TABLE 9______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-41 1-12 -790 2.41-42 1-14 -570 1.91-43 1-15 -1010 2.81-44 1-38 -1220 7.91-45 1-66 -910 5.1______________________________________
EXAMPLE 1-46
A mixture of 2 parts by weight of the bisazo compound No. 1-1 and 98 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge carrier producing layer with a thickness of 1.0 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of methylphenyl-hydrazone-3-methylidene-9-ethylcarbazole, 1 part by weight of poly-N-vinylcarbazole (Trade Name: Rubican M-170 made by BASF), 1 part by weight of a polyester resin (Vylon 200 made by Toyobo Company, Ltd.) and 18 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 16 μm was formed on the charge carrier producing layer, whereby a layered-type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 1-28. The result showed that Vpo was -920 V and E 1/2 was 7.5 lux.sec.
EXAMPLE 1-47˜1-51
Example 1-46 was repeated except that the bisazo compound No. 1-1 employed in Example 1-46 was replaced by the bisazo compounds listed in the following table 10, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-28. The results are shown in Table 10.
TABLE 10______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-47 1-7 -1020 5.71-48 1-13 -1210 5.01-49 1-66 -1130 7.71-50 1-68 -980 4.91-51 1-131 -1010 7.7______________________________________
EXAMPLE 1-52
A mixture of 10 parts by weight of a polyester resin (Trade Name: Vylon 200 made by Toyobo Company, Ltd.), 10 parts by weight of 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole, 2 parts by weight of the bisazo compound No. 1-1 and 108 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at 120° C. for 10 minutes, so that a photoconductive layer with a thickness of 21 μm was formed on the aluminum-evaporated polyester film, whereby an electrophotographic element as shown in FIG. 8 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 1-28, except that the photoconductor was positively charged in the dark under application of +6 KV of corona charge. The result showed that Vpo was +120 V and E 1/2 was 13.1 lux.sec.
EXAMPLE 1-53˜1-57
Example 1-52 was repeated except that the bisazo compound No. 1-1 employed in Example 1-52 was replaced by the bisazo compounds listed in the following table 11, whereby the photoconductors of the type shown in FIG. 8 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-52. The results are shown in Table 11.
TABLE 11______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-53 1-20 +1100 9.81-54 1-66 +1180 10.91-55 1-48 +1200 11.51-56 1-80 +1220 10.01-57 1-130 +1290 12.9______________________________________
EXAMPLE 1-58
A mixture of 1 part by weight of a polyester resin (Trade Name: Polyester Adhesive 49000 made by Du Pont), 1 part by weight of the bisazo compound No. 1-1, and 26 parts by weight of the bisazo compound No. 1-1, and 26 parts by weight of tetrahydrofuran was ground in a ball mill. This dispersion was coated on an aluminum-evaporated polyester film by a doctor blade and was then dried at 100° C. for 10 minutes, so that a photoconductive layer with a thickness of 7 μm was formed on the aluminum-evaporated polyester film, forming an electrophotographic photoconductor of the type as shown in FIG. 7.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 1-28, except that the photoconductor was positively charged in the dark under application of +6 KV of corona charge. The result showed that Vpo was +520 V and E 1/2 was 18.3 lux.sec.
EXAMPLE 1-59˜1-63
Example 1-58 was repeated except that the bisazo compound No. 1-1 employed in Example 1-58 was replaced by the bisazo compounds listed in the following table 12, whereby the photoconductors of the type shown in FIG. 7 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 1-58. The results are shown in Table 12.
TABLE 12______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________1-59 1-2 +420 9.51-60 1-5 +230 18.01-61 1-66 +620 17.01-62 1-67 +730 12.01-63 1-48 +510 11.0______________________________________
EXAMPLE 2-37
A mixture of 1 part by weight of a polyester resin (Trade Name: Polyester Adhesive 49000 made by Du Pont), 1 part by weight of the bisazo compound No. 2-66, and 26 parts by weight of tetrahydrofuran was ground in a ball mill. This dispersion was coated on an aluminum-evaporated polyester film by a doctor blade and was then dried at 100° C. for 10 minutes, so that a photoconductive layer with a thickness of 7 μm was formed on the aluminum-evaporated polyester film, forming an electrophotographic photo-conductor of the type as shown in FIG. 7.
The surface of the photoconductive layer of the electrophotographic photoconductor was charged positively in the dark under application of +6 KV of corona charge for 20 seconds by a commercially available electrostatic copying sheet testing apparatus and was then allowed to stand in the dark for 20 seconds without applying any charge thereto, and the surface potential Vpo (V) of the photoconductor was measured. The photoconductor was then illuminated by a tungsten lamp in such a manner that the illuminance on the illuminated surface of the photoconductor was 20 lux, and the exposure E 1/2 (lux.sec) required to reduce the initial surface potential Vpo (V) to 1/2 the initial surface potential Vpo (V) was measured. The result showed that Vpo was +95 V and E 1/2 was 9.6 lux.sec.
EXAMPLE 2-38
A mixture of 2 parts by weight of the bisazo compound No. 2-5 and 98 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge producing layer with a thickness of 1 μm was formed on the aluminum-evaporated polyester film.
Further, 2 parts by weight of 9-(4-diethylaminostyryl) anthracene, 2 parts by weight of a polycarbonate resin (Trade Name: Panlite L made by Teijin Limited) and 16 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 11 μm was formed on the charge carrier producing layer, whereby a layered type electrophotographic photoconductor as shown in FIG. 9 was prepared.
The surface of the photoconductive layer of the photoconductor was charged negatively in the dark under application of -6 KV of corona charge for 20 seconds by a commercially available electrostatic copying sheet testing apparatus and was then allowed to stand in the dark for 20 seconds without applying any charge thereto, and the surface potential Vpo (V) of the photoconductor was measured. The photoconductor was then illuminated by a tungsten lamp in such a manner that the illuminance on the illuminated surface of the photoconductor was 20 lux, and the exposure E 1/2 (lux.sec) required to reduce the initial surface potential Vpo (V) to 1/2 the initial surface potential Vpo (V) was measured. The results showed that Vpo was -920 V and E 1/2 was 1.8 lux.sec.
EXAMPLE 2-39˜2-43
Example 2-38 was repeated except that the bisazo compound No. 2-5 employed in Example 2-38 was replaced by the bisazo compounds listed in the following Table 13, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are shown in Table 13.
TABLE 13______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-39 2-16 -810 2.02-40 2-66 -840 0.92-41 2-48 -650 0.72-42 2-43 -920 0.82-43 2-47 -820 0.8______________________________________
EXAMPLE 2-44
A mixture of 1 part by weight of the bisazo compound No. 2-6 and 66 parts by weight of a polyester resin tetrahydrofuran solution containing 0.5 wt.% of a polyester resin (Vylon 200 made by Toyobo Company, Ltd.) was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at 80° C. for 2 minutes, so that a charge carrier producing layer with a thickness of 0.7 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of 1,1-bis(4-dibenzylaminophenyl)propane, 2 parts by weight of a polycarbonate resin (Trade Name: Panlite K-1300 made by Teijin Limited) and 16 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 13 μm was formed on the charge carrier producing layer, whereby a layered type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as that in Example 2-38. The result showed that Vpo was -1000 V and E 1/2 was 5.2 lux.sec.
EXAMPLE 2-45˜2-49
Example 2-44 was repeated except that the bisazo compound No. 2-6 employed in Example 2-44 was replaced by the bisazo compounds listed in the following table 14, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are shown in Table 14.
TABLE 14______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-45 2-41 -1010 3.52-46 2-43 -1100 3.12-47 2-45 -1100 4.02-48 2-47 -1020 3.02-49 2-50 -1150 2.3______________________________________
EXAMPLE 2-50
A mixture of 2 parts by weight of the bisazo compound No. 2-36 and 70 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge carrier producing layer with a thickness of 1.5 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of 1-phenyl-3-(4-diethylaminostyryl)-5-(4-diethylaminophenyl)pyrazoline, 3 parts by weight of polystyrene (Trade Name: Toporex made by Mitsui Toatsu Chemicals, Inc.) and 17 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 16 μm was formed on the charge carrier producing layer, whereby a layered-type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as that in Example 2-38. The result showed that Vpo was -520 V and E 1/2 was 2.4 lux.sec.
EXAMPLE 2-51˜2-55
Example 2-50 was repeated except that the bisazo compound No. 2-36 employed in Example 2-50 was replaced by the bisazo compounds listed in the following table 15, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are also shown in Table 15.
TABLE 15______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-51 2-38 -560 2.62-52 2-66 -430 0.72-53 2-46 -610 1.62-54 2-49 -660 1.92-55 2-52 -680 1.3______________________________________
EXAMPLE 2-56
A mixture of 2 parts by weight of the bisazo compound No. 2-5 and 98 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at room temperature, so that a charge carrier producing layer with a thickness of 1.0 μm was formed on the aluminum-evaporated polyester film.
Furthermore, 2 parts by weight of methylphenyl-hydrazone-3-methylidene-9-ethylcarbazole, 1 part by weight of poly-N-vinylcarbazole (Trade Name: Rubican M-170 made by BASF), 1 part by weight of a polyester resin (Vylon 200 made by Toyobo Company, Ltd.) and 18 parts by weight of tetrahydrofuran were mixed to form a solution. This solution was coated on the charge carrier producing layer by a doctor blade and was then dried at 120° C. for 10 minutes, so that a charge transporting layer with a thickness of 16 μm was formed on the charge carrier producing layer, whereby a layered-type photoconductor as shown in FIG. 9 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 2-38. The result showed that Vpo was -820 V and E 1/2 was 1.6 lux.sec.
EXAMPLE 2-57˜2-66
Example 2-56 was repeated except that the bisazo compound No. 2-5 employed in Example 2-56 was replaced by the bisazo compounds listed in the following table 16, whereby the photoconductors of the type shown in FIG. 9 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are shown in Table 16.
TABLE 16______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-57 2-6 -790 2.32-58 2-16 -690 1.42-59 2-66 -910 0.92-60 2-48 -860 1.02-61 2-41 -770 0.92-62 2-43 -880 0.72-63 2-45 -870 0.82-64 2-47 -910 0.82-65 2-50 -860 0.82-66 2-69 -910 0.8______________________________________
EXAMPLE 2-67
A mixture of 10 parts by weight of a polyester resin (Trade Name: Vylon 200 made by Toyobo Company, Ltd.), 10 parts by weight of 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole, 2 parts by weight of the bisazo compound No. 2-66 and 108 parts by weight of tetrahydrofuran was ground in a ball mill. The thus prepared dispersion was coated on an aluminum surface side of an aluminum-evaporated polyester film by a doctor blade and was then dried at 120° C. for 10 minutes, so that a photoconductive layer with a thickness of 21 μm was formed on the aluminum-evaporated polyester film, whereby an electrophotographic photoconductor of the type as shown in FIG. 8 was prepared.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 2-38, except that the photoconductor was positively charged in the dark under application of +6 KV of corona charge. The result showed that Vpo was +1120 V and E 1/2 was 3.3 lux.sec.
EXAMPLE 2-68˜2-72
Example 2-62 was repeated except that the bisazo compound No. 2-43 employed in Example 2-62 was replaced by the bisazo compounds listed in the following table 17, whereby the photoconductors of the type shown in FIG. 8 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are shown in Table 17.
TABLE 17______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-68 2-15 +930 5.22-69 2-48 +1020 3.72-70 2-45 +890 2.02-71 2-80 +920 4.02-72 2-131 +820 5.0______________________________________
EXAMPLE 2-73
A mixture of 1 part by weight of a polyester resin (Trade Name: Polyester Adhesive 49000 made by Du Pont), 1 part by weight of the bisazo compound No. 2-5, and 26 parts by weight of tetrahydrofuran was ground in a ball mill. This dispersion was coated on an aluminum-evaporated polyester film by a doctor blade and was then dried at 100° C. for 10 minutes, so that a photoconductive layer with a thickness of 7 μm was formed on the aluminum-evaporated polyester film, forming an electrophotographic photoconductor of the type as shown in FIG. 7.
Vpo and E 1/2 of this photoconductor were measured in the same manner as in Example 2-38, except that the photoconductor was positively charged in the dark under application of +6 KV of corona charge. The result showed that Vpo was +210 V and E 1/2 was 10.8 lux.sec.
EXAMPLE 2-74˜2-81
Example 2-68 was repeated except that the bisazo compound No. 2-15 employed in Example 2-68 was replaced by the bisazo compounds listed in the following table 18, whereby the photoconductors of the type shown in FIG. 7 were prepared. Vpo and E 1/2 of each of the photoconductors were measured in the same manner as in Example 2-38. The results are shown in Table 18.
TABLE 18______________________________________ Bisazo Vpo E.sub.1/2Example No. Compound No. (volt) (lux · sec)______________________________________2-74 2-6 +190 4.42-75 2-7 +210 7.42-76 2-15 +330 5.32-77 2-48 +290 4.12-78 2-53 +180 8.82-79 2-135 +310 7.92-80 2-137 +220 10.02-81 2-142 +270 9.5______________________________________ | A novel bisazo compound of the formula ##STR1## where n=2 or 3, and A is ##STR2## when n=2, and when n=3, A is the above (a), (b) or (c), and an electrophotographic photoconductor comprising, on an electroconductive support material, a photoconductive layer containing the above bisazo compound, which electrophotographic photoconductor exhibits relatively high photo-sensitivity and usefulness for electrophotographic copying. | 2 |
BACKGROUND OF THE INVENTION
[0001] This invention relates to animal pill magnets that are routinely placed in the stomachs of bovine animals to prevent the adverse condition that is commonly referred to as Hardware Disease. More specifically, this invention pertains to such an animal pill magnet that exhibits a single polarity.
[0002] Bovine animals, particularly cattle, forage hastily without chewing their food initially. Generally, whatever goes into a cow's mouth while it is feeding gets swallowed and enters the animal's rumen. Later, the previously-ingested material is regurgitated, and the animal “chews its cud.” This process is believed to have evolved over many years so that the bovine animal in the wild could quickly ingest huge amounts of grass in a short amount of time, thereby limiting the amount of time that its head, eyes and ears were in a lowered position and the animal was more vulnerable to predator attacks. Later, the animal could complete the digestive process by chewing its cud with its head, eyes and ears in an upright position, on the lookout for advancing predators. While such evolutionary survival traits are not needed today in the typical dairy farm, feed lot, or cattle ranch, the modem bovine still has this quick-foraging trait which served the animal so well in the wild, although that trait now presents a problem for the modern cow confined in spaces that include man-made debris. Specifically, in this process of hastily feeding, the cow, whether in a dairy or feed lot being fed prepared feed in a trough or other confined space, or in open pasture grazing over a wider area, has a tendency to ingest not just the intended grass, hay or other foodstuffs, but also to ingest the small metal objects ubiquitously found on most farms, such as nails, staples, and bits of bailing or barbed wire. These things are often referred to as tramp iron. Because the animal does not chew during the initial eating process, these items are not rejected by the cow at that time. Also, because of their weight, size and shape, these items are not usually regurgitated later as part of the cud, so they cannot be rejected then. Rather, these foreign objects remain in the cow's digestive tract, where they can cause problems.
[0003] The primary problem results when the bits of tramp iron fall to the floor of the animal's rumen, and then get pushed forward and lodged in the honeycombed walls of the animal's recticulum. The powerful churning and contractions of the animal's digestive track can in some instances cause the sharp-edged and sharp-ended bits of metal to irritate and inflame the side walls of the animal's stomach. In some instances, the wire or nail may actually be caused to puncture the stomach wall. Given the close proximity of other organs (such as the heart and lungs), that can lead to the metal's damaging those other organs. Or, the puncture in the stomach wall can lead to leaking digestive juices that can cause infections.
[0004] This condition is generally referred to as Hardware Disease. In its least damaging manifestation, a dairy cow's milk product may fall off significantly, or a feed animal being raised for eventual slaughter may experience weight loss instead of the desired weight gain. In more serious manifestations, the infected animal can die from damage caused to an internal organ, from internal infection or even from starvation, as an animal afflicted with Hardware Disease may actually stop eating altogether. Sometimes, surgery to remove the offending material may be required.
[0005] For these reasons, cattle ranchers and dairy farmers take steps to prevent the animal's ingestion of tramp iron. For example, feed mills will actually install powerful magnets in a late processing stage so that tramp iron is culled from the feed being milled before it is given to the animals. Keeping the feeding areas free of tramp iron is also a goal. These things, while effective to a degree, however, have not been found to be completely effective, and have not eliminated Hardware Disease.
[0006] Indeed, Hardware Disease has plagued cattle ranchers, feed lot operators and dairy farmers for years. Years ago it was discovered that while it was not feasible to prevent all cows from ingesting tramp iron all the time, such that cows were inevitably going to be eating some tramp iron and other metal objects, the advent of Hardware Disease could be substantially reduced by causing the animal to ingest small, powerful magnets that were sufficiently heavy that they would remain in the bottom of the cow's stomach for the animal's lifetime. The magnets would attract and hold the small bits of metal debris as they were ingested, keeping the metal in the bottom portions of the animal stomach where it was much less likely to cause irritation, inflammation or a puncture wound to the stomach wall. Over time, the stomach's acids will actually dissolve some of the metal. For example, a typical iron nail can be dissolved in about 6 months.
[0007] So that the magnets would not themselves cause problems, it has been known in the art that the exterior surface of the magnet should be very smooth. Because of the caustic nature of the animal's digestive juices, it has also been known in the art that the magnets must be sheathed in a protective material, such as stainless steel or suitable plastic coating, that can withstand the caustic digestive juices.
[0008] In addition to administering a magnetic pill to the animal, some of the earlier patented devices directed to this disease were instruments that used retrievable magnets that could used to remove the offending material non-surgically. For example, U.S. Pat. No. 2,753,870, issued in 1956, discloses an “Instrument for Probing the Reticulum” in which a large magnet attached to a tether is introduced to the animal's stomach via the esophagus to retrieve and remove metal objects. As described in the '879 patent, it was already “common practice in the treatment of hardware disease to feed the animal a small magnet.”
[0009] In U.S. Pat. No. 2,799,274, issued in 1957, a “Veterinary Evacuating Probe for Use on Cattle” is disclosed which the veterinary surgeon could insert through the esophagus into the animal's stomach to “feel” for, retrieve and remove foreign objects.
[0010] And in U.S. Pat. No. 2,853,075, issued in 1958, a “Rumen Trocar Extricator” is disclosed that, among other things, could be used to “successfully and satisfactorily introduce the magnet into the intended areas of the cow's stomach.” As these references confirm, Hardware Disease has long plagued the bovine animal industry, and the use of magnets, either tethered so as to be retrievable, or specifically placed using a non-surgical instrument, or administered orally, in the treatment of that disease has long been known.
[0011] Notwithstanding the long use of magnets in this way, there has been a constant effort to improve the magnet in one way or another. Indeed, a rather large number of patents have been issued for these “cow magnets” (as they are sometimes called in addition to “animal pill magnets”). For example, one of the early patented devices was called a “Therapeutic Magnet” in U.S. Pat. No. 3,005,458, issued in 1958, which described the effects of Hardware Disease to be popularly known as “off feed,” or “bloat,” or “indigestion” or “off production.” The disclosed improved magnet had a particular shape (elongated with a dog-bone like cross section) and its ends were of opposite polarity.
[0012] In U.S. Pat. No. 3,187,239, issued in 1965 for a “Holding Magnet for Ferromagnetic Foreign Bodies in Ruminants,” various drawbacks experienced with the prior art magnets were described, including that the metal objects that were held by the magnet were not always attached longitudinally, such that a “hedgehog” was formed around the magnet that could still puncture the animal's stomach wall. The improved magnet disclosed used the prior art N-S cylindrical magnet having opposite polarity at its ends, but encased the magnet in a “cage” of elongate bars that helped properly orient the metal objects attached to the magnet. This supposedly helped reduce the “hedgehog” effect.
[0013] In U.S. Pat. No. 4,303,062, issued in 1981 for a “Therapeutic Magnet,” an improved magnet is disclosed which had a rectangular shape, and in which the opposite N-S polarities were on the opposite sides of the magnet (as opposed to its ends). The '062 patent discusses the problems associated with the use of magnets such as disclosed in U.S. Pat. No. 3,005,458. One such problem identified is that care had to be taken to ensure that two magnets are not administered to the same animal, as the two magnets would attach themselves to each other, N-end to S-end, thus shunting one another and greatly reducing the external magnetic field. The disclosed and claimed magnet used a core of “AlNiCo—V” material (AlNiCo means Aluminum-Nickel-Copper), a polymeric coating, and a prescribed length-to-width overall ratio, such that its pole faces were on the sides of the magnet having the greatest area.
[0014] In U.S. Pat. No. 4,749,978, issued in 1988 for a “Magnet for Catching Thereon Foreign Bodies Within Reticulum of Ruminant, and Method and Instrument for Manufacture Thereof,” the problem of end-to-end attachment of multiple magnets in the cow's stomach was again cited, and the disclosed and claimed cow magnet had its magnetic N-S poles on selected side portions of the elongate device (as opposed to at its respective ends). The description of the prior art in the '978 patent also describes other drawbacks encountered with the typical cow magnet having N-S poles at its opposite ends.
[0015] In U.S. Pat. No. 4,992,768, issued in 1991, a cow magnet is disclosed having a stack of cylindrical permanent magnets with intermediate disk-like spacers of soft magnetic material, all of which are held in place by a central pin or rod which itself was of a soft magnetic material. This arrangement was believed to enhance the magnetic flux lines generated by the overall N-S ends of the composite device.
[0016] In U.S. Pat. No. 5,096,763, the problems with the conventionally used, rod-shaped AlNiCo magnets having magnetic poles at both end surfaces, are described. Also described are the prior art attempts to correct those problems by using a plurality of disc-shaped magnetic members having magnetic poles on each of their end surfaces, such that the resultant composite device has alternating N-S poles (up to 8) along its axial length. The disclosed improved magnet incorporated several ferrite disc magnets each having N-S polarity in order to achieve the desired alternating N-S polarity along the sides of the device.
[0017] In U.S. Pat. No. 5,663,701, issued in 1997, a “Stomach Debris Collecting Magnet” is disclosed that is described as being an improvement over the prior art by creating a magnetic “dead zone” intermediate of the two ends of the device, which the patent describes as enhancing the device's ability to create a “ball” of attracted metal that maximized the amount of material collected, and minimizes the risk that on end an attracted piece of metal would still puncture the stomach wall.
[0018] In U.S. Pat. No. 5,905,425, issued in 1999 for a “Cow Magnet,” the preferred cow magnet is described as one having seven attributes: 1) sufficiently strong magnetic field; 2) non toxic to the cow; 3) able to withstand the corrosive stomach acids; 4) dimensioned so as not to pass through to the cow's intestines; 5) easily inserted down the cow's throat; 6) inexpensive to manufacture; and 7) configured so that the attracted metal will gather in a fashion that poses the least risk to the animal. The improved cow magnet disclosed comprises two elongate semi-circular ceramic magnets having a metal plate between them, all encased in a plastic outer coating.
[0019] And perhaps most recently, U.S. Pat. No. 6,357,446 B1 issued in 2002 for an “Animal Pill Magnet” having the usual elongate, cylindrical shape, and N-S poles at each end, in which the claimed improvement relates to the manner in which the two capsule halves are secured together.
[0020] As this brief review of some of the prior art patents on cow magnets shows, there has been a continuing attempt to improve a device that has been in common usage for over 50 years. As this review also shows, much of the attempts at improvement have been directed to the polarity of the device. For example, at least 25 years ago a problem with having a cow magnet with N-S polarity at its ends was described in that if two cow magnets were administered to the same animal, the two cow magnets would become attached end-to-end, reducing the magnetic field, and hence reducing the device's effectiveness. However, as the prior art also discloses, the preferred device has a shape, size and weight such that it remains in the bottom of the cow's stomach for its lifetime. Therefore, as the cow magnet attracts more and more material (creating the “ball” described above), the magnet's ability to attract and hold additional objects decreases. According, administering additional magnets to the same cow is commonplace. Indeed, the West Virginia University Veterinary Sciences Extension Service's admonition to veterinarians in the field on Hardware Disease is to “[j]ust remember that if enough metal is ingested the magnet will ‘fill up’” such that the veterinarian should “[a]dminister a second magnet if signs resembling hardware disease are present.” Yet, the most commonly used standard cow magnet today still has an AlNiCo magnet that has a different pole on each end. (See, for example, the cow magnets available at http://www.magneticsource.com or http://www.physlink.com). The metal that is attracted to one end of the magnet can become partially magnetized itself, and can be repelled by the other end, leading to the situation in which the magnet “holds” a wire segment (for example) at one end thereof, while the other end thereof can be “held” in an outwardly extending position that can damage or even puncture the stomach wall, even though one end of it is attached to the magnet. Therefore, after over 50 years of improvement, the problems with the traditional N-S polarity at the opposite ends of the typical cow magnet remain.
[0021] Thus, there still exists a need in the art for an improved animal pill (or cow) magnet that can attract and hold large quantities of metal debris without creating a puncture risk to the animal, and which can be administered repeatedly to the same cow without adversely affecting the efficacy of the device.
SUMMARY OF THE INVENTION
[0022] The improved cow magnet herein describes has a unique arrangement of interior NdFeB (Neodymium-Iron-Boron) magnets separated by carbon steel such that the resultant device exhibits a single polarity at each end, and that polarity can by design be either N or S. The resultant cow magnet thus can attract and hold more metal (as it attracts only and does not repel), and acts to bring the metal pieces it attracted into axial alignment so as to minimize extending sharp ends of the attached metal objects.
DESCRIPTION OF THE FIGURES
[0023] FIG. 1 is a perspective view showing the overall size and shape of the magnet.
[0024] FIG. 2 is a cross-sectional side view showing the internal components of one embodiment.
[0025] FIG. 3 shows the flux lines for the embodiment shown in FIG. 2 .
[0026] FIG. 4 is an end view showing the radiant magnetic flux orientation of the magnet.
[0027] FIG. 5 is a schematic view showing the major anatomical components of a cow's digestive system of interest here.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0028] The device of this invention is intended to be orally administered to a bovine animal and once administered, to permanently reside in the animal's reticulum, where it attracts and holds tramp iron that the animal ingests, thereby preventing the animal from contracting Hardware Disease. In order to understand this process, a diagram of the main anatomical components of a bovine digestive system of interest here are shown in FIG. 5 . Beginning at the animal's head and mouth depicted at the right side of the diagram and moving to the left, the esophagus 100 leads to the animal's multi-compartment stomach including the reticulum 102 and the rumen 104 . Although not shown on this diagram, the animals heart and lungs are located generally in the area adjacent to the reticulum 102 . The animal's liver 106 , pancreas 108 , and gall bladder 110 are located adjacent the rumen 104 , and to the abomasum 112 , which leads to the small intestines 114 . As this diagram shows, sharp-pointed or sharp-edged pieces of metal, once ingested by the cow, have many opportunities to cause problems for the animal. If the metal object is forced into the reticulum 102 , it can puncture the reticulum wall and injure the heart or lungs. If the object is moved along the animal's digestive tract, it can puncture the intestines and perhaps injure the liver or other important internal organs.
[0029] Looking now at FIG. 1 , it is seen that the overall animal or cow magnet 10 of the preferred embodiment of this invention has a traditional elongated, cylindrical shape that resembles a large pill or bolus. The preferred dimensions are approximately 3 inches in length and ½ inch in diameter, with rounded ends such that there are no sharp edges anywhere on its exterior.
[0030] Looking at FIG. 2 , it is seen that this device has an outer casing 12 that encases various interior components. In the preferred embodiment, outer casing 12 is constructed entirely of stainless steel, and is comprised of a cylindrical sleeve portion 14 and two end caps 16 and 18 . Of course, many other materials could be used for the outer casing 12 , such as other metals or plastics that would be sufficiently resistant to corrosion from the animal's gastric juices. The overall shape of the device, while preferable a cylinder with rounded ends, could be of any other shape and size. The only limiting aspect is that the design must be one which the animal can be forced to swallow, and which does not its pose a danger to the animal stomach walls.
[0031] FIG. 2 also discloses a preferred embodiment in which the interior space of the overall magnet 10 comprises a first NdFeB (Neodymium-Iron-Boron) magnet 20 , and intermediate carbon steel section 22 ; and a second NdFeB magnet 24 , all being of approximately the same size (hereinafter this assembly of the steel section 22 sandwiched between magnets 20 and 24 is referred to as to the “magnet/steel assembly”). As depicted here, each of the magnets 20 and 24 and the steel section 22 are shaped as cylindrical segments, having an exterior diameter that is slightly less than the interior diameter of the outer sleeve 14 so that they can be easily inserted into the sleeve.
[0032] The disclosed NdFeB magnets are of rather recent creation in the magnet art, having first become commercially available in 1984. They are generally regarded as the most powerful “rare-earth” permanent magnet composition commercially available today. “Permanent” in this context means that the material “remembers” the magnetic field to which it has been subjected. Therefore, once the “permanent” magnetic material has been subjected to a sufficient strong magnetic field, the material becomes and stays “magnetized”—exhibiting a high constant magnetic flux even in the absence of an exciting magnetic field or current—unless and until it is subjected to a similarly strong opposing magnetic field. These NdFeB magnets exhibit the highest or among the highest magnetic characteristics of Maximum Energy and Remanence of any commercially available material. For example, NdFeB magnets can provide 4-5 times as much power output (e.g., 28 MGOe to 50 MGOe) as similarly sized ceramic magnets. And because Neodymium is one of the most plentiful so-called “rare earth” elements, and because Iron and Boron are very plentiful, these magnets provide excellent cost-performance ratios.
[0033] NdFeB magnets are, however, difficult to manufacture (typically requiring that the powdered material be sintered in a mold), are quite brittle, are difficult to machine, and can be sensitive to corrosion and high temperatures. Nevertheless, their strength vs. size ratio makes them the preferred choice in this invention. They are commercially available in many sizes and shapes from several suppliers around the world, many of whom can be located on the Internet by searching the term “NdFeB magnets.” Any of the commercially available grade magnets, such as N33 through N50, are acceptable and can be utilized.
[0034] It is not necessary that the relative sizes of the first and second magnets 20 and 24 , and the intermediate carbon steel, be precisely as shown in FIG. 2 . While it is generally preferred (but not required) that the two magnets 20 and 24 be of about the same size and hence power, the size of the intermediate carbon steel section 22 can be of a significantly smaller size than is depicted in FIG. 2 . For example, as shown in FIG. 2 , each of the two magnets 20 and 24 , and the carbon steel section, are each slightly less than 1 inch in length. The length of the magnets 20 and 24 can be significantly increased (up to approximately 1.2 inches in length or even longer); with the steel segment being respectively shorter.
[0035] As also shown in FIG. 2 , a pair of simple springs 26 and 28 can be used to hold the magnet/steel assembly stationary within the outer casing 12 . Although is not absolutely necessary that the magnet/steel assembly remain stationary, that is preferred. Also, although this preferred embodiment uses springs to do so, there are of course countless other ways to keep the magnet/steel assembly stationary. For just a couple examples, the overall assembly length could be designed to occupy the entire length of the sleeve portion 14 , such that the interior peripheral edge of the end caps 16 and 18 act as “stops;” or other compressible material could also be used instead of the springs 26 and 28 .
[0036] To construct the preferred embodiment, one of the end caps 16 and 18 is welded onto one end of sleeve 14 . The spring 26 (or other compressive material of appropriate size, if used) is then inserted. The assembly of the magnet 20 , the steel section 22 and the other magnet 24 are then inserted into the sleeve 14 in that order and against the spring 26 in the now-welded end cap 16 . The remaining spring 28 is inserted into the other end cap 18 , which is welded to the other end of the sleeve 14 . The overall exterior is then sanded and polished to a smooth and bright finish, and the device is subjected to a sufficiently strong magnetic field so that the interior magnets 20 and 24 are magnetized to the desired polarity.
[0037] The resultant magnetic flux lines 30 are shown in FIG. 3 . It will be noted that the polarity is the same at the ends and the middle of the device, such that the magnetic field radiates around the entire device, as shown in FIG. 4 . Although the N polarity is shown in FIG. 4 , it will be understood that a S polarity could be achieved as well by reversing the magnetic field by which the overall device is magnetized after construction.
[0038] The device of this invention can be easily administered to a cow using the usually pill or bolus apparatus. Once administered, the animal pill magnet remains in the cow's stomach were it will collect and hold a large amount of tramp iron.
[0039] Although preferred embodiments have been shown and described, the disclosed invention and the protection afforded by this patent are not limited thereto, but are of the full scope of the following claims, and equivalents thereto. | An improved animal pill or cow magnet that is inserted into the stomach of a bovine animal to attract and hold tramp metal ingested by the animal so as to prevent the adverse condition commonly referred to as “hardware disease.” The disclosed device has at least a pair of NdFeB magnets separated by a carbon steel section within the stainless steel outer casing. The resulting magnetic field for the overall animal pill magnet has a single polarity, which by design can be either N or S. | 0 |
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to compounds having activity against mycobacteria. Certain compounds of the invention may be used in the treatment of mycobacterial infections. The invention also provides radiolabelled compounds that are useful for in vivo imaging in the diagnosis of mycobacterial infections. Methods and intermediates useful for the preparation of certain compounds of the invention are also provided. The invention also provides methods for using the compounds of the invention in treatment and diagnosis.
DESCRIPTION OF RELATED ART
[0002] Pulmonary tuberculosis (TB) is an airborne infection caused by Mycobacterium tuberculosis (MTB) that causes high mortality and morbidity, particularly in developing countries (Dye et al JAMA 1999; 282(7): 677-686). A recent factsheet produced by the World Health Organisation reported that the number of new cases of TB continues to increase each year in South-East Asia, the Eastern Mediterranean and Africa (http://wwww.who.int/mediacentre/factsheets/fs104/en/print.html). The antitubercular nitroimidazoles, including two classes of new bicyclic agents with either fused oxazole or oxazine rings, are one of the most exciting recent developments in the field of antituberculosis chemotherapy, and two candidates are already in human clinical trials for the treatment of both drug-susceptible and drug-resistant disease (in this regard the reader is referred to the website http://www.newtbdrugs.org/pipeline.php). Sasaki et al (J Med Chem 2006; 49(26): 7854-7860) have reported a series of novel optically active 6-nitro-2,3-dihydroimidazo oxazoles having various phenoxymethyl groups and a methyl group at the 2-position. A particular compound that is potent and orally active was found that is a promising candidate (OPC-67683) for the treatment of tuberculosis, which is currently in clinical trials:
[0000]
[0003] The unique structure of the cell wall of mycobacteria, rich in waxy mycolic acid, is the target of action of OPC-67683, which inhibits methoxy-mycolic and keto-mycolic acid synthesis but at significantly lower concentrations.
[0004] With the recent emergence of drug-resistant strains of MTB there is still scope for further improved agents to treat an otherwise incurable disease.
[0005] Radiolabelled nitroimidazoles are well-known for hypoxia imaging. Examples include 1 F-misonidazole ([ 18 F]FMISO) and 99m TcO(PnAO)-1-2-nitroimidazole (known as BMS-181321):
[0000]
[0006] These and other radiolabelled nitroimidazoles have been described as being particularly useful in the detection of myocardial hypoxia (Strauss et at J Nuc Cardiol 1995; 2: 437-445).
[0007] Accurate and prompt diagnosis is important in order to control the infection and also to ensure the appropriate therapy for infected patients. Currently, a definitive diagnosis of TB requires culture of MTB from a sample taken from a patient. Patients with clear signs and symptoms of pulmonary disease with a sputum smear-positive result present no problems to diagnose. However, there can be difficulty culturing the slow-growing MTB organism in the laboratory. Furthermore the emergence of HIV has resulted in a decreased likelihood of sputum smear positivity and an increase in non-respiratory disease, such that ease of diagnosis is more difficult in these cases (see reviews by Jeong & Lee Am J Roent 2008; 191: 834-844; Davies & Pai Int J Tuberc Lung Dis 2008; 12(11): 1226-1234; and, Lange & Mori Respirology 2010; 15: 220-240).
[0008] In vivo imaging methods are known to be useful in the diagnosis of TB. Chest x-ray is a widely-used in vivo imaging method for screening, diagnosis and treatment monitoring in patients with known or suspected TB. Chest computed tomography (CT) is more sensitive than conventional x-ray and may be applied to identify early parenchymal lesions or mediastinal lymph node enlargements and to determine disease activity in tuberculosis (Lee & Im AJR 1995; 164(6): 1361-1367).
[0009] Nuclear imaging methods have also been reported for diagnosis and treatment monitoring of TB. The positron-emission tomography (PET) tracer 18 F-fluorodeoxyglucose ([ 18 F]FDG) has been proposed as useful in the diagnosis of disease activity and therapy monitoring in patients with TB (Demura et at Eur J Nuc Med Mol Imag 2009; 36: 632-639). Roohi et at (Radiochim Acta 2006; 94: 147-152) describe a 99m Tc-labelled isoniazid derivative, which localised to tubercular lesions in rabbits and enabled the lesions to be visualised 2 hours following administration of the 99m Tc-labelled derivative. However, this 99m Tc-labelled derivative comprises a 99m Tc-chelate at a location believed to be the active pharmacophore, which is not ideal.
[0010] There is therefore scope for improved strategies in the treatment and diagnosis of TB.
SUMMARY OF THE INVENTION
[0011] The present invention provides novel compounds useful in the treatment and diagnosis of mycobacterial infections. Compounds of the present invention have enhanced biological properties as compared to the related known compounds. The present invention also provides a precursor compound useful in the synthesis of certain compounds of the invention, and a method to obtain these compounds using said precursor compound. Methods of treatment and diagnosis in which the compounds of the invention find use are also provided.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Compound
[0013] In one aspect, the present invention provides a compound of Formula I:
[0000]
[0014] wherein:
[0015] R 1 is absent or is C 1-4 alkyl;
[0016] R 2 is a halogen isotope; and,
[0017] X is —O— or —NH—.
[0018] Unless otherwise specified, the term “alkyl” alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably from 1 to 4 carbon atoms. Examples of such radicals include, methyl, ethyl, and propyl.
[0019] The term “halogen isotope” refers to any radioactive or non-radioactive isotope of a halogen (also referred to herein as “radioactive halogen” and “non-radioactive halogen”, respectively). The terms radioactive and non-radioactive take their commonly-known meaning, i.e. “radioactive” refers to giving off, or capable of giving off, radiant energy in the form of particles or rays, as alpha, beta, and gamma rays, by the spontaneous disintegration of atomic nuclei. The term “non-radioactive” means not radioactive. The term “halogen” suitably refers to an atom selected from iodine, fluorine, chlorine and bromine, preferably to iodine and fluorine and most preferably to iodine.
[0020] R 1 is preferably C 1-4 alkyl, and is most preferably methyl.
[0021] X is preferably —O—.
[0022] In one preferred embodiment, R 2 is a gamma-emitting radioactive halogen selected from 123 I, 131 I and 77 Br. For this embodiment said gamma-emitting radioactive halogen is preferably 123 I.
[0023] In another preferred embodiment, R 2 is a positron-emitting radioactive halogen selected from 17 F, 18 F, 75 Br, 75 Br and 124 I. For this embodiment, said positron-emitting radioactive halogen is selected from 18 F and 124 I, and is most preferably 124 I.
[0024] In a further preferred embodiment, R 2 is a non-radioactive halogen selected from 127 I, 79 Br, 81 Br, 19 F. For this embodiment, said non-radioactive halogen is preferably selected from 127 I and 19 F, and is most preferably 127 I.
[0025] If a chiral centre or another form of an isomeric centre is present in a compound according to the present invention, all forms of such isomer, including enantiomers and diastereoisomers, are encompassed by the present invention. Compounds of the invention containing a chiral centre may be used as racemic mixture or as an enantiomerically-enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer maybe used alone. In a preferred embodiment, an individual enantiomer is used alone. Preferably, individual enantiomer of the compound as defined herein is of Formula Ia:
[0000]
wherein R 11 , R 12 and X 1 are as suitably and preferably defined herein for R 1 , R 2 and X, respectively.
[0027] Precursor Compound
[0028] In another aspect, the present invention provides a precursor compound for the preparation of compound of Formula I wherein R 2 is a radioactive halogen as defined above, wherein said precursor compound is a compound of Formula II:
[0000]
[0029] wherein:
[0030] R 21 is as defined above for R 1 of Formula I;
[0031] R 22 is a non-radioactive iodine or bromine, an organometallic derivative such as a trialkylstannane or a trialkylsilane, an organoboron compound such as a boronate ester or an organotrifluoroborate, or is selected from amino, hydroxy, nitro, bromo, iodo, tri-C 1-3 -alkylammonium, quaternary ammonium, diazonium, iodonium, tosylate, mesylate and triflate; and,
[0032] X 2 is as defined above for X of Formula I.
[0033] A “precursor compound” comprises a non-radioactive derivative of a radiolabelled compound, designed so that chemical reaction with a convenient chemical form of the detectable label occurs site-specifically; can be conducted in the minimum number of steps (ideally a single step); and without the need for significant purification (ideally no further purification), to give the desired radiolabelled compound. In the context of the present invention, the term “radiolabelled compound” refers to the compound of Formula I wherein R 2 is a radioactive halogen. Such precursor compounds are synthetic and can conveniently be obtained in good chemical purity. In order to facilitate site-specific reaction, the precursor compound of the invention may optionally comprise a suitable protecting group.
[0034] By the term “protecting group” is meant a group which inhibits or suppresses undesirable chemical reactions, but which is designed to be sufficiently reactive that it may be cleaved from the functional group in question to obtain the desired product under mild enough conditions that do not modify the rest of the molecule. Protecting groups are well known to those skilled in the art and are described in ‘Protective Groups in Organic Synthesis’, Theorodora W. Greene and Peter G. M. Wuts, (Fourth Edition, John Wiley & Sons, 2007).
[0035] An “organometallic derivative” is an organic substituent containing a metal, especially a wherein a metal atom is bonded directly to a carbon atom. In the context of the present invention the term preferably relates to trialkylstannane and trialkylsilane substituents. The term “trialkylstannane” refers to the moiety —Sn-(alkyl) 3 , wherein each alkyl is the same and wherein the term alkyl is as defined above, and is preferably a C 1-6 alkyl, most preferably methyl or butyl, and most especially preferably butyl. The term “trialkylsilane” refers to the moiety —Si-(alkyl) 3 wherein the (alkyl) 3 portion is as defined for trialkylstannane.
[0036] The term “organoboron compound” (also known as organoborane compound) refers to a substituent that is an organic derivative of BH 3 . A “boronate ester” is a substituent derived from an alkyl or aryl substituted boric acid containing a carbon-boron bond belonging to the larger class of organoboranes, wherein the terms alky and aryl are as defined herein. An “organotrifluoroborate” is a substituent derivaed from an organoboron compound that contains an anion with the general formula [RBF 3 ] − .
[0037] The term “amino” refers to the group —NH 2 .
[0038] The term “hydroxyl” refers to the group —OH.
[0039] The term “nitro” refers to the group —NO 2 .
[0040] The term “bromo” refers to a bromine substituent.
[0041] The term “iodo” refers to an iodine substituent.
[0042] The term “quaternary ammonium” refers to the group —NR 3 wherein each R is an alkyl or an aryl, wherein the terms alkyl and aryl are as defined herein. Preferably, each R is an alkyl, most preferably a C 1-3 alkyl.
[0043] The term “diazonium” refers to the —N + ≡N group.
[0044] The term “iodonium” in the context of the present invention refers to the ion RI + wherein R is any organic residue. R is preferably an aryl wherein the term “aryl” refers to aromatic rings or ring systems having 5 to 12 carbon atoms, preferably 5 to 6 carbon atoms, in the ring system, e.g. phenyl or naphthyl.
[0045] The term “tosylate” refers to the group —O—S(O 2 ) -p-toluene.
[0046] The term “mesylate” refers to the group —O—S(O 2 )-methyl.
[0047] The term “triflate” refers to the group —O—S(O 2 )—CF 3 .
[0048] The preferred embodiments provided above for R 1 and X of Formula I apply equally to R 21 and X 2 , respectively of Formula II.
[0049] In a preferred embodiment, the precursor compound of the invention is of Formula IIa:
[0000]
[0050] wherein:
[0051] R 31 is as defined above for R 21 of Formula II;
[0052] R 32 is as defined above for R 22 of Formula II;
[0053] X 3 is as defined above for X 2 of Formula II.
[0054] Precursor compounds of the present invention may be obtained by following the methods described by Nagarajan et at (1989 Eur J Med Chem; 24: 631-633) by reaction of 2,4-dinitroimidazole (1) with a substituted oxirane (2) as illustrated in Scheme 1 below:
[0000]
[0055] wherein R 11 , R 12 and X 1 are as suitably and preferably defined herein. R 42 is either an R 12 group, or is an R 12 group protected by a suitable protecting group wherein the protecting group is removed in step (ii) of Scheme 1 following reaction in step (i) of 1 and 2 to obtain the precursor compound of the invention following deprotection. R 42 may alternatively be a chemical group, or a suitably protected version thereof, which may be converted using known organic chemistry methods into an R 12 group in step (ii) following completion of step (i).
[0056] In an alternative, the precursor compounds of the invention may be obtained by following the methods described by Sasaki et at (2006 J Med Chem; 49 (26):7854-7860), wherein a 2-chloro-5-nitro imidazole starting material (3) is converted to the corresponding epoxide (4) and then reacted with the desired phenol (for X 1 ═—NH—) or phenylamine (for X 1 ═—NH—) (5) to obtain the precursor compound of the invention, as illustrated below in Scheme 2:
[0000]
[0057] In Scheme 2, R 11 , R 12 , R 42 and X 1 are as described above for Scheme 1.
[0058] The precursor compound of the invention is ideally provided in sterile, apyrogenic form. The precursor compound can accordingly be used for the preparation of a radiopharmaceutical composition comprising the compound of the invention wherein R 2 is a radioactive halogen, together with a biocompatible carrier suitable for mammalian administration, which forms another aspect of the invention as described in more detail below.
[0059] The precursor compound is also suitable for inclusion as a component in a kit or a cassette for the preparation of such a pharmaceutical composition. These aspects of the invention are also discussed in greater detail below.
[0060] Method to Prepare Compounds
[0061] With routine adaption, the above-described methods to obtain precursor compounds of the invention can also be applied to obtain a compound of Formula I wherein R 2 is a non-radioactive halogen isotope.
[0062] In another embodiment, the present invention relates to a method for the preparation of the compound of the invention wherein said compound comprises a radioactive halogen, and wherein said method comprises reaction of the precursor compound as defined herein with a suitable source of said radioactive halogen. The suitable and preferred aspects of the compound of Formula I and the precursor compound of Formula II as defined herein apply equally to this aspect of the invention.
[0063] The term “a suitable source said radioactive halogen” means the radioactive halogen in a chemical form that is reactive with a substituent of the precursor compound such that the radioisotope becomes covalently attached to the precursor compound. The person skilled in the art of in vivo imaging agents will be familiar with sources of radioactive halogen that are suitable for application in the present invention. The reader is referred to the “Handbook of Radiopharmaceuticals” for a detailed presentation of the field (2003; Wiley: Welch and Redvanly, Eds).
[0064] The step of “reaction” of the precursor compound with the suitable source of a radioactive halogen involves bringing the two reactants together under reaction conditions suitable for formation of the desired compound in as high a radiochemical yield (RCY) as possible. Synthetic routes for obtaining particular compounds of the present invention are presented in the experimental section below.
[0065] Methods of introducing radioactive halogens are described by Bolton (2002 J LabCompRadiopharm; 45: 485-528).
[0066] It is known in the art that to introduce a radioactive halogen (which can be either a gamma-emitting radioactive halogen or a positron-emitting radioactive halogen) the precursor suitably comprises the following reactive groups: a non-radioactive precursor halogen atom such as an aryl iodide or bromide (to permit radioiodine exchange); an activated aryl ring (e.g. phenol or aniline groups); an imidazole ring; an indole ring; an organometallic compound (eg. trialkyltin or trialkylsilyl); or an organic compound such as triazene or a good leaving group for nucleophilic substitution such as an iodonium salt. Methods of introducing radioactive halogens are described by Bolton (2002 J LabCompRadiopharm; 45: 485-528). Examples of suitable aryl groups to which radioactive halogens, especially iodine can be attached are given below:
[0000]
[0067] Both contain substituents which permit facile radioiodine substitution onto the aromatic ring. Alternative substituents containing radioactive iodine can be synthesised by direct iodination via radiohalogen exchange wherein radioiodide ion is the suitable source of radioactive iodine, e.g.:
[0000]
[0068] Where R 2 is radioactive iodine, a preferred precursor compound of Formula II comprises at R 22 a derivative which either undergoes electrophilic iodination. Examples of this are organometallic derivatives such as a trialkylstannane (e.g. trimethylstannyl or tributylstannyl), or a trialkylsilane (e.g. trimethylsilyl) or an organoboron compound (e.g. boronate esters or organotrifluoroborates).
[0069] For electrophilic radioiodination, R 22 of the precursor compound of Formula II preferably comprises: an activated organometallic precursor compound (e.g. trialkyltin, trialkylsilyl or organoboron compound). Precursor compounds and methods of introducing radioiodine into organic molecules are described by Bolton (2002 J Lab Comp Radiopharm; 45: 485-528). Suitable boronate ester organoboron compounds and their preparation are described by Kabalaka et at (2002 Nucl Med Biol; 29: 841-843 and 2003 Nucl Med Biol; 30: 369-373). Suitable organotrifluoroborates and their preparation are described by Kabalaka et at (2004 Nucl Med Biol 2004; 31: 935-938). Preferred precursor compounds of Formula II for radioiodination comprise at R 22 an organometallic precursor compound, most preferably a trialkyltin, and especially tributyltin.
[0070] Radiobromination can be achieved by methods similar to those described above for radioiodination. Kabalka and Varma have reviewed various methods for the synthesis of radiohalogenated compounds, including radiobrominated compounds (1989 Tetrahedron; 45(21): 6601-21).
[0071] The methods used when the radioactive halogen is 18 F are described in detail in Chapter 6 of the Handbook of Radiopharmaceuticals (2003; Wiley: Welch and Redvanly, Eds). 18 F has a relatively short half-life and therefore special considerations are required in the synthesis of compounds comprising 18 F.
[0072] Labelling with 18 F can be achieved by nucleophilic displacement of a leaving group from a precursor compound. In this way, the precursor compound may be labelled in one step by reaction with a suitable source of [ 18 F]-fluoride ion ( 18 F), which is normally obtained as an aqueous solution from the nuclear reaction 18 O(p,n) 18 F and which is made reactive by the addition of a cationic counterion and the subsequent removal of water to form a suitable source of 18 F. T he radiofluorine atom attaches via a direct covalent bond to the aromatic ring. 18 F-fluoride nucleophilic displacement from an aryl diazonium salt, aryl nitro compound or an aryl quaternary ammonium salt are suitable routes. Preferably, where it is desired to add radioactive fluorine, R 22 of said precursor compound is a leaving group selected from hydroxyl, nitro, bromo, iodo, tri-C 1-3 -alkylammonium, quaternary ammonium, diazonium, iodonium, tosylate, mesylate and triflate, and said suitable source of radioactive halogen is 18 F-fluoride ( 18 F − ).
[0073] In one embodiment, the method for the preparation is automated. A cassette useful in this automated method forms a further aspect of the invention describe in more detail below.
[0074] Kit and Cassette
[0075] In a yet further aspect, the present invention provides a kit for the preparation of a compound of the invention wherein R 2 is a radioactive halogen, said kit comprising a precursor compound of the invention as defined herein, so that reaction with a sterile source of a radioactive halogen gives the desired compound with the minimum number of manipulations. Such considerations are particularly important where the radioisotope has a relatively short half-life, and for ease of handling and hence reduced radiation dose for the radiopharmacist. The precursor compound is preferably present in the kit in lyophilized form, and the reaction medium for reconstitution of such kits is preferably a biocompatible carrier. Suitable and preferred embodiments of the precursor compound for the kit of the invention are as provided above for the precursor compound of the invention.
[0076] A “biocompatible carrier” is a fluid, especially a liquid, in which the resultant radiolabelled compound of the invention is suspended or dissolved, such that the composition is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort. The biocompatible carrier is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity-adjusting substances (e.g. salts of plasma cations with biocompatible counterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g. sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionic polyol materials (e.g. polyethyleneglycols, propylene glycols and the like). The biocompatible carrier may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations. Preferably the biocompatible carrier comprises pyrogen-free water for injection, or isotonic saline. The pH of the biocompatible carrier for intravenous injection is suitably in the range 4.0 to 10.5.
[0077] In the kit of the invention, the precursor compound is preferably presented in a sealed container which permits maintenance of sterile integrity and/or radioactive safety, plus optionally an inert headspace gas (e.g. nitrogen or argon), whilst permitting addition and withdrawal of solutions by syringe. A preferred sealed container is a septum-sealed vial, wherein the gas-tight closure is crimped on with an overseal (typically of aluminium). Such sealed containers have the additional advantage that the closure can withstand vacuum if desired e.g. to change the headspace gas or degas solutions.
[0078] The precursor compound for use in the kit may be employed under aseptic manufacture conditions to give the desired sterile, non-pyrogenic material. The precursor compound may alternatively be employed under non-sterile conditions, followed by terminal sterilisation using e.g. gamma-irradiation, autoclaving, dry heat or chemical treatment (e.g. with ethylene oxide). Preferably, the precursor compound is provided in sterile, non-pyrogenic form. Most preferably the sterile, non-pyrogenic precursor compound is provided in the sealed container as described above.
[0079] Preferably, all components of the kit are disposable to minimise the possibilities of contamination between runs and to ensure sterility and quality assurance.
[0080] [ 18 F]-radiotracers in particular are now often conveniently prepared on an automated radiosynthesis apparatus. There are several commercially-available examples of such apparatus, including Tracerlab™ and Fastlab™ (GE Healthcare Ltd). Such apparatus commonly comprises a “cassette”, often disposable, in which the radiochemistry is performed, which is fitted to the apparatus in order to perform a radiosynthesis. The cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up steps.
[0081] The present invention therefore provides in another aspect a cassette for the automated synthesis of compound of Formula I comprising 18 F, wherein said cassette comprises:
(i) a vessel containing a precursor compound comprising a leaving group wherein said leaving group is as defined herein for the precursor compound of the invention; and (ii) means for eluting the vessel with a suitable source of 18 F-fluoride ( 18 F − ).
[0084] The cassette may additionally comprise:
(iii) an ion-exchange cartridge for removal of excess 18 F-fluoride ( 18 F − ).
[0086] Pharmaceutical Composition
[0087] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of Formula I together with a biocompatible carrier in a form suitable for mammalian administration.
[0088] When R 2 of the compound of Formula I in said pharmaceutical composition is a radioactive halogen, said pharmaceutical composition is a radiopharmaceutical composition and the biocompatible carrier is as defined above in relation to the kit of the invention. The radiopharmaceutical composition may be administered parenterally, i.e. by injection, and is most preferably an aqueous solution. Such a composition may optionally contain further ingredients such as buffers; pharmaceutically acceptable solubilisers (e.g. cyclodextrins or surfactants such as Pluronic, Tween or phospholipids); pharmaceutically acceptable stabilisers or antioxidants (such as ascorbic acid, gentisic acid orpara-aminobenzoic acid). Where the compound of the invention is provided as a radiopharmaceutical composition, the method for preparation of said compound may further comprise the steps required to obtain a radiopharmaceutical composition, e.g. removal of organic solvent, addition of a biocompatible buffer and any optional further ingredients. For parenteral administration, steps to ensure that the radiopharmaceutical composition is sterile and apyrogenic also need to be taken.
[0089] The suitable and preferred embodiments described herein for the compound of Formula I wherein R 2 is a radioactive halogen apply equally to the radiopharmaceutical composition of the invention.
[0090] Where the pharmaceutical composition comprises the compound of Formula I wherein R 2 is a non-radioactive halogen, the biocompatible carrier may be a solid or liquid pharmaceutically acceptable nontoxic carrier. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerols solutions are also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesium stearate, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. These compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” (18 th Edition; E. W. Martin, Ed: 1990 Mack Publishing). Such compositions will contain an effective therapeutic amount of the compound together with a suitable amount of carrier so as to provide the form for proper administration to the host. While intravenous injection is a very effective form of administration, other modes can be employed, e.g. oral administration.
[0091] In Vivo Imaging and Diagnosis
[0092] In a further aspect, the present invention provides an in vivo imaging method comprising:
(a) administration of the compound of Formula I wherein R 2 is a radioactive halogen; (b) allowing said compound to bind to the cell wall of any mycobacteria present in said subject; (c) detecting by an appropriate in vivo imaging procedure signals emitted by the radioactive halogen comprised in said compound; (d) generating an image representative of the location and/or amount of said signals; and, (e) determining the distribution of mycobacteria in said subject wherein said distribution is directly correlated with said signals emitted by said radioactive halogen.
[0098] The “administration” step is preferably carried out parenterally, and most preferably intravenously. The intravenous route represents the most efficient way to deliver the compound throughout the body of the subject, and also does not represent a substantial physical intervention on the body of the subject. By the term “substantial” is meant an intervention which requires professional medical expertise to be carried out, or which entails a substantial health risk even when carried out with the required professional care and expertise. The compound is preferably administered as the pharmaceutical composition of the invention, as defined herein. The in vivo imaging method of the invention can also be understood as comprising the above-defined steps (b)-(e) carried out on a subject to whom said compound has been pre-administered. In this embodiment, the compound is preferably administered as the radiopharmaceutical composition of the invention.
[0099] Following the administering step and preceding the detecting step, the compound is allowed to bind to mycobacteria within said subject. For example, when the subject is an intact mammal, the compound will dynamically move through the mammal's body, coming into contact with various tissues therein. Once the compound comes into contact with any mycobacteria, the two entities bind such that clearance of the compound from tissue in which mycobacteria are present takes longer than from tissue without any mycobacteria present. A certain point in time will be reached when detection of compound specifically bound to mycobacteria is enabled as a result of the ratio between compound bound to tissue with mycobacteria versus that bound in tissue without any mycobacteria. This is the optimal time for the detecting step to be carried out.
[0100] The “detecting” step of the method of the invention involves detection of signals emitted by the radioactive halogen by means of a detector sensitive to said signals. This detection step can also be understood as the acquisition of signal data. Single-photon emission tomography (SPECT) and positron-emission tomography (PET) are suitable in vivo imaging procedures for use in the method of the invention. When R 2 is a gamma-emitting radioactive halogen, SPECT is suitable, and when R 2 is a positron-emitting radioactive halogen, PET is suitable.
[0101] The “generating” step of the method of the invention is carried out by a computer which applies a reconstruction algorithm to the acquired signal data to yield a dataset. This dataset is then manipulated to generate images showing the location and/or amount of signals emitted by the radioactive halogen which is comprised in the compound used in said in vivo imaging method. The signals emitted directly correlate with the presence of mycobacteria such that the “determining” step can be made by evaluating the generated image.
[0102] The “subject” of the invention can be any human or animal subject. Preferably the subject of the invention is a mammal. Most preferably, said subject is an intact mammalian body in vivo. In an especially preferred embodiment, the subject of the invention is a human. The in vivo imaging method may be used in subjects known or suspected to have a pathological condition associated with a mycobacterial infection. Preferably, said method relates to the in vivo imaging of a subject known or suspected to have tuberculosis caused by Mycobacrerium tuberculosis , and therefore has utility in a method for the diagnosis of said condition. Where a subject is known to have tuberculosis caused by Mycobacrerium tuberculosis , the in vivo imaging method of the invention may be carried out repeatedly during the course of a treatment regimen for said subject, said regimen comprising administration of a drug to combat tuberculosis caused by Mycobacrerium tuberculosis.
[0103] The present invention additionally provides a method for diagnosis of a mycobacterial infection in a subject wherein said method comprises the in vivo imaging method as defined herein, together with a further step (vi) of attributing the distribution of mycobacteria to a mycobacterial infection. The term “mycobacterial infection” is defined herein as an infection caused by a mycobacterium. The method of diagnosis is preferably used to diagnose tuberculosis caused by Mycobacterium tuberculosis.
[0104] In a yet further aspect, the present invention provides the radiopharmaceutical composition as suitably and preferably defined herein for use in a method of in vivo imaging wherein said method of in vivo imaging is as suitably and preferably defined herein.
[0105] The present invention also provides the radiopharmaceutical composition as suitably and preferably defined herein for use in a method of diagnosis wherein said method of diagnosis is as suitably and preferably defined herein.
[0106] Treatment
[0107] In a yet further aspect, the present invention provides a method for the treatment of a mycobacterial infection comprising administration of the compound of Formula I wherein R 2 is a non-radioactive halogen. Preferably, said compound is administered as a pharmaceutical composition. A suitable pharmaceutical composition for a compound of Formula I wherein R 2 is a non-radioactive halogen is defined above. As for the methods of in vivo imaging and diagnosis of the invention, said mycobacterial infection is preferably tuberculosis caused by
[0108]
Mycobacterium tuberculosis.
[0109] As presented in the experimental examples herein, the compound of Formula I of the present invention wherein R 2 is a non-radioactive halogen has good activity against Mycobacterium tuberculosis and as such has properties which make it a potentially useful treatment against Mycobacterium tuberculosis.
[0110] The suitable and preferred embodiments of R 2 as a non-radioactive halogen as presented above in connection with the compound of Formula I apply equally to the method of treatment of the invention.
[0111] In one embodiment, the method of treatment may also comprise the combined administration of the compound of the invention with other known treatments for tuberculosis. Non-limiting examples of such other treatments including isoniazid, rifampicin, pyrazinamide, and ethambutol.
BRIEF DESCRIPTION OF THE EXAMPLES
[0112] Example 1 describes the synthesis of the unlabelled prior art compound, (R)-2-Methyl-6-nitro-2-(phenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole.
[0113] Example 2 describes the synthesis of an iodinated version of the prior art compound prepared in Example 1, (R)-2-((4-Iodophenoxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole, a compound of Formula I of the invention wherein R 2 is non-radioactive iodine.
[0114] Example 3 describes the in vitro screening methods used to evaluate the compounds obtained in Examples 1 and 2.
[0115] Example 4 describes the synthesis of (R)-2-((4-fluorophenoxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole, a compound of Formula I of the invention wherein R 2 is non-radioactive fluorine.
[0116] Example 5 describes the synthesis of (R)-2-methyl-6-nitro-2-((4-(tributylstannyl)phenoxy)methyl)-2,3-dihydroimidazo[2,1-b]oxazole, a precursor compound of the invention.
LIST OF ABBREVIATIONS USED IN THE EXAMPLES
[0000]
ATP adenosine triphosphate
DCM dichloromethane
DMF dimethylformamide
HPLC high-performance liquid chromatography
IC50 half maximal inhibitory concentration
LCMS liquid chromatography mass spectrometry
LORA low-oxygen recovery assay
MABAmicroplate alamar blue assay
MIC minimum inhibitory concentration
RBF round-bottom flask
VERO “verda reno” meaning “green kidney” in Esperanto; used to refer to a line of kidney epithelial cells extracted from an African green monkey (Cercopithecus aethiops).
EXAMPLES
Example 1
Synthesis of (R)-2-Methyl-6-nitro-2-(phenoxymethyl)-2,3-dihydroimidazo[2,1-bloxazole (Prior Art Compound)
[0128]
[0129] (R)-2-chloro-1- (2-methyl-2,3-epoxypropyl)-4-nitroimidazole was obtained by conversion of commercially-available 2-chloro-5-nitro imidazole starting material to the corresponding epoxide following the method described by Sasaki et at (2006 J Med Chem; 49: 7854-7860). (R)-2-chloro-1- (2-methyl-2,3-epoxypropyl)-4-nitroimidazole (57.7 mg, 0.267 mmol), and phenol (20.12 mg, 0.214 mmol) were placed in a 50 ml RBF and dissolved in 2 ml of DMF. The reaction mixture was cooled to 0° C. and then to it, NaH (16.48 mg, 0.256 mmol) was added carefully. The temperature was then increased to 50° C. and the reaction mass was stirred for 24-36 hours. The reaction was checked for completion using the HPLC/LCMS and the reaction mass was concentrated on a rotary evaporator. The dried material was then taken for purification on a CombiFlash (Teledyne Isco) chromatography system (using a DCM-methanol solvent system). The purified material was then taken for recrystallization using a DCM-hexane solvent system to yield a pale yellow powder as the product. Yield=7.4 mg; Purity=96%; 1 H NMR (CDCl3): δ 1.8(dd (J=3.0,9.0), 2H,CH 2 ), 4.22 (d (J=9), 1H, CH2), 4.5 (d (J=9), 1H, CH2), 6.86 (d (J=9.0), 2H, ArH), 7.6 (t (J=6.0, 1H, ArH), 7.33 (d (J=6.0), 2H, ArH), 7.6 (s, 1H, ArH); MS: m/z 276 (M+1, 100%).
Example 2
Synthesis of (R)-2-((4-Iodophenoxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazol[2,1-b]oxazole (iodinated derivative of the prior art compound of Example 1)
[0130]
[0131] The method as described in Example 1 was used except that p-iodo phenol (28.38 mg, 0.129 mmol) was used in place of phenol. Yield=4.2 mg; Purity=96%; 1H NMR (CDCl3): δ 1.8(dd (J=3.0,9.0), 2H,CH2), 4.22 (d (J=9), 1H, CH2), 4.5 (d (J=9), 1H, CH2), 6.64 (d (j=9.0), 2H, ArH), 7.6 (m, 3H, ArH) ; MS: m/z 402 (M+1, 100%).
Example 3
Methods used to Screen Compounds In Vitro
[0132] 3(i)Methods for Determining Minimum Inhibition Concentration (MIC)
[0133] Screening was done to get MIC for M. tuberculosis using both the microplate alamar blue assay (MABA) and low-oxygen recovery assay (LORA).
[0134] The initial screen was conducted against Mycobacterium tuberculosis strain H37Rv (American Type Culture Collection number 27294) in BACTEC 12B medium (Becton-Dickinson) using the MABA. Compounds were tested in ten 2-fold dilutions, typically from 100 μg/mL to 0.19 μg/mL. The MIC90 is defined as the concentration effecting a reduction in fluorescence of 90% relative to controls. This value is determined from the dose-response curve using a curve-fitting program. Any MIC90 value of ≦10 μg/mL was considered “active” for antitubercular activity. 3(h) Method for Determining IC50
[0135] A VERO cell cytotoxicity assay was carried out in parallel with the TB Dose Response assay. After 72 hours exposure, viability was assessed using Promega's Cell Titer Glo Luminescent Cell Viability Assay, a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present. Cytotoxicity was determined from the dose-response curve as the IC50 using a curve-fitting program.
[0136] 3(iii) Method for Determining Calculated clogP
[0137] Chemdraw Ultra 10.0 (Cambridge Soft Software) was used to determine calculated clogP values.
[0138] 3(iv) In Vitro Screening Results
[0000]
Compound
MABA MIC (μg/ml)
IC50(μg/ml)
Calcd clogP
Example 1
1.329
>50
2.4
Example 2
<0.195
>50
3.63
[0139] The above screening data demonstrates that introduction of iodine has reduced the MIC, by a factor of over 6 which means iodine introduction has surprisingly increased the activity of the parent compound.
Example 4
Synthesis of (R)-2-((4-fluorophenoxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole
[0140]
[0141] (R)-2-chloro-1-((2-methyloxiran-2-yl)methyl)-4-nitro-1H-imidazole (50.0 mg, 0.230 mmol) was transferred to clean, dry RBF and to it, added anhydrous DMF (2.0 ml). To this mass, added p-fluoro phenol (20.66 mg, 0.184 mmol) and stirred under nitrogen for 10 minutes. The mixture was then cooled to 0° C. and then added sodium hydride (60%) (8.84 mg, 0.221 mmol) portion wise. The contents of the flask were allowed to stir in cold conditions for about 10 minutes and then heated to 50° C. The reaction showed completion within 30 hours on the LC/MS. The contents of the flask were allowed to cool to room temperature and then concentrated on the rotary evaporator. The resulting mass as such was taken for purification on the CombiFlash system using DCM/Methanol as the gradient system. The resulting solid was then recrystallized using a DCM/Hexane system to yield 5 mg (74.6%) of the product as a whitish solid.
[0142] LC-MS: m/z calcd for C13H12FN3O4, 293.08; found, 294 (M+H).
Example 5
Synthesis of (R)-2-methyl-6-nitro-2-((4-(tributylstannyl)phenoxy)methyl)-2,3-dihydromidazo[2,1-b]oxazole
[0143]
[0144] A mixture of (R)-2-((4-iodophenoxy)methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared according to Example 2 (25 mg, 0.0623 mmol), bis- (tributyltin) (54.25 mg, 47 μl, 0.0935 mmol) and tetrakis triphenylphosphine) palladium (0) (5.11 mg, 0.004426 mmol) was taken in a mixed solvent (2.0 ml, 1:1 dioxane/triethyl amine) and stirred under reflux for 36 hours. Upon checking for completion, the solvent was removed, and to the residue added 4-5 ml of water. The reaction mixture was then extracted using ethyl acetate, separated, dried and evaporated. The residue was then purified using the HPLC system. However, once purified, the compound could not be isolated from the solvent as the molecule is not stable once removed from it. The confirmation of product formation was from the LC/MS system with a single peak with m/z 565 (M+H) − . | The present invention provides novel compounds useful in the treatment and diagnosis of mycobacterial infections. Compounds of the present invention have enhanced biological properties as compared to the related known compounds. The present invention also provides a precursor compound useful in the synthesis of certain compounds of the invention, and a method to obtain these compounds using said precursor compound. Methods of treatment and diagnosis in which the compounds of the invention fmd use are also provided. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit under 35 U.S.C. § 119(e) of Provisional Application Serial No. 60/193,036, filed Mar. 29, 2000, which is incorporated by reference herein, in its entirety.
FIELD OF THE INVENTION
[0002] This invention is directed, inter alia, towards a method of using the oxidative stress response system in E. coli as a tool for mechanistic screening of anti-tumor drugs and other applications.
BACKGROUND OF THE INVENTION
[0003] The current state-of-the-art in screening technology is primarily based on a molecular recognition event, typically a small molecule binding a target receptor/ligand or a nucleic acid sequence binding to a target. High Throughput Screening (HTS) technologies have been developed to allow for massive parallel processing. In particular, gene-chip technology has revolutionized the analysis of gene expression (Lockhart et al, Nature Biotechnol., 14:1675-1680 (1996); Gray et al, Science, 281:533-538 (1998); Wang et al, FEBS Letter, 445:269-273 (1999); Alon et al, Proc. Natl. Acad. Sci., USA, 96:6745-6750 (1999); and Zhu et al, Proc. Natl. Acad. Sci., USA, 95:14470-14475 (1998)). Here, thousands of DNA sequences of known genes are arrayed on a surface and the location of each is known. If one wishes to determine which genes are expressed in a sample, the mRNA from the sample is extracted, reverse transcribed to the corresponding cDNA, amplified, fluorescently labeled and allowed to hybridize with the sequences on the chip. Only the sequence-specific labels are captured on the surface of the chip. By reading the fluorescence, one can determine which of the genes were expressed.
[0004] While this technology is extremely effective and semiconductor fabrication technology has allowed for the packing of thousands of gene sequences into square centimeter surfaces at relatively low cost, there are a few limitations to its use. The actual experimental work involved is non-trivial, as one must first extract mRNA, convert the mRNA to cDNA, then amplify the cDNA, which then must be labeled for capture and detection. Each step is time and labor intensive and is not conducive for temporal studies involving a large number of samples. Furthermore, each of the steps involved in sample preparation for reading on a chip is prone to errors and artifacts.
[0005] For example, it is certain that the amount of mRNA does not necessarily correspond to the amount of final protein expression (Anderson et al, Electrophoresis, 19:1853-1861 (1998)). Secondly, converting mRNA to cDNA is potentially error prone with all mRNAs not being transcribed with equal efficiencies, which is known as reverse transcription bias. Any incomplete mRNA transcription will result in sequences that do not bind efficiently to their complements on the chip array. Additionally, specialized equipment is needed to produce and read the chip.
[0006] The present invention solves the above problems in that it can be easily executed by microbial culture and requires only generic equipment such as a plate reader, which is readily available in most labs, unlike a confocal gene-chip reader.
[0007] Anti-tumor drugs are typically screened using cell culture or mouse models. Only recently have genetic approaches towards screening been applied using simpler model species (Hartwell et al, Science, 278:1064-1068 (1997) ). The method of the present invention is similar to the SOS chromotest (Quillardet et al, Mut. Res., 147:65-78 (1985) ; and Quillardet et al, Proc. Natl. Acad. Sci., USA, 79:5971-5975 (1982)) and Ames test (Ames et al, Proc. Natl. Acad. Sci., USA, 70:782-786 (1973)) for mutagenicity, but offers additional specificity. The data resulting from screening in the method of the present invention can be used to interpret the in vivo mode of action of anti-tumor drugs and categorize them mechanistically. Additionally, the method of the present invention is adaptable to a high throughput-screening program for elucidating specific gene expression under a variety of conditions. In the present invention, various promoter probe-Green Fluorescent Protein fusions may be cultured in semisolid media in a multi-well plate and subjected to a battery of test compounds of varying concentration. In addition, several hues of Green Fluorescent Protein (GFP) are now available, and as a result, multiple genes within the same cell can be followed to elucidate temporal gene expression.
SUMMARY OF THE INVENTION
[0008] In an embodiment of the present invention, known gene promoters are systemically cloned upstream of a readily measurable reporter gene and the gene expression is simply monitored by exposing the living cells to the perturbation (test compound). The advantage of such an approach is that the labor is shifted upstream of the experiment, i.e., to the creation of the clones. The experiments themselves become trivial by comparison, and are almost free of artifacts to which gene-chip experiments are subject.
[0009] As a model system, the examples herein use the oxidative stress response system in E. coli and show its applicability as a tool for mechanistic screening of anti-tumor drugs. The oxidative stress response of E. coli has previously been well characterized. In addition, many of the molecular mechanisms responsible for gene induction are understood and reflect high precision and sensitivity. It is shown in the present invention that specific genes are induced in response to reactive oxygen species such as superoxide anion, hydrogen peroxide and hydroxyl radicals and other DNA damaging (e.g. alkylating) agents.
[0010] [0010]FIG. 1 shows for the known genes of the E. coli oxidative stress response system and the regulons of which they are a part and to which active oxygen species they respond. In the examples herein, the delineated genes in FIG. 1 have been successfully cloned. The specific genes shown in FIG. 1 were deliberately selected from completely separate and different regulons in order to demonstrate that the present invention has the necessary specificity and generates a response only to stresses that are known to turn on only genes specific for each regulon. This demonstrates that the present invention has broad applications, i.e., it can be concluded with some confidence that if a gene is turned on, it is because of an exposure to a specific stress.
[0011] It is shown in the present invention that the unique fluorescence of GFP makes it a natural system for use as a reporter gene in the present invention. GFP is a relatively new reporter gene that is making an impact due to the many advantages it has over other reporter genes. These advantages include, but are not limited to: autofluorescence (Chalfie et al, Science, 263:802-805 (1994); and Prasher et al, Gene, 111:229-233 (1992)), in vivo detection (Chalfie et al, supra), no requirement for co-factors (Chalfie et al, supra), protein stability (Ward et al, Biochem., 21:4535-4540 (1982); and Bokman et al, Biochem. Biophys. Res. Comm., 101(4):1372-1380 (1981)), and availability of altered spectral mutants (Heim et al, Proc. Natl. Acad. sci., USA, 91:12501-12504 (1994); Delagave et al, Bio/Technol., 13:151-154 (1995); and Ehrig et al, FEBS Letter, 367:163-166 (1995)). GFP was originally discovered and isolated from the bioluminescent jellyfish Aequorea victoria (Shimomura et al, Aequorea J. Cell. Comp. Physiol., 59:223-239 (1962)). It absorbs light in the ultraviolet or blue range at 395 and 470 nm, respectively, and emits green fluorescence at 509 nm (Chalfie et al, supra) Recently, entirely new GFP families with additional colors have been reported (Matz et al, Nature Biotechnol., 17:969-973 (1999); and Mikhail, Nature Biotechnol., in press (1999)). However, it should noted that the present invention is not limited to use of GFP, and any reporter molecule can be employed in the present invention. Preferred reporter molecules include fluorescent reporter molecules, such as GFP, Yellow Fluorescent Protein, Red Fluorescent Protein and Cyan Fluorescent Protein.
[0012] GFP fluorescence has been shown to be quantitatively linked to the expression of a co-expressed heterologous protein (Albano et al, Biotechnol. Prog., 14:351-354 (1998)). The reporting abilities of GFP to those of the well-established chloramphenicol acetyl transferase (CAT) gene has also been compared. CAT is a bacterial gene that confers antibiotic resistance to chloramphenicol through acetylation. Its enzymatic activity can be assayed in a number of ways, making CAT a reliable reporter gene (Kain et al, In: Current Protocols in Molecular Biology, Ausubel et al, Ed., John Wiley & Sons, New York, NY, pages 9.6.1-9.6.12 (1995); and Rodriquez et al, Recombinant DNA Techniques: An Introduction, The Benjamin/Cummings Publishing Company, Inc., Menlo Park, Calif., pages 187-191 (1983)). In situ, GFP fluorescence was shown to be a measure of CAT activity and concentration when both GFP and CAT were expressed as an operon fusion (Albano et al (1998), supra). Using a number of proteins, it has been shown that GFP is a quantitative measure of the fusion product as extracted and assayed independently via both enzymatic analysis and Western blot (Albano et al (1998), supra; and Cha et al, Appl. Eviron. Microbiol., 65:409-414 (1999)).
[0013] In the present invention, after constructing cells containing stress-probe-GFP fusions, the cells were exposed to known oxidative stressors such as paraquat (a common name for methyl viologen), a known redox cycling generator of O 2 from O 2 , or H 2 O 2 for verifying the specificity of response. Unexpectedly, the GFP reporter gene allowed for a straightforward and rapid analysis of the oxidative stress response. In addition, the present invention only requires generic equipment such as a plate reader.
[0014] Pro-Tox© Assay, a related methodology developed by Xenometrix, Inc., utilizes 16 E. coli stress promoters fused to lacZ. The stress promoters used this assay are gyrA, katG, micE, osinY, uspA, katE, recA, zwf, dnaK, clpB, umuDC, merR, ada, dinD, soi28, and nfo. In the Pro-Tox© Assay, transfected cell lines are reconstituted from lyophilized vials and grown overnight. The optical density of the 16 cell lines are normalized to one another, aliquoted into the wells of a 96-well microtiter cell plate already containing additional media and are further incubated for 90 minutes.
[0015] A separate chemical plate containing 7 serial concentrations of the compound to be tested is prepared, aliquots are transferred to the cell plate and incubated for 90 minutes. A cell lysis reagent is then added to the cell plate and incubated for 15 minutes. The aliquots are then transferred to an assay plate containing the ONPG substrate and incubated for 10 to 30 minutes and read on a spectrophotometer plate reader at 420 nm. This entire procedure provides a single data point at the end, since the cells are lysed and destroyed.
[0016] In contrast, in the present invention one preferably starts with the growth of overnight cultures. Fresh cultures can then be prepared and grown for approximately 4 hours. Aliquots of these cultures can then be added to the wells of a microtiter cell plate containing the serial dilutions of the compound to be tested that are incubated overnight. The cell plates can then be read in a spectrofluorimeter at 509 nm. The two incubation steps, 4 hours and overnight, can be optimized. In addition, the cell plates can be read continuously to provide kinetic data on the actual rates of gene expression. A step-by-step comparison of the two methods is listed in Table I.
TABLE I Xenoanetrix Pro-Tox © Assay GFP-Stress Probes 1. Begin with a Lyophilized 1. Begin with a culture frozen culture 2. Grown overnight 2. Grown overnight 3. Aliquot and dilute to 3. Transfer reinoculate microtiter plate (fresh media) 4. Incubate 90 minutes 4. Incubate 4 hours (may be changed) 5. Add compound to be tested 5. Aliquot to microtiter cell plate 6. Incubate 90 minutes 6. Add compound to be tested 7. Add lysis reagents 7. Incubate (can also be read continuously) 8. Incubate 15 minutes 8. Read at 509 nm 9. Transfer to assay plate 10. Incubate 10-30 minutes 11. Read at 420 nm
[0017] Overall, the procedure of the present invention offers a clear advantage over the Xenometrix, Inc. Pro-Tox© Assay in that less steps are incurred in practicing the method of the present invention, thereby saving time and reducing chance of error when other reagents are added to the assay. In addition, the plates can be read continuously with the method of the present invention, whereas this does not occur with the Xenometrix assay due to lysis and destruction of cells to the point of providing a single data point at the end.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] [0018]FIG. 1 shows the interplay between the reactive oxygen species, regulons in which they induce and the identified genes.
[0019] [0019]FIGS. 2A and 2B show the specificity of the response of various promoter probes to superoxide generating paraquat (PQ). neg is the negative control consisting of cells that express GFP based on an arabinose promoter.
[0020] [0020]FIGS. 3A and 3B show the specificity of the response of various promoter probes to hydrogen peroxide. neg is the negative control consisting of cells that express GFP based on an arabinose promoter.
[0021] [0021]FIG. 4 shows the induction of soda and recA promoter probes. A LB agar plate was overlaid with inoculated E. coli transformed with either the pCRAll, sodA promoter probe construct (FIG. 4A); or pCRA16, the recA promoter probe construct (FIG. 4B).
[0022] [0022]FIG. 5A shows the results of serially diluting Daunorubicin (DNR) for dose-response testing in a high throughput format; while FIG. 5B shows the results of serially diluting paraquat for dose-response testing in a high throughput format.
[0023] [0023]FIG. 6 compares the response of the sodA promoter to stresses in the form of a bolus of paraquat in one culture and transient exposure to hyperoxia in another. A control culture consisting of uninduced sodA:GFP is also included for comparison.
[0024] [0024]FIG. 7 illustrates a preferred embodiment of a system for screening for a compound that affects gene expression. The system comprises a computer 7.10 with a CPU and memory. A membrane 7.20 comprises an array, with each item in the array further comprising immobilized cell cultures and a test compound. 7.21 is an example of one such culture. Each culture, for example 7.21, is transformed with a DNA molecule encoding a reporter molecule fused to a promoter of a gene of interest, e.g., a GFP-promoter fusion. When the corresponding gene is expressed, the reporter molecule (GFP) is also expressed, resulting in a fluorescent spot. A light emitting diode 7.30, directs light onto a culture, thereby illuminating it. A photodiode 7.40 scans the illuminated culture and reads the fluorescent light emitted by the illuminated culture. An interface 7.50 receives signals from the photodiode and generates corresponding information for processing by the computer 7.10. The computer processes the information received from the interface to identify the gene whose expression was affected by the test compound.
DETAILED DESCRIPTION OF THE INVENTION
[0025] In order that the invention herein described may be more fully understood, the following detailed description is set forth.
[0026] “Regulon” as used herein refers to a set of genes that are all regulated by a common element or regulatory gene.
[0027] The GFP-stress probe fusions shown here clearly have great specificity and allow for the simple measurement of gene expression rapidly and continuously in vivo. Two promoter probes, containing the sodA: :gfp and recA: :gfp fusions, show the most striking results as shown in FIG. 4A and 4B. There appears to be a wide disparity in the effects the drugs have on the two promoter probes, which might be expected as they are from different regulons. sodA regulates superoxide dismutase production, while recA is a DNA repair protein that is presumably induced when hydroxyl radicals damage DNA.
[0028] Some drugs appear to have a very potent but limited induction range represented by a very narrow and bright emission of fluorescence. Other drugs appear to have a very large range of induction with the green fluorescence halo spread over a large area. FIGS. 4A and 4B show the sodA and recA plates that have been spotted at the same concentration of 500 μM for each drug. These panels can be used to compare the induction between drugs. As demonstrated and discussed earlier, the intensity of GFP fluorescence is quantitatively related to the level of gene expression (Albano et al, Biotech. Techniques, 10(12):953-958 (1996); and Albano et al (1998), supra). None of the anti-tumor drugs exceeded the ability of paraquat to induce the soda promoter. From this, the relative ability of drugs to induce a particular response in comparison to one another has been determined.
[0029] Many of the drugs induce both the recA and soda promoter probe suggesting the production of both the superoxide anion and the hydroxyl radical. This can be seen where higher and varied concentrations of drugs were used. In each case with one exception, the sodA promoter probe is induced to a lesser extent than recA. The sole exception is doxorubicin (K). Doxorubicin shows a stronger induction of sodA than its induction of recA.
[0030] Importantly, the microbial system of the present invention provides information relevant to mammalian cells. Three of the drugs examined, AZQ, DZQ, and MeDZQ, are structurally related to one another except for the substitution of side groups on the compound. These function as an alkylating agent that binds or cross-links DNA and also have the ability to generate superoxide anions, hydrogen peroxide, and hydroxyl radicals. Elsewhere, studies have been conducted to determine which of these two characteristics of the three drugs are responsible for the cytotoxicity in mammalian cells (Berardini et al, Biochem., 32:3306-3312 (1993); Lee et al, Biochem., 31:3019-3025 (1992); and Ngo et al, Chem. Res. in Toxicol., 11:360-368 (1998)). Consistent with these studies in mammalian cells, MeDZQ, DZQ, and AZQ, were ranked in decreasing order of toxicity response in the system of the present invention as well.
[0031] While the petri plate experiments initially carried out were encouraging, the data from such a format are not easy to quantify or use in a high throughput format. As noted from the high throughput format of the present invention, however, that DNR and paraquat have a similar mode of action, such as generating superoxide and turning on soxs and sodA, but also demonstrate different dose responses (See FIG. 5A and 5B). Maximal response is observed with 20 μM DNR after which it becomes toxic and kills cells, while paraquat continues to generate a monotonically increasing response. This indicates that the method of the present invention should allow for more precise investigation of the mode of action of anti-cancer drugs.
[0032] As the GFP derivative data in FIG. 6 demonstrate, continuous stress causes concomitant continual gene expression of sodA. In contrast, the short-term stress acts in a limited fashion where the rate of sodA expression reverts to the control value after an initial increase that is markedly lower than in the paraquat exposed cells.
[0033] The results herein demonstrate the further utility of GFP as a reporter gene for use in high throughput screening applications and in the creation of living chips. Here, an entire family of genes of known sequence but unknown function may be cloned upstream of a reporter gene, such as GFP. These cells could be plated at high density and exposed to a variety of conditions to elucidate their expression conditions. In combination with high sensitivity techniques such as fluorescence correlation microscopy, several thousand single cell clones can be placed on a chip. The availability of the entire human genome will require such a technology in order to elucidate the functions of the various gene sequences.
[0034] In order that the invention as described herein may be more fully understood, the following examples' are set forth. It should be understood that the following examples are for illustrative purposes only and are not to be construed as limiting the invention.
EXAMPLE 1
Construction of the Genes in the Oxidative Stress Response System
[0035] Using GenBank to obtain the genomic sequence for each of the oxidative stress response genes, PCR primers are designed to amplify the promoter region. Generally the target for amplification was approximately 300 base pairs and encompasses the sequence upstream from the native translational start site. The PCR primers had an approximately 18 base pair homology with the genomic sequence, included an appropriate endonuclease restriction digestion site and were flanked by 5 additional bases at each end. The entire promoter region flanked by incorporated restriction sites was cloned in frame with GFP on a plasmid. The stress probes were then transformed into E. coli.
EXAMPLE 2
Fluorescence Intensity After Oxidative Stresses
[0036] Cells containing each stress probe-GFP fusion were cultured to early log phase, stressed with varying concentrations of paraquat or H 2 O 2 , and the fluorescence intensity measured at 4 hours post-stress. Due to the lethality of the higher concentrations of stresses, dividing by optical density (OD) normalized the fluorescence intensity values.
[0037] [0037]FIGS. 2A and 2B show the representative results of the promoter probes when stressed with paraquat. The sodA, zwf, and acna promoter probes, all belonging to the SoxRS regulon, show a dose dependent response (FIG. 2A). In contrast, the recA and dps promoter probes (FIG. 2B) do not show a dose dependent response and are only inducible when exposed to higher paraquat concentrations where presumably the greater 02 flux is converted to H 2 O 2 and further exposed to the DNA damaging hydroxyl radical.
[0038] [0038]FIGS. 3A and 3B show the responses of each promoter probe when exposed to hydrogen peroxide. Hydrogen peroxide may cause DNA damage via hydroxyl radical formation. The recA and dps promoter probes shown in FIG. 3A show a dose dependent response to the hydrogen peroxide, while there is no inducible response seen in any of the SoxRS regulon promoter probes (sodA, acnA, and zwf) shown in FIG. 3B.
EXAMPLE 3
Mechanistic Studies with Anti-tumor Drugs
[0039] This Example involves the induction of sodA and recA promoter probes. A LB agar place was overlaid with inoculated E. coli transformed with oxidative promoter probe constructs. These probe constructs were either the pCRA11, sodA promoter probe construct (FIG. 4A); or pCRA16, the recA promoter probe construct (FIG. 4B). The desired transformants were selected by their resistance to ampicillin when plated on LB plates containing ampicillin.
[0040] 2.0% cultures were grown from saturated overnight cultures at 350° C. with shaking at 260 rpm for 3 hours. A 4.0% inoculum was mixed with 550° C. top agar (10 g/L NaCl, 5.0 g/L yeast extract, 10 g/L tryptone, 7.0 g/L agar) and 10 ml was layered on 150 mm petri dishes containing LB and ampicillin. 10 μl of each drug to be tested was spotted onto the plate and incubated at 35° C. overnight. Colonies were screened when plated onto LB plates containing compounds that are known to activate oxidative stress genes, paraquat and hydrogen peroxide.
[0041] In FIG. 4A and 4B, spotting was carried out with each of the anti-tumor drugs at 500 μM concentration at different positions. The initial behind each anti-tumor drug description indicates its positioning in FIG. 4 and 4 B. The anti-tumor drugs included: mitomycin C (MMC), A; streptonigrin, B; actinomycin-D,C; stretozotocin, D; diaziquone (AZQ), E; methyl diaziridinequinone (MeDZQ), F; paraquat (PQ), G; hydrogen peroxide, H; mitoxantrone, I; daunorubicin (DNR), J; doxombicin (ADR), K; cisplatin, L; and camptothecin, M.
[0042] Similarly, spotting was carried out with various concentrations of the anti-tumor drugs using the anti-tumor drugs as used above except their concentrations vary; MMC (1.5 mM), A; streptonigrin (1.0 mM), B; actinomycin-D (1.0 mM), C; streptozotocin (100 mM), D; diaziquinone (10 mM), E; methyl diaziridinequinone (12 mM), F; paraquat (100 mM), G; hydrogen peroxide (5.0 mM), H; mitoxantrone (10 mM), I; daunorubicin (5.0 mM), J; doxorubicin (100 mM), K; cisplatin (500 μM), L; and camptothecin (500 μM), M.
[0043] The plates were photographed on top of a longwave (365 nm) ultra-violet box with a Kodak DC200 digital camera, photographed while illuminated by a UV light box. In FIG. 4A and 4B, bright blue fluorescence was noted that is thought to be the autofluorescence of carnptothecin in the M position of each panel.
[0044] It was found herein that an E. coli based system could respond in a manner useful for interpreting data for drugs to be used in mammalian cells. Unexpectedly, the GFP reporter gene allowed for a straightforward and rapid analysis of the oxidative stress response. As the drug diffuses through the media, it created a concentration gradient. After overnight incubation, drugs may or may not show a zone of killing, and those capable of inducing the stress response promoter probe show a zone of induction that appears as a green halo when illuminated with a hand-held UV light.
[0045] The two promoter probes, containing the sodA: :gfp and recA: :gfp fusions, show the most striking results in FIG. 4A and 4B. There appears to be a wide disparity in the effects the drugs have on the two promoter probes, which might be expected as they are from different regulons. sodA regulates superoxide dismutase production, while recA is a DNA repair protein that is presumably induced when hydroxyl radicals damage DNA. Some drugs appear to have a very potent but limited induction range represented by a very narrow and bright emission of fluorescence. Others appear to have a very large range of induction with the green fluorescence halo spread over a large area.
[0046] [0046]FIG. 4A and 4B show the sodA and recA plates that have been spotted at the same drug concentration of 500 μM, and can be used to compare the induction between drugs. As demonstrated and discussed earlier, the intensity of GFP fluorescence is quantitatively related to the level of gene expression (Albano et al (1996), supra; and Albano et al (1998), supra) . None of the anti-tumor drugs exceeded the ability of paraquat to induce the sodA promoter. From this, the relative ability of drugs to induce a particular response in comparison to one, another can be determined.
[0047] Importantly, the microbial system of the present invention provides information relevant to mammalian cells. Three of the drugs examined, AZQ, DZQ, and MeDZQ, are structurally related to one another except for the substitution of side groups on the compound. These function as an alkylating agent that binds or cross-links DNA and these also have the ability to generate superoxide anions, hydrogen peroxide, and hydroxyl radicals. Elsewhere, studies have been conducted to determine which of these two characteristics of the three drugs are responsible for the cytotoxicity in mammalian cells (Berardini et al, supra; Lee et al, supra; and Ngo et al, supra) . Consistent with these studies from mammalian cells, MeDZQ, DZQ, and AZQ, were ranked in decreasing order of toxicity response in the system of the present invention as well.
EXAMPLE 4
Fluorescence Intensity and Optical Density
[0048] 4. 0% cultures of E. coli harboring the stress probes were grown from a saturated overnight culture in 250 ml shake flasks containing 25 ml LB media and 100 μg/ml ampicillin at 35° C. with shaking at 260 rpm until the optical density reached 0.8 at 600 nm. 100 μl aliquots of culture were added to each well of a 96-well plate, along with 10 μl of various concentrations of the drug to be tested and incubated overnight. Experiments were run in duplicate. Fluorescence intensity and optical density measurements were taken using a Wallac 1420 VICTOR multilabel counter.
EXAMPLE 5
High Throughput Studies
[0049] To test whether the procedure of Example 4 would work in a quantitative high throughput format, an experiment was conducted where the anti-tumor drug DNR was serially diluted and dose-response tested in a 96-well plate. For comparison, a similar experiment was conducted with paraquat. FIGS. 5A and 5B show these results. As can be seen from the data, a rapid determination of an optimal dose response at the genetic level can be carried out. Experiments were conducted in duplicate and showed similar responses.
[0050] What is noteworthy is that DNR shown in FIG. 5A and paraquat shown in FIG. 5B have a similar mode of action in generating superoxide and turning on soxS and sodA, but the two also have different dose responses. Maximal response is observed with 20 μM DNR, after which it becomes toxic and kills cells, while paraquat continues to generate a monotonically increasing response. This demonstrates that the method of the present invention pertains to the mode of action of anti-cancer drugs.
EXAMPLE 6
Rate Measurement of GFP
[0051] The rate of change of the GFP signal measures the rate of the stress protein induction. This experiment compares the response of the sodA promoter to stresses in the form of a bolus of paraquat in one culture and a transient exposure to hyperoxia in another. A control culture consisting of uninduced sodA:GFP was included for comparison. FIG. 6 shows the rate of change of the GFP signal that measures the rate of the stress protein induction. FIG. 6 also shows the differential rate of gene expression when the culture containing the sodA-GFP stress probe was exposed to continuous stress by paraquat versus a 10 minute pulse of short-term stress by pure oxygen. An uninduced culture was included for comparison purposes.
EXAMPLE 7
Rate of Change of the GFP Fluorescence Measurement
[0052] The disadvantages of GFP as a reporter gene are its lag time for fluorescence (approximately 90 minutes) and extraordinary stability. One way to compensate for these is to measure the rate of change of the GFP fluorescence, which is possible using an LED-based sensor that permits continuous in situ measurements. The cell specific rate of change of GFP normalized to optical density is then a measure of the rate of gene expression of the stress protein.
[0053] While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. | In a model system, Green fluorescent Protein fusions were constructed with several oxidative stress promoter probes from E. coli. These were chosen from the superoxide, hydrogen peroxide and hydroxyl radical inducible genes. When exposed to various free radical insults, the cells fluoresced with great specificity based on the corresponding regulon. These constructs are thus useful as a tool for mechanistic screening of a variety of anti-tumor drugs. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of copending provisional application Ser. No. 60/225,876, filed on Aug. 17, 2000, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to compositions useful as defoamers for water-based compositions, and to the aqueous compositions containing the defoamers.
BACKGROUND OF THE INVENTION
[0003] In the preparation and use of aqueous paints and other aqueous-based compositions, problems with foaming are frequently present, causing the encapsulation of air bubbles in the aqueous compositions. These air bubbles are especially troublesome in latex paints and in the coatings resulting therefrom.
[0004] Consequently, there is a continuing demand for defoaming agents that will successfully defoam aqueous compositions while not interfering with the desirable properties of the aqueous compositions.
SUMMARY OF THE INVENTION
[0005] This invention relates to defoaming compositions, and to aqueous-based compositions containing them.
[0006] The defoaming compositions of the invention comprise
[0007] A) at least one organosilicone compound; and
[0008] B) at least one reaction product comprising the following reactants:
[0009] a) a linking agent of formula I
R 4 (Y) 3 (I)
[0010] wherein each Y group is a halogen atom or one Y group is a halogen atom and two Y groups with two adjacent carbon atoms in the R 4 group and an oxygen atom form an epoxy group, and R 4 is an alkanetriyl group containing from 3 to 10 carbon atoms, the preferred linking agent being epichlorohydrin; and
[0011] b) a compound of formula II
R 3 (EO) n (PO) m (BO) p X (II)
[0012] wherein R 3 is a substituted or unsubstituted, saturated or unsaturated, organic oxy or thio group having from 1 to 36 carbon atoms or a secondary amino group having from 2 to 36 carbon atoms; n is a number of from 0 to 50, e.g., from 1 to 50; m is a number of from 0 to 50 e.g., from 1 to 50; p is a number of from 0 to 50 e.g., from 1 to 50; and X is hydrogen, or X can be a mercapto group or an amino group in place of a terminal —OH group, provided that when X is mercapto or amino; the sum of n, m, and p must be at least 1.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0013] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood as modified in all instances by the term “about”.
[0014] It is to be understood that the terms “defoaming compositions”, “defoaming agents”, “defoamers”, and the like as used herein refer to compositions that reduce or eliminate foaming when added to water-based compositions.
[0015] In the component B) product of the reaction between the linking agent of formula I and the compound of formula II, the mole ratio of I:II is from 0.2:1 to 5:1, preferably from 0.4:1 to 2:1, and more preferably from 0.6:1 to 1.4:1.
[0016] The linking agent of formula I is preferably epichlorohydrin although other epihalohydrins can be used. Also, trihaloalkanes can be used, such as 1,2,3-trichloropropane, 1,2,4-trichlorobutane, 1,3,6-trichlorohexane and the like. Instead of chlorine in the epihalohydrins and the trihaloalkanes, the corresponding bromine and iodine compounds can also be used, including compounds containing two or even three of the above halogens.
[0017] In the compounds of formula II, it is understood that EO stands for the residue of ethylene oxide and PO stands for the residue of propylene oxide and BO stands for the residue of butylene oxide.
[0018] When the X group of formula (II) is a mercapto group, the R 3 group will preferably have from about 4 to about 36 carbon atoms, examples of which include but are not limited to, alkoxylated dodecyl mercaptan and alkoxylated 1-hexadecanethiol.
[0019] The compounds of formula (II) can be alkoxylated or non-alkoxylated secondary amines. When the compounds of formula II are secondary amines, n is a number from 0 to 50, preferably from 1 to 50, m is a number from 0 to 50 and p is a number from 0 to 50, preferably from 1 to 50. Examples of the secondary amines useful for the purposes of the invention include but are not limited to, alkoxylated dibutyl amine, alkoxylated dicyclohexyl amine, alkoxylated diethylethanolamine, and alkoxylated dioctylamine.
[0020] The substituent that can be present on the substituted R 3 groups can be single or multiple substitutions such as a halogen substitution, for example Cl, Fl, I and Br: a sulfur functionality such as a mercaptan or thio group; a nitrogen functionality such as an amine or amide functionality; an alcohol functionality, a silicon functionality, e.g., a siloxane; an ether functionality; or any combination thereof.
[0021] In general, compounds of formula II wherein the sum of n, m, and p is at least 1, especially at least 2, are preferred.
[0022] When R 3 is a secondary amino group, the group preferably contains from 4 to 22 carbon atoms.
[0023] Also, when X is hydrogen p is preferably a number of from 1 to 50. When R 3 is a secondary amino group, p is preferably a number of from 1 to 50.
[0024] The nonoxy and nonthio components of the R 3 group can be any substituted or unsubstituted, saturated or unsaturated organic moiety having from 1 to 36 carbon atoms. Thus, the nonthio and the nonoxy components of the R 3 aliphatic group can be linear or branched alkyl groups, linear or branched alkenyl or alkynyl groups, saturated carbocyclic moieties, unsaturated carbocyclic moieties having one or more multiple bonds, saturated heterocyclic moieties, unsaturated heterocyclic moieties having one or more multiple bonds, substituted linear or branched alkyl groups, substituted linear or branched alkenyl or alkynyl groups, substituted saturated carbocyclic moieties, substituted unsaturated carbocyclic moieties having one or more multiple bonds, substituted saturated heterocyclic moieties, and substituted unsaturated heterocyclic moieties having one or more multiple bonds. Examples of the above include but are not limited to an alkyl group having from 4 to 22 carbon atoms, an alkenyl group having from 4 to 22 carbon atoms, and an alkynyl group having from 4 to 22 carbon atoms. R 3 can also be an arenyl group. Arenyl groups are alkyl-substituted aromatic radicals having a free valence at an alkyl carbon atom such as a benzylic group. Alkyl groups having from 4 to 12 carbon atoms are preferred, and alkyl groups having from 8 to 10 carbon atoms are most preferred. The degree of ethoxylation is preferably from 2 to about 50 with the most preferred being from about 4 to about 50 while the degree of propoxylation and butoxylation can vary from 0 to about 50, preferably from 1 to about 10. The degree of propoxylation and or butoxylation will be determined by the desired degree of solubility or miscibility in the aqueous compositions of the invention. The solubility or miscibility will ultimately be determined by such factors as the number of carbon atoms in R 3 and the relative amounts EO, PO and BO.
[0025] Optionally, an additional component can be reacted with the linking agent of formula (I) and the compound of formula (II). A glycidyl ether or amine can be added to the reaction of formula (I) and formula (II). The amount of the glycidyl ether or glycidyl amine is from about1 to about 20 mole percent based on the moles of formula (II) used in the reaction. When the glycidyl ether or glycidyl amine is added to the monofunctional starting material of formula II, the ratio of formula I to formula II plus the glycidyl ether or glycidyl amine is preferably from about 0.8 to about 1.4. Examples of the glycidyl ethers include, but are not limited to, PEG 600 Diglycidyl ether, TETRONIC™ 701 Tetraglycidyl ether, Triglycidyl Di or Triethanolamine, Polyoxyethylene (POE) 200 Tallow amine diglycidyl ether, Propoxylated (POP10) Trimethylol propane triglycidyl ether, Propoxylated (POP7) Pentaerythritol tetraglycidyl ether. Examples of glycidyl amines include, but are not limited to, Tetraglycidyl 1,6-Hexane diamine, JEFFAMINE™ Tetraglycidyl EDR-148, and Tetraglycidyl Isophorone diamine.
[0026] The component B) reaction products can be prepared by the process disclosed in U.S. Pat. No. 5,827,453, the disclosure of which is expressly incorporated herein by reference.
[0027] With respect to the component A) organosilicone compounds, most of these are organopolysiloxanes, preferably those having defoaming activity in aqueous-based compositions. Examples of the latter compounds are TEGO FOAMEX® 3062, 810, and 840, which are organo-modified polysiloxanes, manufactured by Tego Corporation of Hopewell, Virginia; AF 9000, an organo-modified polyether polysiloxane manufactured by General Electric Co. of Waterford, New York; and DC 2000, an organo-modified polysiloxane manufactured by Dow Corning of Midland, Michigan.
[0028] The defoaming compositions of the invention can also contain other components, such as polyethylene glycols, surfactants, mineral oils, water, silicas, waxes, and the like.
[0029] The proportions of components A) and B) that can be present in the defoaming compositions can range from 90:10 to 10:90 percent by weight, preferably from 80:20 to 50:50.
[0030] The defoaming-effective quantities of the present defoaming compositions in aqueous compositions can be readily determined for any particular aqueous composition, and are generally in the range of from 0.01 to 2% by weight, more usually in the range of from 0.025 to 1.5% by weight, based on the weight of the aqueous composition.
[0031] The defoaming compositions of the invention are prepared by mixing the components together, which can be done at room temperature or at an elevated temperature, e.g., from 30 to 160° C., depending on the particular components selected.
[0032] The aqueous compositions to which the defoaming compositions of the invention can be added to include latex paints, inks, adhesives, latex processing, metal working, and the like.
[0033] The aqueous compositions of the invention when formulated with the present defoamers have very low levels of air entrapment. When used in latex paint compositions, the paints when cured have almost no surface defects such as orange peel, fish eyes, cratering or pin holing. In addition, not only do the defoamers of the invention provide excellent defoaming action during formulation, but they also act as flow and leveling agents in latex paints, with very low levels of trapped air and high gloss when the coating is applied to a substrate. In some cases, the present defoamers may actually enhance gloss in the dried coatings.
[0034] The invention will be illustrated but not limited by the following examples.
EXAMPLES
Example 1
[0035] Various defoaming agents were added to Rohm and Haas Interior/Exterior Gloss Enamel G-95-1 in several concentrations. The defoaming agents were shaken with the latex paints for five minutes, in a concentration of 0.25, 0.50 and 0.75% by weight, based on the weight of the latex paint. Bubble break times for each paint were tested by rolling and brushing onto 12″×12″Sherwin Williams Test Paper. A stopwatch was used to measure the time it took for all the bubbles to break. Timing was stopped after five minutes if complete bubble break was not achieved.
[0036] The defoaming agents, concentrations, and results obtained are set forth in Table 1 below.
[0037] The defoaming agents (#1 through #12) that were employed are identified below:
[0038] Surfactant A—100% C 12-14 fatty alcohol with about 3 moles of EO and 6 moles of PO, manufactured by Cognis Corporation of Ambler, PA.
[0039] Silicone A—A polyether polysiloxane, manufactured by Tego Corporation of Hopewell, Virginia.
[0040] Silicone B—a polyether polysiloxane, manufactured by CK-Witco Corporation of Greenwich, CT.
[0041] Surfactant B—100% 1045S STAR POLYMER—the reaction product of isodecyl alcohol.4EO and epichlorohydrin (mole ratio 1.1:1).
[0042] Surfactant C—100% STAR 31-40, which is the reaction product of C 12-14 fatty alcohol.3EO6PO and epichlorohydrin (mole ratio 1:1), manufactured by Cognis Corporation of Ambler, PA.
[0043] Blend 1—80% by weight Surfactant A and 20% by weight Silicone A.
[0044] Blend 2—76% by weight of Silicone A and 24% by weight of Surfactant B.
[0045] Blend 3—80.6% by weight of Silicone A and 19.4% by weight of Surfactant B.
[0046] Blend 4—78% by weight of Surfactant A, 19.6% by weight of Silicone A, and 2% by weight of Surfactant B.
[0047] Blend 5—76.2% by weight of Surfactant A, 19% by weight of Silicone A, and 4.8% by weight of Surfactant B.
[0048] Blend 6—74.1% by weight of Surfactant A, 18.5% by weight of Silicone A, and 7.4% by weight of Surfactant B.
[0049] Blend 7—75% by weight of Surfactant A, 20% by weight of Silicone A, and 5% by weight of Surfactant C.
TABLE I Blank Paint Surfactant A Silicone A Silicone B Surfactant B Surfactant C Blend 3 DEFOAMER USED-% BY 0.00 0.75 0.75 0.75 0.75 0.75 0.75 WT WEIGHT PER GALLON- 9.71 9.91 10.13 10.12 10.16 10.14 10.14 LBS PERCENT AIR 5.26 3.31 1.17 1.26 0.87 1.07 1.07 ROLLER BB TIME-SECS >300 >300 >300 >300 >300 >300 >300 BRUSH BB TIME-SECS >300 >300 >300 >300 70 >300 43 20 DEGREE GLOSS 70.8 71.8 26.0 30.0 68.2 68.1 68.0 60 DEGREE GLOSS 88.9 89.2 60.9 64.5 87.7 88.0 87.4 CONTRAST RATIO-3 MILS 95.70 95.72 95.74 95.84 95.81 95.88 95.94 DD SURFACE DEFECTS CRT CRT CRT NONE CRT CRT NONE ROLLER SURFACE DEFECTS CRT CRT CRT NONE NONE CRT NONE BRUSH SURFACE DEFECTS-3 MILS None NONE CRT/FE NONE NONE CRT NONE DD KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel FE = Fish Eyes Blend 1 Blend 2 Blend 4 Blend 5 Blend 6 Blend 7 DEFOAMER USED-% BY WT 0.75 0.75 0.75 0.75 0.75 0.75 WEIGHT PER GALLON-LBS 10.14 10.15 10.15 10.13 10.14 10.13 PERCENT AIR 1.07 0.97 0.97 1.17 1.07 1.17 ROLLER BB TIME-SECS 184 80 75 35 30 65 BRUSH BB TIME-SECS 70 36 17 8 6 45 20 DEGREE GLOSS 40.8 66.6 68.8 68.6 70.3 59.5 60 DEGREE GLOSS 75.0 86.4 88.5 88.5 89.0 84.4 CONTRAST RATIO-3 MILS 95.71 95.98 95.95 96.02 95.92 95.68 DD SURFACE DEFECTS ROLLER NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-BRUSH NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-3MILS CRT CRT NONE NONE NONE NONE DD KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel E = Fish Eyes Blank Paint Surfactant A Silicone A Silicone B Surfactant B Surfactant C Blend 3 DEFOAMER USED-% BY WT 0.00 0.50 0.50 0.50 0.50 0.50 0.50 WEIGHT PER GALLON-LBS 9.71 8.46 10.11 10.11 10.16 10.09 10.15 PERCENT AIR 5.28 17.48 1.38 1.35 0.87 1.56 0.97 ROLLER BUBBLE BREAK >300 >300 >300 >300 >300 >300 >300 TIME-SECS BRUSH BUBBLE BREAK >300 >300 >300 >300 >300 >300 >300 TIME-SECS 20 DEGREE GLOSS 70.6 69.5 32.3 40.1 67.9 67.7 70.9 60 DEGREE GLOSS 88.9 88.2 87.7 70.8 87.9 87.9 87.9 CONTRAST RATIO-3 MILS 95.73 95.82 95.50 95.73 95.96 95.94 95.92 DD SURFACE DEFECTS CRT CRT PH PH PH PH/FE NONE ROLLER SURFACE DEFECTS-BRUSH CRT CRT NONE NONE NONE PH NONE SURFACE DEFECTS-3MILS None NONE OP/FE NONE NONE CRT NONE DD KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel FE = Fish Eyes Blend 1 Blend 2 Blend 4 Blend 5 Blend 6 Blend 7 DEFOAMER USED-% BY WT 0.50 0.50 0.50 0.50 0.50 0.50 WEIGHT PER GALLON-LBS 10.15 10.12 10.15 10.15 10.15 10.14 PERCENT AIR 0.97 1.26 0.97 0.97 0.97 1.07 ROLLER BUBBLE BREAK TIME- 180 63 93 51 32 70 SECS BRUSH BUBBLE BREAK TIME-SECS 56 28 36 18 12 52 20 DEGREE GLOSS 54.7 86.3 57.0 70.8 71.6 67.0 60 DEGREE GLOSS 81.5 86.6 87.1 88.6 88.8 87.1 CONTRAST RATIO-3 MILS DD 95.88 95.92 96.05 98.01 95.28 95.81 SURFACE DEFECTS ROLLER NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-BRUSH NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-3MILS DD CRT CRT NONE NONE NONE NONE KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel FE = Fish Eyes QUALITY CONTROL TESTS Blank PERFORMED Paint Surfactant A Silicone A Silicone B Surfactant B Surfactant C Blend 3 DEFOAMER USED-% BY WT 0.00 0.25 0.25 0.25 0.25 0.25 0.25 WEIGHT PER GALLON-LBS 9.71 9.00 10.12 10.12 10.14 9.94 10.12 PERCENT AIR 5.26 12.18 1.26 1.28 1.07 3.02 1.26 ROLLER BUBBLE BREAK >300 >300 >300 >300 >300 >300 >300 TIME-SECS BRUSH BUBBLE BREAK >300 >300 >300 >300 >300 >300 >300 TIME-SECS 20 DEGREE GLOSS 68.9 69.6 47.8 51.4 68.6 68.8 69.8 60 DEGREE GLOSS 88.5 88.8 76.9 78.4 88.0 88.4 88.3 CONTRAST RATIO-3 MILS 95.80 95.90 95.61 95.92 96.05 95.98 96.17 DD SURFACE DEFECTS CRT CRT PH PH CRT CRT NONE ROLLER SURFACE DEFECTS-BRUSH CRT CRT PH PH CRT CRT NONE SURFACE DEFECTS-3MILS NONE NONE NONE NONE NONE NONE NONE DD KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel FE = Fish Eyes QUALITY CONTROL TESTS PERFORMED Blend 1 Blend 2 Blend 4 Blend 5 Blend 6 Blend 7 DEFOAMER USED-% BY WT 0.25 0.25 0.25 0.25 0.25 0.25 WEIGHT PER GALLON-LBS 10.15 10.14 10.14 10.14 10.13 10.12 PERCENT AIR 0.97 1.07 1.07 1.07 1.17 1.28 ROLLER BUBBLE BREAK TIME- 50 30 110 61 45 >300 SECS BRUSH BUBBLE BREAK TIME-SECS 26 20 39 18 27 >300 20 DEGREE GLOSS 61.8 69.9 59.7 69.3 70.0 70.0 60 DEGREE GLOSS 84.7 88.3 88.7 87.9 88.7 88.6 CONTRAST RATIO-3 MILS DD 95.79 96.78 95.77 95.90 95.95 96.17 SURFACE DEFECTS ROLLER NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-BRUSH NONE NONE NONE NONE NONE NONE SURFACE DEFECTS-3MILS DD CRT CRT NONE NONE NONE NONE KEY−> CRT = Cratering PH = Pin Holing OP = Orange Peel FE = Fish Eyes | Defoaming compositions comprising:
A) at least one organosilicone compound which has defoaming activity in aqueous based compositions; and
B) at least one reaction product comprising the following reactants:
a) a linking agent of formula I
R 4 (Y) 3 (I)
wherein each Y group is a halogen atom or one Y group is a halogen atom and two Y groups with two adjacent carbon atoms in the R 4 group and an oxygen atom form an epoxy group, and R 4 is an alkanetriyl group containing from 3 to 10 carbon atoms; and
b) a compound of formula II
R 3 (EO) n (PO) m (BO) p X (II)
wherein R 3 is a substituted or unsubstituted, saturated or unsaturated, aliphatic or araliphatic oxy or thio group having 1 to 36 carbon atoms or a secondary amino group having from 2 to 36 carbon atoms; n is a number of from 0 to 50; m is a number of from 0 to 50; p is a number of from 0 to 50; and X is hydrogen, or X can be a mercapto group or an amino group in place of a terminal —OH group, provided that when X is mercapto or amino; the sum of n, m, and p must be at least 1; and the mole ratio of I:II is from about 0.2:1 to about 5:1; and aqueous compositions containing them. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
This application is a divisional of U.S. patent application Ser. No. 12/565,425, filed Sep. 23, 2009, the entire content of which is incorporated herein by reference.
TECHNICAL FIELD
This invention relates generally to methods of using novel foamer compositions for treatment of oil and gas wells to enhance production. More specifically, the invention relates to novel foamer compositions having a tall oil fatty acid component and an organic solvent. The invention has particular relevance to foamer compositions having a tall oil fatty acid component and a glycol component.
BACKGROUND OF THE INVENTION
Declining reservoir pressure in natural gas wells may lead to gas production decreases. The typical cause of this decrease is liquid loading that occurs when water and condensate enter the bottom of the well. Foaming agents (sometimes referred to as “foamers”) are frequently used to aid in the unloading of water and condensate accumulated in the wellbore, thereby increasing production from a loaded well. Such agents are generally applied either by batch treatments or continuous applications via injecting down a capillary string or via the casing/tubing annulus. Foamers function by reducing the surface tension and fluid density in the wellbore, and may also be used in conjunction with a lift gas to enhance oil recovery from oil wells.
U.S. Pat. App. Pub. No. 2006/0128990 teaches a method of treating a gas well comprising a chloride-free amphoteric surfactant. U.S. Pat. No. 7,122,509 discloses a method of preparing a foamer composition having an anionic surfactant and a neutralizing amine In U.S. Pat. App. Pub. 2005/0137114 an aqueous foaming composition comprising an anionic surfactant, a cationic surfactant, and a zwitterionic compound is disclosed. PCT App. Pub. No. WO 02/092963 and U.S. Pat. App. Pub. No. 2007/0079963 disclose methods for recovering oil from a gas-lifted oil well using a lift gas and a foaming surfactant which consists of nonionic surfactants, anionic surfactants, betaines, and siloxanes.
While such foamers represent a significant contribution to the art of unloading fluids in oil and gas wells, there still remains a need for improved foamers and methods of using improved foamers. It is thus an objective of this invention to provide a cost-effective foamer for unloading oil, water, or mixtures thereof from oil and/or gas wells. Such improved foamers would also ideally be compatible with anti-corrosive and anti-scale agents.
SUMMARY OF THE INVENTION
This invention provides a method of foaming a fluid. In a preferred aspect, the method includes introducing into the fluid a foam-forming amount of a composition comprising at least one long chain fatty acid and at least one organic solvent. In preferential embodiments, the long chain fatty acid is preferably tall oil fatty acid and the organic solvent is preferably ethyleneglycol monobutyl ether.
It is an advantage of the invention to provide novel foaming agents for downhole injection in oil and gas wells.
It is a further advantage of the invention to provide an efficient method of recovering oil from a gas-lifted oil well penetrating a subterranean oil-bearing formation.
Another advantage of the invention is to provide an efficient method to remove hydrocarbon fluids from a gas-producing well.
Additional features and advantages are described herein, and will be apparent from, the following Detailed Description and Examples.
DETAILED DESCRIPTION OF THE INVENTION
The method of using the foaming compositions of this invention have been shown to be effective for recovering natural gas from a gas well and recovering crude oil from a gas-lifted oil well penetrating a subterranean oil-bearing formation. That is, the foaming agents of the present invention effectively remove hydrocarbon and/or water or mixtures thereof from the wells. The effective amount of active ingredient in a formulation required to sufficiently foam varies with the system in which it is used. Methods for monitoring foaming rates in different systems are well known to those skilled in the art and may be used to decide the effective amount of active ingredient required in a particular situation. The described compounds may be used to impart the property of foaming to a composition for use in an oil or gas field application.
The foamers of the invention can be applied by batch treatments or continuous applications via the casing/tubing annulus or via capillary strings and are typically introduced into the downhole end of a well. A batch treatment involves the application of a single volume of foamer to the well, as opposed to a smaller volume applied continuously for the case of a continuous application. The next batch is applied after a period of time when the foamer starts to lose its effectiveness.
The described foaming compositions are particularly effective for unloading fluids (oil and/or water) from oil and gas wells under a variety of conditions. These compounds/compositions may be used in wells in which oil cuts in the field can range from about 0% (oil field) to 100% (refinery) oil, while the nature of the water can range from 0 to 300,000 ppm TDS (total dissolved solids). In addition, the bottom hole temperature can be between 60° F. and 400° F. In a preferred method, the described foamers can be applied by batch treatments or continuously via the casing/tubing annulus or via capillary strings. Batch treatment typically involves the application of a single volume of foamer to the well, where a subsequent batch is applied when the foamer begins to lose its effectiveness. In a typical continuous application, in contrast, a smaller volume is applied continuously.
In an embodiment, a synergistic foaming agent is formed by mixing one or more long chain fatty acids with one or more organic solvents. A preferred composition is prepared by blending by blending a TOFA with EGMBE. According to alternative embodiments of the invention, the organic solvent is present in an amount from about 5 to about 70% by weight of actives based on the total weight of the mixture. Mixtures of TOFA and other long chain fatty acids are used in other embodiments of the invention as well as mixture of EGMBE and other organic solvents. The effectiveness of the foaming agent formulation of this invention can generate stable foams levels from about 10 ppm to about 100,000 ppm of actives. A more preferred range is about 100 ppm to about 20,000 ppm of actives. Most preferably, the range is from about 200 ppm to about 10,000 ppm of actives. Each dosage is based on total volume of fluid.
“Organic solvent” generally refers to one or more organic solvents or a mixture of water and organic solvent(s). Examples of suitable solvents are alcohols such as methanol, ethanol, isopropanol, isobutanol, secondary butanol; glycols such as ethylene glycol, and ethylene glycol monobutyl ether (“EGMBE”), and the like; and aliphatic and aromatic hydrocarbons including heavy aromatic naphtha. The selection of the solvent system may be made empirically based on the characteristics of the system being treated. The preferred organic solvent is EGMBE.
“Long chain fatty acids” refers to fatty acids of the type R 1 CO 2 H. Representative long chain fatty acids include caprylic acid; nonanoic acid; capric acid; undecanoic acid; lauric acid; tridecanoic acid; myristic acid; palmitoleic acid; tall oil fatty acid (“TOFA”), such a mixture of oleic, linoleic and linolenic acids; stearic acid; palmitic acid; arachidic acid; arachidonic acid; oleic acid; 9,11,13-octadecatrienoic acid; 5,8,11,14-eicosatetraenoic acid; eicosenoic acid; heneicosenoic acid; erucic acid; heneicosanoic acid; behenic acid; 3-methylhexadecanoic acid; 7-methylhexadecanoic acid; 13-methylhexadecanoic acid; 14-methyl-11-eicosenoic acid; the like; and mixtures thereof.
The preferred long chain fatty acid is TOFA, which in an embodiment refers to a distilled product derived from trees and which consists of a mixture of fatty acids, C 17 H 31-35 COOH with a CAS No. 61790-12-3. It is a mixture of oleic acid as a major component, linoleic acid and saturated fatty acids. For purposes of this invention the radical obtained therefrom will be identified as heptadecenyl. In another embodiment, TOFA refers to tall oil fatty acid stock and typically includes about 1% palmitic acid; about 2% stearic acid; about 48% oleic acid; about 35% linoleic acid; about 7% conjugated linoleic acid (CH 3 (CH 2 ) X CH═CHCH═CH(CH 2 ) Y COOH, where x is generally 4 or 5, y is usually 7 or 8, and X+Y is 12); about 4% other acids, such as 5,9,12-octadecatrienoic acid, linolenic acid, 5,11,14-eicosatrenoic acid, cis,cis-5,9-octadecadienoic acid, eicosadienoic acid, elaidic acid, cis-11 octadecanoic acid, and C-20, C-22, C-24 saturated acids; and about 2% unsaponifiable matter. In other embodiments, TOFA includes any suitable tall oil fatty acid or mixture known in the art or equivalents thereof.
It should be appreciated that the described compounds may be used alone or in combination with other compounds to further increase the effect and delivery of the products. Typical combinations include pour point depressants and/or surfactants. Examples of suitable pour point depressants are C 1 to C 3 linear or branched alcohols, ethylene, and propylene glycol. Examples of suitable surfactants are nonionic surfactants, such as alkoxylated alcohols, carboxylic acids or ethers, alkyl ethoxylates, and sorbitan derivatives; anionic surfactants, such as fatty carboxylates, alkyl phosphates, alkyl sulfonates, and alkyl sulfates; cationic surfactants, such as mono- and di-alkyl quaternary amines; amphoteric surfactants, such as alkyl betaines, alkylamido propyl betaines, alklyampho acetates, and alkylamidopropyl hydroxysultaines. Moreover, the described foamers may also be used in conjunction with other foamers, such as those disclosed in U.S. patent application Ser. No. 11/940,777, “Imidazoline-Based Heterocyclic Foamers for Downhole Injection” and any other suitable foamers.
The described foamers or foaming agents of this invention have been shown to be effective for penetrating subterranean oil-bearing or gas-bearing formations to recover natural gas from a gas well or recover crude oil from a gas-lifted oil well. Exemplary gas-lift methods for producing oil are disclosed in U.S. Pat. No. 5,871,048 and U.S. Patent Application No. 2004-0177968 A1. In other words, the foaming agents of the invention are effective at aiding and making more efficient removal of hydrocarbon and/or water or mixtures thereof from wells. It should be appreciated that in some embodiments other corrosion inhibitors, scale inhibitors, and/or biocides may be used in conjunction with or in formulations including the foamers of this invention.
Representative corrosion inhibitors include amidoamines, quaternary amines, amides, phosphate esters, other suitable corrosion inhibitors, and combinations thereof. Representative scale inhibitors include polyphosphates, polyphosphonates, other suitable scale inhibitors, and combinatios thereof. Exemplary corrosion inhibitors are disclosed in U.S. patent application Ser. No. 11/763,006, “Mono and Bis-Ester Derivatives of Pyridinium and Quinolinium Compounds as Environmentally Friendly Corrosion Inhibitors” or any other suitable corrosion inhibitor. The composition may also include one or more suitable solvents including, but not limited to water, monoethylene glycol, ethylene glycol, ethylene glycol monobutyl ether, methanol, isopropanol, the like, derivatives thereof, and combinations thereof.
Even though this disclosure is directed primarily to oil and gas recovery applications, it is contemplated that the composition of the invention may also be used in other applications. For example, the composition may be used as a deposit control agent or cleaner to remove deposits (e.g., hydrocarbonaceous deposits) from wells and/or pipelines. “Hydrocarbonaceous deposit” refers generally to any deposit including at least one hydrocarbon constituent and forming on the inner surface of flowlines, pipelines, injection lines, wellbore surfaces, storage tanks, process equipment, vessels, the like, and other components in oil and gas applications. Such deposits also include “schmoo,” which refers to a solid, paste-like, or sludge-like substance that adheres to almost any surface with which it comes in contact and is particularly difficult to remove. Deposits contributing to schmoo may include, for example, sand, clays, sulfur, naphthenic acid salts, corrosion byproducts, biomass, and other hydrocarbonaceous materials bound together with oil. The compositions of this invention may be used in conjunction with other deposit control agents, such as those disclosed in U.S. patent application Ser. No. 11/952,211, “Environmentally Friendly Bis-Quaternary Compounds for Inhibiting Corrosion and Removing Hydrocarbonaceous Deposits in Oil and Gas Applications.”
EXAMPLE
The foregoing may be better understood by reference to the following example, which is intended for illustrative purposes and is not intended to limit the scope of the invention.
This example illustrates the effectiveness of the foamer composition of the invention. In a preferred method of preparation, the foaming composition of the invention was prepared by mixing 70 grams of TOFA with 5% rosin with 30 grams of EGMBE at room temperature. A homogeneous solution was observed. The product was identified as Product 1. TOFA with 5% rosin in the absence of EGMBE was identified as Product 2. TOFA containing 1% rosin and zero EGMBE was identified as Product 3.
The table below displays the results when a foaming agent was added to a mixture of hydrocarbon condensate received from the field and brine (10.2% NaCl and 3.7% CaCl 2 .2H 2 O) in a ratio of 9 to 1, respectively. The condensate-to-brine ratios were 90/10 (vol/vol) for all tests. Cocoamidopropyl betaine (C. Betaine in the table below), a conventional foaming agent, was also tested as a control. The test cell included a nitrogen supply; a jacketed 1,000 ml graduated cylinder with a glass frit on the bottom for gas flow; a flow meter; a temperature-controlled water bath; a container for collecting unloaded liquid; a condenser for transporting the liquid from a cylinder to another container; and a balance connected to a computer for recording real-time measurements. The gas flow rate was held constant at 15 SCFH.
The weight percent liquid unloading was calculated by dividing the weight of the collected liquid in the container at 5 min (i.e., the amount overflowed) by the initial weight placed in the cylinder times 100. The weight percent of the liquid removed (i.e., percent unloading) was then calculated from 100 grams of fluid. It can be seen that Products 1, 2, and 3 of the present invention are superior to the conventional foamer. It can also be seen that addition of EGMBE increases the liquid unloading efficiency (Product 1 vs. Product 2).
Foamer
Percent
Product
Actives
Unloading
C. Betaine
1%
0
Product 1
7,000 ppm
62
Product 2
1%
45
Product 3
1%
35
All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While this invention may be embodied in many different forms, there are described in detail herein specific preferred embodiments of the invention. The present disclosure is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated.
Any ranges given either in absolute terms or in approximate terms are intended to encompass both, and any definitions used herein are intended to be clarifying and not limiting. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges (including all fractional and whole values) subsumed therein.
Furthermore, the invention encompasses any and all possible combinations of some or all of the various embodiments described herein. Any and all patents, patent applications, scientific papers, and other references cited in this application, as well as any references cited therein and parent or continuation patents or patent applications, are hereby incorporated by reference in their entirety. It should also be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. | This invention relates generally to novel foamer compositions for treatment of oil and gas wells to enhance production. The invention provides a method of foaming a fluid. The method includes introducing into the fluid a foam-forming amount of a composition comprising at least one long chain fatty acid and at least one organic solvent. An example of the long chain fatty acid is tall oil fatty acid and an example of the organic solvent is ethyleneglycol monobutyl ether. | 2 |
The invention concerns a large round baler of the type designed for operating non-stop during the processes of forming, binding and/or wrapping and discharging formed bales.
BACKGROUND OF THE INVENTION
EP-A-0 064 116 discloses a large round baler with a first and a second baling chamber, that can be charged alternately and thereby permit an uninterrupted operation. For this purpose, a set of belts is provided that extends over a front and a rear housing section and over an intervening region. In the central region, two tension arms are provided that are connected to each other in joints and that control the corresponding section of the belts in such a way that the baling chamber is formed in the front or the rear housing section. As soon as a cylindrical bale is formed in the rear baling chamber, it is wrapped there and ejected. At the same time, a cylindrical bale is formed in the front baling chamber and laid upon a side conveyor after its completion for deposit alongside the baler.
The problem underlying the invention is seen in the fact that a separate conveyor is required for the delivery of the cylindrical bale from the front baling chamber and that a costly mechanism is necessary in order to guide the belts correspondingly.
SUMMARY OF THE INVENTION
According to the present invention there is provided a novel continuously operating baler.
An object of the invention is to provide a continuous baler wherein an upper baling chamber section including a pair of side walls is movable fore-and-aft relative to front and rear conveyors of a lower baling chamber section so as to cooperate with the latter to respectively define front and rear baling chambers for alternately receiving crop during the baling process.
A more specific object of the invention is to provide a continuous baler, as defined in the previous object, wherein the upper chamber section includes front and rear portions in the form of a plurality of rolls located so as to define a circular arc when in respective lowered positions, and so as to permit wrapping of a formed bale located on the rear conveyor, and its discharge from the baler after being wrapped, when the front and rear chamber portions of the upper chamber section are in their respective raised positions.
These and other objects of the invention will become apparent from a reading of the ensuing description together with the appended drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a schematic side view of a large round baler constructed in accordance with the principles of the present invention, with the baler being shown in a condition filling a rear baling chamber.
FIG. 2 shows the large round baler of FIG. 1 in a condition wherein the rear baling chamber has become filled with crop material.
FIG. 3 shows the baler of FIG. 1 during a binding process.
FIG. 4 shows the baler of FIG. 1 during the feeding of crop into a region above a front conveyor and with upper front and rear wall portions of the upper baling chamber section being shown in a raised condition.
FIG. 5 shows the baler of FIG. 1 in a condition where the front and rear wall portions of the upper chamber section, together with opposite side walls of the baling chamber, are shifted to a forward region above a floor conveyor.
FIG. 6 shows the baler of FIG. 1, where the front and rear wall portions of the upper chamber section are once again lowered to form a forward-located baling chamber and the cylindrical bale previously formed in the rear-located baling chamber is being wrapped with sheeting.
FIG. 7 shows the baler of FIG. 1 where the wrapping process has been completed.
FIG. 8 shows the baler of FIG. 1 at the time where the wrapped bale is ejected.
DESCRIPTION OF THE PREFERRED EMBODIMENT
A large round baler 10 , constructed in accordance with the present invention, is shown in the drawing and includes a chassis 12 , wheels 14 , a crop intake arrangement 16 , a lower baling chamber section 18 , an upper baling chamber section 20 , a housing 8 defining opposite baling chamber side walls, a wrapping device 22 , a binding device 24 and a rotary feeder 26 .
The baler 10 generally represents a machine that can be operated continuously, that is to say, without interrupting the operation during discharge of a completed cylindrical bale 28 . Beyond that, it is equipped with the necessary devices to bind the cylindrical bale 28 with twine or wrap it with foil, such as plastic sheeting, for example. Crops such as grass, hay, straw and the like can be baled in dry or wet condition, in order to produce silage.
The chassis 12 is joined to a support frame, not shown, that can be attached by a towbar, also not shown, to a towing vehicle for operation across a field. The chassis 12 is configured relatively long so as to form space for rear and front baling chambers 30 (FIGS. 1-3) and 30 ′ (FIGS. 6 - 8 ), respectively, but, as will be presently described, these baling chambers are not composed of two sets of entirely different components but rather are of a configuration where a considerable part of the baling chambers is movable so as to respectively form a part of each baling chamber. This simplification of the configuration is accompanied by a corresponding reduction in the total weight.
A guide arrangement 32 is provided that is generally parallel to the ground on which the baler is supported or operated, which extends fore-and-aft in the direction of travel generally over the entire length of the chassis 12 and provides a free space to the support frame which, in the preferred embodiment, corresponds to the height of the baling chambers 30 or 30 ′. Nevertheless, the guide arrangement 32 can also extend lower than the height of the baling chambers 30 or 30 ′.
In the preferred embodiment, the wheels 14 are attached to two tandem axles and spring-mounted to the chassis 12 , but this is not an absolute requirement.
The crop intake arrangement 16 is configured in a known manner as a pick-up conveyor, that is, it is provided with a multitude of tines circulating in vertical planes that raise crop from the ground and convey it upward. At the outlet end of the crop intake arrangement 16 , an intermediate conveyor 34 is provided, which can be configured as a rotary cutter, and conveys crop through a channel defined by and located between a bottom 36 of the crop intake arrangement 16 and a sheet metal guide vane 38 that extends at an upward inclination, where the intermediate conveyor 34 extends with tines, not described in any further detail, through slits, not shown clearly, in the sheet-metal guide vane 38 , and grasps the crop. The inclined sheet-metal guide vane 38 has a rear end joined to a front end of opposite side guide vanes 40 , that generally extend horizontally and border the lower chamber section 18 at their sides so as to continue the aforementioned channel. In this way the crop is prevented from falling down at the sides.
In this special embodiment, the lower chamber section 18 includes a front conveyor 42 immediately followed by a rear conveyor 44 , with the conveyors serving to carry the crop taken in on their upper surfaces. Altogether, the two conveyors 42 and 44 extend generally over the length of the chassis 12 . Both conveyors 42 and 44 have a conveying surface of the same width, but not necessarily of the same length. The conveyors 42 and 44 are driven in a conventional manner, for example, by chains or shafts or by means of hydraulic motors, preferably synchronously. Nevertheless, differing drive speeds can be selected, in particular, if the front conveyor 42 is incorporated into the baling process of the cylindrical bale 28 and the rear conveyor 44 is incorporated into the wrapping process of another cylindrical bale 28 . The lower baling chamber section 18 can be configured as a one-piece component and be provided over its entire length, for example, with a belt conveyor or a bar-chain conveyor or a multitude of rolls on parallel axes.
The front conveyor 42 follows immediately upon the outlet end of the crop intake arrangement 16 , that is, at the outlet end of the channel formed by the bottom 36 and the sheet-metal guide vane 38 . The front conveyor 42 is configured as a belt conveyor and contains a conveyor belt 46 and several deflecting or driven pulleys 48 that support the belt. The pulleys 48 are arranged in such a way that the upper span of the conveyor belt 46 is planar; nevertheless, the rolls 48 could also be arranged in such a way that a depression or cavity that forms a circular segment in side view results in which the cylindrical bale 28 can be partially accommodated. The front conveyor 42 spans the region between the crop intake arrangement 16 and the rear conveyor 44 in the condition according to FIGS. 1 and 2, and in the condition according to FIGS. 3 through 5, as a storage area for crop that has been accepted by the crop intake arrangement 16 , but cannot be delivered to the baling chamber 30 located at the rear, and, in the condition according to FIGS. 6 through 8, as a carrier and drive means for a cylindrical bale 28 that is being formed.
The rear conveyor 44 is configured in the form of a pan, whose bottom is formed by rolls 50 , that are arranged so as to lie along a segment of a circle. The rolls 50 are supported, as by bearings, for free rotation in side walls 52 located at the opposite ends of the rolls, with at least some of the rolls 50 being driven. The rear conveyor 44 is mounted to the chassis 12 for vertical pivotal movement about a horizontal axis that is coincident with the longitudinal axis of the front-most roll 50 , with the conveyor 44 being movable between a raised, operating condition, as shown in FIGS. 1-7, and a lowered, discharge position, as shown in FIG. 8 . The rear lower conveyor 44 is retained in its raised operating position by a locking arrangement, not shown, and can be repositioned, for example, by a hydraulic motor. Except for the discharge condition, the conveyor 44 always carries crop, either for the forming of a cylindrical bale 28 , and then for supporting the formed bale for wrapping and discharge. As will become apparent from the following description, with the front and rear conveyors 42 and 44 , respectively, being formed by belts, chains or the like and by a plurality of rolls located on a circular arc, different functions may be attained. For example, the rolls are appropriate for resisting the high compacting forces during the baling process, while the belts, chains or the like can border the underside of an intermediate storage area for the crop in the starting phase of the formation of the bale, and convey the loose crop. With loose or crumbling crop, the application of a belt conveyor forming the entire lower housing section has the advantage that leaves and other loose plant components are not lost, but remain contained in the mass of the crop.
The upper baling chamber section 20 cooperates with the lower chamber section 18 to form the upper region of the rear baling chamber 30 when the chamber section 20 is above the rear conveyor 44 , and to form the upper region of the front baling chamber 30 ′ when the chamber section 20 is in a forward location above the front conveyor 42 . The upper chamber section 20 is supported in bearings for movement in the direction of travel along the fore-and-aft extending guide arrangement 32 so as to move horizontally, relative to the lower chamber section 18 , between rear and front positions respectively above the rear and front conveyors 44 and 42 . The upper chamber section 20 is divided into front and rear chamber wall portions 54 and 56 , respectively, that extend between and have respective upper rear and upper front ends pivotally attached to opposite side walls 58 .
The front and rear upper chamber wall portions 54 and 56 are configured generally similarly and are arranged in mirror image manner to each other and surround the circumference of the baling chamber 30 or 30 ′ to approximately 240°. Both wall portions 54 and 56 include rolls 50 that are retained, free to rotate, in arcuate side frames, the axes of rotation of the rolls 50 being located along a circular path when the wall portions 54 and 56 are in their respective lowered working positions as illustrated in FIGS. 1 through 3. An inlet opening is provided between the lower end roll 50 of the upper front wall portion 54 and the upper surface of the front conveyor 42 when the wall portion 54 is in its lowered working position. The upper rear and upper front ends respectively of the chamber wall portions 54 and 56 are connected to each other by a joint 62 and are each mounted in the joint 62 for pivoting vertically, so that they can be swung upwardly from their respective lowered working position to a raised non-working position, as illustrated in FIG. 5 . For moving the chamber wall portions 54 and 56 between their working and non-working positions, combined or separate actuation devices, not shown, for example, hydraulic cylinders or rope pulls may be employed.
The actuation devices can be controlled, configured or arranged in such a way that the chamber wall portions 54 and 56 can simultaneously assume the raised position, shown in FIG. 5, wherein the opposite ends of each portion lie on a substantially horizontal plane. Both of the chamber wall portions 54 and 56 can be moved as a unit, together with the opposite side walls 58 , along the guide arrangement 32 .
Although the chamber wall portions 54 and 56 are shown as including a plurality of the rolls 50 , the rolls can be replaced by rolls, or the like, over which belts or chains can be conducted. Instead of there just being two chamber wall portions 54 and 56 interconnected by a single joint 62 , it is possible to employ a multitude of chamber wall portions connected to each other by joints which, nevertheless, can assume the shapes of the chamber wall portions 54 and 56 that are shown in FIGS. 3 and 4.
The side walls 58 extend to the side of the rolls 50 and form the vertical side walls of the baler housing 8 . The walls 58 are so dimensioned that they enclose the baling chamber 30 or 30 ′ at the sides when the chamber wall portions 54 and 56 are located in their lower working positions as well as form a chamber 72 that is bordered at the bottom by the front conveyor 42 and at the rear by the front side of the upper front chamber wall portion 54 . The sheet-metal side guide vanes 40 project by a small degree into the chamber 72 , so that crop is safely conducted into it. The sheet-metal side guide vanes 40 and the walls 58 can also be connected to each other so that the guide vanes 40 are moved as a whole, or only in some regions, when the walls 58 are moved. The outside of the walls 58 are located opposite the inside of a pair of rails 70 forming part of the guide structure 32 , so that the entire upper baling chamber section 20 can be shifted within the space located between the rails 70 . The walls 58 are aligned with the side walls 52 of the lower chamber section 18 and end in their upper edge in a horizontal intersecting point, so that they cannot collide when the upper chamber section 20 is moved horizontally.
At the lower end region of the upper front chamber wall portion 54 that borders the inlet opening 60 , the feeder 26 is provided in such a way that it can pivot vertically with the upper front chamber wall portion 54 .
The wrapping device 22 is used for wrapping a completed cylindrical bale 28 with foil, such as plastic sheeting, so that the bale 28 containing moist crop becomes silage feed. As can best be seen in FIG. 6, the wrapping device 24 includes a carrier 64 , a wrapping arm 66 and wrapping material 68 . The wrapping arm 66 is supported in bearings, free to rotate about a vertical axis, on the carrier 64 and extends from the axis of rotation initially inclined radially outward and downward, and subsequently downward so as to be disposed along the axis of the roll of wrapping material 68 , in order to carry and deliver the wrapping material 68 . The wrapping arm 66 is dimensioned and arranged in such a way that the inclined region remains between the guide rails 70 and that the region carrying the wrapping material 68 can move diametrically about the cylindrical bale 28 . Instead of only one, several wrapping arms 66 could be provided, in order to reduce the wrapping time. The wrapping arm 66 is brought into rotation by a drive (not shown) supported by the carrier 64 and coupled to the axle carrying the arms 66 .
As a rule, the wrapping material 68 is formed by a stretch foil that is applied to the cylindrical bale 28 under high tension and adheres to previous layers on the basis of adhesion. While the wrapping material 68 is applied to the cylindrical bale 28 , the cylindrical bale 28 continues to rotate slowly, so that the individual layers come to lie offset from one another.
Furthermore, the wrapping device 22 is provided with retaining, tensioning and separating or severing devices for the wrapping material 28 , each of which is not shown but is known in itself and are used to initiate the beginning and the end of the bale wrapping process. The bale wrapping process always occurs after the cylindrical bale 28 is deposited on the rear conveyor 44 . The wrapping arm 66 can move freely around the cylindrical bale 28 as soon as the upper chamber section wall portions 54 and 56 are raised from their respective operating region and moved forward on the guide rails 70 , along with the side walls 58 .
The binding device 24 is configured as a net binding device and is attached to an upper forward location of the opposite side walls 58 so as to be adjacent the front of the upper forward chamber wall portion 54 , when the latter is in its lowered working position. Alternatively, the binding device 24 could be mounted to the support structure for the rolls 50 of the chamber wall portion 54 so as to move with the portion 54 when it is pivoted vertically. Instead of net, a twine binding or foil binding device could be provided. In each case, the binding material is introduced in a known manner through the inlet opening 60 or through a gap between the rolls 50 into the baler housing 8 and wound around the rotating cylindrical bale 28 . The binding device 24 is located at the upper chamber section 20 because the cylindrical bale 28 is bound while it is still subject to the pressure in the baler housing 8 .
The feeder 26 is configured as a driven rotor that rotates about a horizontal axis and is equipped with fingers, tines or other conveying elements. The feeder 26 is arranged in such a way that the crop arriving from the front conveyor 42 is slid safely into the inlet opening 60 and is not jammed there. This function is accomplished by the feeder 26 in that it rotates in a clockwise direction, as viewed in FIG. 1, for example. The drive to the feeder 26 is reversible and when the feeder 26 rotates in the reverse direction, it moves the crop from the inlet opening 60 and conveys it into the region of the baling chamber 30 ′ for being partially formed into a bale there. Alternatively, the front lower conveyor 42 could also be temporarily driven slowly in reverse, or it could be brought to a halt and thereby either move the incoming crop away from the inlet opening 60 or momentarily hold it back.
In the preferred embodiment, the guide arrangement 32 is provided with rails 70 that extend over the entire length of the chassis 12 and are configured or arranged to be so stable that they can carry the weight of the upper chamber section 20 . The guide arrangement 32 is provided with a drive, not described in any further detail, that contains, for example, a rack and a gear motor or rope pulls and sliding or rolling guides with which the upper chamber section 20 can be moved along the rails 70 of the guide arrangement 32 .
The rails 70 are arranged parallel to each other and considerably above the chassis 12 and formed, for example, by an U-profile, an L-profile or a T-profile, so that the joint 62 and possibly stabilizing struts can be guided along their lengths for the retention of the upper chamber section 20 .
On the basis of the above description, the large round baler 10 operates as follows.
Assume the large round baler 10 to be in a condition where it has not taken any crop up and that the upper chamber section 20 is located above the rear, lower conveyor 44 . This condition is shown generally in FIG. 1, where however, some crop already taken up is shown.
At the beginning of the operation of the large round baler 10 , the crop intake arrangement 16 takes up crop from the ground and conveys it upward to the rear through the channel defined between the bottom 36 and the inclined sheet-metal guide vane 38 , and then into the channel defined between the front lower conveyor 42 and the horizontal sheet-metal guide 40 . The front lower conveyor 42 carries the crop on the conveyor belt 46 that is equipped, if necessary, with battens or other drivers, up to the intake opening 60 , where it is grasped by the feeder 26 and forced through the inlet opening 60 into the baling chamber 30 , this condition being that shown in FIG. 1 .
The crop collects on the rear lower conveyor 44 until it is brought into rotation as a mound by the rotating rolls 50 . The more the baling chamber 30 is filled, the more the crop is compressed into a cylindrical bale 28 and continuously rotated. This condition is shown in FIG. 2 .
As soon as the bale 28 has reached the desired density, the binding device 24 is brought into operation and the cylindrical bale 28 is bound with net, twine or the like, in accordance with a known process. During the binding process, the crop intake arrangement 16 continues to operate and delivers crop to the front lower conveyor 42 . This crop is not forced into the intake opening 60 , but is collected in front of it by the feeder 26 that is now operating in the backward direction. This condition is shown in FIG. 3 . After the binding process and while crop principally accumulates in the chamber 72 , the front and the rear chamber wall portions 54 and 56 are pivoted upward and free the cylindrical bale 28 . This condition is shown in FIG. 4 .
While the chamber wall portions 54 and 56 are raised, they are shifted along the guide arrangement 32 to the front over the cylindrical bale 28 and over the crop accumulated on the front conveyor 42 . Since both chamber wall portions 54 and 56 are raised, the baling chamber 30 is open at the front and the rear, and the front chamber wall portion 54 does not push the crop along in front of it on the lower conveyor 42 during its forward movement. In the end position of the upper chamber section 20 , both chamber wall portions 54 and 56 are located as a pincer above the mound of crop formed on the front lower conveyor 42 . This condition is shown in FIG. 5 .
After the upper chamber section 20 has been slid, rolled or otherwise moved, the two chamber wall portions 54 and 56 are lowered so that they enclose the crop between themselves and the front lower conveyor 42 and form the baling chamber 30 ′ at the front of the baler 10 . The crop brought in by the crop intake arrangement 16 now moves again through the intake opening 60 and reaches the baling chamber 30 ′, if necessary supported by the feeder 26 , which is now again driven in the clockwise direction as seen in the drawing. While the crop in the front baling chamber 30 ′ is at least being pre-compressed, in the case that the previously formed cylindrical bale 28 is to be wrapped with foil, then the wrapping arm or arms 66 are brought into rotation and thereby apply wrapping material 68 to the bale 28 , until an airtight surface is attained. This condition being shown in FIG. 6 .
As soon as the wrapping of the cylindrical bale 28 is completed, the wrapping process is ended and the wrapping arm or arms 66 are brought into a position in which they do not hinder an unloading of the cylindrical bale 28 . This condition can be seen in FIG. 7 .
After the wrapping process, the rear lower conveyor 44 is pivoted vertically in the counterclockwise direction, as viewed in FIG. 8 for example, so that the cylindrical bale 28 resting on it is slid to the rear onto the ground, while in the baling chamber 30 ′ located at the front, crop continues to be compressed.
Finally the upper chamber section 20 , with the crop contained in it, is moved to the rear, up to the rear lower conveyor 44 , where the baling process is continued and ended. Except for the fact that there is less crop material contained in the baling chamber 30 than what is shown in FIG. 8, the condition of the baler 10 is once again like that illustrated in FIG. 1 . | A large round baler, designed as a non-stop baler, includes a mobile chassis supporting a lower baling chamber section, defined by a floor conveyor arrangement, and an upper baling chamber section. The upper baling chamber section, together with opposite side walls, is mounted for fore-and-aft movement relative to the lower baling chamber section between a rear location, wherein it cooperates with the floor conveyor arrangement to define a rear baling chamber, and a front location wherein it cooperates with the floor conveyor arrangement to define a front baling chamber. The upper chamber section includes front and rear wall portions which are mounted for being raised once a bale is formed in the rear baling chamber so that the upper section may be moved to its forward location. A wrapping device is provided which is operable once the upper chamber section is moved to its front location, for wrapping the bale with overlapping wraps of sheeting made from plastic or the like so as to provide an air tight casing for the crop material so as to make silage. | 0 |
BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to a seat for a motor vehicle and particularly to one of the type being removably fastened to the vehicle structure.
In some types of motor vehicles, and in particular multipurpose passenger vehicles (MPV's) there is a demand for passenger seats which can be installed to carry passengers or conveniently removed to provide a large compartment area for transporting articles. Irrespective of the design of the mounting system for a removable seat, it must have a high degree of structural integrity since extreme loads can be put on the mounting structure in the event of vehicle impact.
Various designs for removable seat mounting mechanisms are presently used in vehicles today. In order to provide the necessary structural integrity, the mounting system typically engages the floor pan of the vehicle below the front and rear edges of the seat, often pairs of front and rear seat mounts are provided at the four corners of the seat bottom. For these types of seats the forward laterally mounting points are merely hinge points with the rear mounts having a latching mechanism. Once the rear mounts are released, the seat can be pivoted forward and pulled from the forward seat mounts. The seat mounting points on the vehicle are typically comprised of bars or other structural features which are positioned below the floor pan surface in seat mounting sockets.
Since releasable mounting systems are required to have a high degree of structural integrity, some type of secure latching mechanism is required. In order to remove a seat having a pair of separate rear mounts the mechanisms are either designed to have separate release levers which must be simultaneously actuated by the user to remove the seat, or some type of remote control system is provided in which the pair of latches are both actuated through a single lever or release. Providing two separately actuated release mechanisms has the disadvantage that they must both be actuated simultaneously, which can be inconvenient to the user. If a single release mechanism is employed with a remote control system, a cable, torsion rod or another remote control element must be provided which adds to the complexity and costs of the seat mechanism.
Another shortcoming present in some existing seat mounting systems is their tendency to allow the seat to rattle against the seat mounts provisions, leading to undesirable noise and customer complaints.
In accordance with the present invention, a seat mounting system is provided which overcomes the previously mentioned shortcomings of prior art seat mounting mechanisms. In the seat of the present invention, two laterally separated rear latching mechanisms are provided. One of the latching mechanisms is a manually actuated release in which a latch plate is caused to engage and disengage a mounting bar attached to the vehicle floor pan. The latch plate is mounted to pivot about an eccentric cam such that it is cinched through spring tension to firmly clamp against the mounting bar, thereby reducing the possibility of rattling problems. Another releasable latch mechanism is provided which does not require a manual release since it is inertia sensitive, and will engage with a mounting bar in the event that the vehicle is subjected to a deceleration load above a certain level as might be expected in a vehicle impact. In the absence of the deceleration load, however, the inertia sensitive latch mechanism releases automatically when the manually actuated latch is released and the seat is pulled from its mounts. By providing a combination of a manually actuated and an inertia actuated latch, the requirement of dual manual release or remote actuation is eliminated. The design of the present invention also provides the significant advantage that an identical latch plate can be used for both the inertia sensitive latch and the manually actuated latch, thereby simplifying assembly and reducing the number of unique components which comprise the seat structure.
Additional benefits and advantages of the present invention will become apparent to those skilled in the art to which this invention relates from the subsequent description of the preferred embodiments and the appended claims, taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a pictorial view of a motor vehicle seat incorporating the mounting mechanisms of the present invention.
FIG. 2 is a partial side view taken in the direction of arrow 2 from FIG. 1 which is partially cut away to show in greater detail the outboard seat mounting latch mechanism.
FIG. 3 is a cross sectional view of the latch mechanism from FIG. 2 taken along line 3--3 from that figure.
FIG. 4 is an exploded pictorial view of the outboard mechanism shown in FIGS. 2 and 3.
FIG. 5 is a partial side elevational view of the seat shown in FIG. 1 taken in the direction of arrow 5 which is partially cut away to show the details of the inboard inertially actuated seat mounting latch mechanism.
FIG. 6 is a cross sectional view of the latch mechanism shown in FIG. 5 taken along lines 6--6 from that Figure.
FIGS. 7, 8 and 9 are enlarged fragmentary views of the inertially actuated seat mounting latch mechanism of FIG. 5 shown in various operating positions.
DETAILED DESCRIPTION OF THE INVENTION
A motor vehicle seat having latch mechanisms in accordance with this invention is shown in FIG. 1 and is generally designated there by reference number 10. Seat 10 has the seat bottom 12, back 14, and head restraint 16.
Seat 10 has provisions for enabling it to be securely mounted to the motor vehicle floor pan yet can be conveniently removed as required. Seat 10 is designed to face the direction of normal forward travel of the motor vehicle. At the forward edge of seat bottom 12, a pair of forward opening hooks 18 are provided as best shown in FIG. 2. The forward facing notch 20 of hooks 18 engages mounting bars 22 which are provided in separated mounting sockets 24 which are attached to the vehicle floor pan or are made integral with the floor pan.
Motor vehicle seat 10 also includes a pair of separated rear mounting latch assemblies 26 and 28. While seat 10 could be mounted in various positions within a motor vehicle, seat mounting latch 26 will be designated an outboard latch assembly and is partially shown in FIG. 1, and in greater detail in FIGS. 2, 3 and 4. Seat mounting latch 28 is designated as an inboard latch assembly shown in detail in FIGS. 5 and 6. As mentioned previously, seat 10 includes both a manually actuated seat mounting latch and an inertia sensitive or automatic releasing latch. Seat mounting latch 26 is a manually actuated latch mechanism and latch 28 is inertially actuated.
With reference to FIG. 4, manually actuated latch 26 is shown in detail. Seat frame rail 30 is shown which comprises a structural portion of the seat frame, a pair of which are positioned at both the inboard and the outboard sides of seat 10. Attached to frame rail 30 is a projecting notched plate 32 having a downward opening notch 34 which engages with mounting bar 22. Notched plate 32 supports the weight of the seat and occupant against the rearward positioned mounting bars 22.
Without some additional latch provisions to engage the rear mounting bars 22, seat 10 would be free to rotate about the forward mounting bars 22 if the seat were pushed by an occupant, or if the vehicle experienced a deceleration force. As shown in FIGS. 2 through 4, seat mounting latch 26 also includes a pivotable latch plate 38 having a pivot bore 40. Latch plate 38 also defines a forward facing engagement notch 42, and notches 44 and 46 which are provided to limit the range of angular pivoting of latch plate 38. Mounting bolt 48 is provided to assemble the components of latch 26 and includes an enlarged head 49 with a radially projecting flange 50 and a cylindrical surface 52 concentric with the bolt head. A reduced diameter cylindrical post 54 projects from the mounting bolt head 49 and is eccentrically positioned with respect to the head.
Mounting bolt 48 is journaled for rotation through rail hole 64. Actuation lever 58 includes a circular aperture 60 and an actuation tab 62. Actuation lever 58 is pressed onto mounting bolt 48 and has an interference fit with cylindrical surface 52 so that it can be used to rotate mounting bolt 48. Latch plate 38 is journaled for free pivoting movement about pivot bore 40 on eccentric mounting bolt post 54. The elements are maintained in an assembled condition by threading nut 66 onto post 54. Antifriction washer 67 made of a suitable material is provided to allow latch plate 38 to freely pivot. A tension spring 68 is provided having a pair of ends, one of which engages frame rail 30 at aperture 70, and the other which engages aperture 72 of lever 58. Tension spring 68 biases lever 58 in a clockwise direction, when viewing the elements of latch 26 as presented in FIG. 2.
FIG. 2 illustrates the orientation of the elements of seat mounting latch 26 when the seat is mounted. In this condition, latch plate 38 is rotated in a clockwise direction so that mounting bar 22 is engaged both by notched plate 32 and latch plate engagement notch 42. As is evident from FIG. 2, latch plate 38 and notched plate 32 cooperate to trap bar 22, thus preventing the seat from being withdrawn. Due to the biasing of spring 68 acting on actuation lever 58, mounting bolt 48, through eccentric post 54, exerts an upward force on latch plate 38. This occurs since the center of eccentric post 54 is forward of the center of rail hole 64. The lower surface 74 of engagement notch 42 defines a concave surface so that, as latch plate 38 is cinched up, the latch plate is maintained firmly in engagement with mounting bar 22. Due to this cinching effect, latch plate 38 and notched plate 32 are securely clamped against bar 22, thus reducing the possibility of seat rattling problems. When it is desired to release mounting latch 2 and remove seat 10, an upward or counter clockwise force is exerted on actuation lever tab 62. Due to the eccentricity of mounting bolt post 54, latch plate 38 is caused to drop slightly such that the lower surface 74 of the latch plate no longer engages mounting bar 22. In that condition, latch plate 38 rotates in a counter-clockwise direction on its own accord, due to the fact that its center of gravity 76 positioned as shown in FIGS. 2 and 4, is positioned forward of its point of rotation about bolt post 54. This rotation is sufficient to allow mounting bar 22 to escape from latch plate engagement notch 42. A pair of pins 78 and 80 are fastened to frame rail 30 and are provided to limit the angular motion of latch plate 38. Pin 78 engages with notch 44 when latch plate 38 reaches its extreme counter-clockwise rotated position, whereas pin 80 engages notch 46 to restrain the plate at its extreme clockwise rotated position.
When seat 10 is removed from the vehicle and it is desired to replace it, the forward seat mounting hooks 18 are first engaged with the forward positioned mounting bars 22. Thereafter, seat 10 is rotated downwardly about the front mounting bars 22, bringing notched plate 32 and seat mounting latch 26 (and 28) into engagement with rearward mounting bars 22. The lowermost ramped surface 82 of latch plate 38 engages mounting bars 22, rotating the latch plate so that the mounting bars are engaged by forward facing engagement notch 42. The upper surface 84 of engagement notch 42 is angled with respect to pivot bore 40 to interact with the mounting bar 22, causing the plate to be cammed to rotate clockwise into the fully engaged position shown in FIG. 2 when a downward force is exerted on the seat.
Now with specific reference to FIGS. 5 and 6, inertia sensitive seat mounting latch 28 will be described in detail. Seat mounting latch 28 differs from latch 26 in that it automatically operates and is not manually released. Seat mounting latch 28 responds to inertial loads to engage with the rear mounting bars 22, but when the vehicle is not subjected to deceleration loads, it can be released without manual actuation. In accordance with a significant advantage of the present invention, seat mounting latch 28 employs a latch plate having a configuration identical to that used for manually actuated seat mounting latch 26. Many of the elements and features of seat mounting latch 28 are identical to those of seat mounting latch 26 and are identified by like reference numbers with 100 added to them. Since these elements are identical, a separate description of them is unnecessary.
Since seat mounting latch 28 does not incorporate an eccentric mounting bolt, that element is replaced by mounting bolt 86 which is pressed into hole 88 of frame rail 90 and is secured by nut 92. Washer 167 provides an antifriction effect for pivoting of the latch plate. Latch 28 also does not incorporate actuation lever 58 and spring 68. In other respects, however, latch plate 138 is identical to latch plate 38, and in fact, a common part can be used for both applications.
FIG. 5 represents the orientation of the element of seat mounting latch 28 in a normal operating condition when seat 10 is mounted in position. In the event the user wishes to remove the seat, seat mounting latch 26 is manually actuated and the seat is forced to rotate about the forward mounting bars 22. As seat bottom 12 is lifted, mounting bar 22 no longer engages either upper or lower surface 184 or 174 of latch plate 138. See FIG. 7. The clearance between the mounting bar 22 and the latch plate 133 have been exaggerated for illustration in FIGS. 7 and 9. Due to the positioning of the center of gravity 176 of latch plate 138, it is biased to rotate in a clockwise direction, as viewed in FIGS. 5, 7, 8 and 9, allowing forward facing engagement notch 142 to escape from its engagement with mounting bar 22, see FIG. 8, and allowing the seat to be removed. As stated previously, since seat mounting latch 28 operates automatically, it does not have to be separately actuated and thus does not require a remote actuation system or separate manual release lever.
If the vehicle is subjected to a forward deceleration load above some predetermined level while seat 10 is fastened to the vehicle, that deceleration will exert an inertial force on latch plate 138, acting through center of gravity of 176. Since the center of gravity 176 is positioned below pivot bore 40, a counter-clockwise rotational force is exerted on the latch plate, thus maintaining it in engagement with mounting bar 22. If the seat pitches forward slightly, mounting bar 22 will engage with lower latch plate surface 174, see FIG. 9, which as stated previously is concave shaped and, therefore, tends to retain the latch plate in engagement with the mounting bar.
When seat 10 is removed from the vehicle and being installed, latch plate 138 behaves in a manner identical to that of latch plate 38 in that lower surface 182 engages mounting bar 22, rotating the latch plate to a position where the latch bar will engage upper surface 184 which urges latch plate 138 into its engaged position. Surface 184 maintains latch plate 138 in a position of engagement with bar 22 so long as a downward force is present on the latch 28. This feature enables latch 28 to react quickly to deceleration loads, since it does not have to move from its normal position to engage. As with latch plate 38, latch plate 138 also includes means for limiting its range of angular motion through engagement with posts 178 and 180.
While the above description constitutes the preferred embodiments of the present invention, it will be appreciated that the invention is susceptible of modification, variation and change without departing from the proper scope and fair meaning of the accompanying claims. | A seat mounting system for a removable motor vehicle seat. The mounting system incorporates a pair of seat mounting latch assemblies laterally displaced at the rear of the vehicle seat and which engage with mounting bars secured to the motor vehicle structure. One of the seat mounting latches features a manually actuated mechanism for engaging the mounting bar. On the opposite lateral side of the seat, an inertia sensitive seat mounting latch is provided which engages the locking bar when a forward deceleration force is applied onto the vehicle as in the case of vehicle impact. By providing one of the latching mechanisms with an automatically operating inertia mechanism, only one of the latch mounts needs to have a manually actuated release. In addition, this configuration avoids the requirement of remote actuation of a pair of separated latches. The manual actuated mechanism of this invention also has means for cinching against the mounting bar to reduce seat rattling. | 1 |
BACKGROUND OF THE INVENTION
The invention relates to a device for securing a vehicle against theft of wheels as well as against unauthorized towing away.
Various anti-theft devices for vehicles are known which trip an alarm in the event of the improper opening of vehicle doors, of the trunk or of the hood, if the ignition is switched on by an unauthorized person. These known types of anti-theft devices are usually put in a state of alarm readiness by locking the vehicle door after leaving the vehicle; the parts of the vehicle to be given special protection are in general provided with contact switches which are actuated when manipulated by unauthorized persons.
Heretofore it has been a problem to secure vehicles against theft of wheels as well as against unauthorized towing away, since the above-mentioned anti-theft devices of the known type do not respond in these cases.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a device for securing motor vehicles against theft of wheels as well as against unauthorized towing away, the device being highly effective and of simple construction.
According to the invention, this object is attached by positioning a switch, which is part of an anti-theft system equipped with an alarm, as well as a movable member for actuating the switch, in such a manner between the automobile body, or the chassis, and a wheel support that the movable actuating member exhibits sufficient dead movement with respect to the switch during normal operation of the vehicle. The switch is tripped in the event of the distance between the car body or chassis and the wheel support being extended to an unusual degree.
If a vehicle equipped with a device according to this invention has one of its sides, or its front or rear end, raised in any manner whatsoever; for example, by means of a jack for lifting vehicles, a winch or the like, then the distance between the automobile body or chassis and the wheel supports increases beyond that which occurs in normal operation, and this results in the movable actuating member tripping the switch and hence actuating the alarm. On the other hand, during normal operation of the vehicle, the movable actuating member has sufficient dead motion with respect to the switch to the switch so that the switch is not actuated inadvertently. The anti-theft principle of the present invention can be implemented either with a mechanically actuated switch or with a magnetically tripped switch.
Thus in one embodiment of the invention, a resilient member is positioned between the automobile body or chassis and the wheel support, the resilient member being in association with the switch as well as with a connecting member that constitutes the movable actuating member for the switch, the arrangement being such that the connecting member first travels through an idle path when the distance between the automobile body or chassis and the wheel support is enlarged to an unusual degree, and then trips the switch, whence the spring member flexibly takes up yet a further increase in the distance. Such an anti-theft device consists of a few simple parts and is distinguished by its very robust and easily assembled construction.
In a second embodiment of the invention, a magnetic proximity switch; for example, a reed relay, is actuated by a movable actuating magnet that is connected with the wheel support. Here it is expedient to position the actuating magnet next to the switch in such a manner that there is sufficient dead motion allowed for normal vehicle operation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 to 4 are: diagrammatic views of four practical mechanical switch embodiments of the device according to the invention;
FIG. 5 is: a diagrammatic plan of a magnetic proximity switch embodiments of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the embodiment of the invention depicted in FIG. 1, the anti-theft device 1 is secured to a vehicle having a rigid rear axle 2 of which the one essential half is illustrated. The anti-theft device 1 comprises an electrical switch, which in this case takes the form of a pull swtich 3, a resilient member in the form of a tension spring 4 which is cased in at the lower end of the switch, as well as a connecting member that is depicted as a flexible cable 5 hung as a loop. The looped cable 5 is pushed through the lower eye of the tension spring 4 and is passed around the axle tube 6 approximatey at the centre of the rear axle 2. The two free ends 5a of this cable 5 are firmly joined together at the bottom by means of a common screw nipple 7. The screw nipple 7 is adjusted so that the rigid rear axle 2 can travel over a specific idle path when subjected to upward and downward movement (spring suspension) during normal operating conditions without the connecting cable 5 being able to trip the switch 3, which is secured to the vehicle body 8. On the other hand, the switch 3 is tripped by the connecting cable 5 when the distance between the automobile body 8 and the rear axle 2 is increased to an extent that is greater than that which prevails during normal operation, as is the case when lifting the body for the purpose of removing a wheel or towing.
As can be recognized, the anti-theft device 1 according to the invention can be simply adapted to any vehicle type by moving the screw nipple 7 on the connecting cable 5 upwards or downwards after slackening screw 7a, and then tightening it again, whereby an appropriate lengthening or shortening of the cable loop can be attained according to the vehicle type. The electrical pull swtich 3 preferably has normally open contacts and is connected to one cable 3a for grounding and to a second cable 3b for the anti-theft installation (not shown) such as an anti-theft device for the trunk.
The tension spring 4 between the cable 5 and the pull switch 3 can flexibly take up a further extension of the distance between the body 8 and the rear axle 2 after the pull switch 3 has been actuated so that the pull switch is not unduly subjected to strain; accordingly, the tension of the spring 4 is adjusted correspondingly.
FIG. 2 shows an anti-theft device 1' according to the invention which is similar to that in the previous example, and the corresponding parts of this appliance are therefore marked with the same reference symbols with the addition of a prime mark; detailed description of these parts can, therefore, be omitted.
The difference between FIG. 2 and FIG. 1 is to be seen in the fact that in the construction according to FIG. 2 the anti-theft device 1' is employed with a vehicle having single wheel suspension. In this embodiment, the electrical pull switch 3' can be attached to the body 8'. The point of attachment here is chosen so that the device 1' is allocated to a single wheel 10--in contrast to the previous embodiment wherein the wheel 10 is driven by a driving shaft 11 and mounted on a traverse link 12.
The looped connecting cable 5' in this case has its lower free end wound around the traverse link 12 supporting the wheel 10. The screw nipple 7' which is pushed over the cable ends onto the cable 5' is likewise fixed with consideration given to the necessary idle path for normal operating conditions.
In the embodiment of the invention illustrated in FIG. 3, the anti-theft device 1" is provided for a vehicle having a rear engine drive, whereby the wheels of the vehicle may again be individually suspended, with each single wheel 20 having one anti-theft device 1" allocated to it.
As can be seen from FIG. 3, in this embodiment an axle tube 21 and the wheel 20 are carried by a shock absorber 22 which in turn is mounted on a self-supporting vehicle body 8". A stop bracket 23 is attached to the lower end 22a of the shock absorber 22 with the aid of a retaining clip 24. The stop bracket 23 may be ring shaped at its end to accommodate one end of the looped connecting cable, while the other cable end is passed around the outside. The cable ends are then once again connected together with the aid of a screw nipple 7" so that the necessary idle path is provided during normal operation. The connecting cable rope provided between the tension spring and the point of connection with the rear axle or the wheel carrier does not have to be designed as a loop in the three embodiments of the invention that have previously been described. Often it is sufficient to provide a simple, flexible cable which is connected at its upper end to the tension spring, while the lower end is passed through an appropriately sized hole in the retaining angle plate mounted at the point of connection of the rear axle or the wheel carrier, whereby a screw nipple or an appropriate setscrew is fixed at the lower free end while maintaining the necessary idle path.
In the three examples of mounting that have been given in FIGS. 1 to 3 for the anti-theft device according to the invention, it is also possible to replace the flexible connecting cable with a linkage system. The lower end of this linkage can be expediently led through a stop bracket secured to a wheel carrier, while making allowance for the idle path which can be adjusted to the required length by means of a setscrew. In the case of a vehicle with a rigid rear axle (FIG. 1), this stop bracket can be attached at the central area of the rear axle, and preferably to the housing of the differential gearing, while in the case of a vehicle having individually suspended wheels as in FIGS. 2 and 3 it can be affixed to the traverse link (see FIG. 2) or at the lower end of the shock absorber (see FIG. 3). In this case it is expedient to provide the upper end of the linkage with a tension spring connection, which in turn is attached to the switch member on the electric switch mounted on the automobile body.
In conclusion, FIG. 4 depicts another embodiment of the invention having a connecting member in the form of a linkage system, this being an example of an assembly in the case of a vehicle having a rigid rear axle.
The anti-theft appliance 30 according to the invention as shown in this embodiment comprises a pull switch 32 that is secured to the automobile body 31, a rigid linkage system 33 and a flat spring 34, which at the same time constitutes the resilient member of the anti-theft device 30 as well as the arm of a stop bracket 35 guiding the linkage rod 33. The stop bracket 35 is affixed in the central portion of the rigid rear axle 36, and preferably to the housing of the differential gearing. The upper end of the linkage 33 is connected to the switching member 32a of the pull switch 32, while the lower end of the linkage 33 is inserted into a hole in the flat spring 34 and carries a setscrew 38. This setscrew 38 is also fixed in a position such that an adequate idle path (dead stroke) is ensured for the vehicle during normal operation.
If, in the case of the practical embodiment illustrated in FIG. 4, the distance between the automobile body 31 and the rear axle 36 is increased to a degree that goes beyond that encountered during normal operation, then the linkage 33 actuates the pull switch 32 and its corresponding alarm after travelling along the aforesaid idle path. A further increase in the distance between the vehicle body and the rear axle is then flexibly taken up by the flat spring 34, which is deformed in the direction of the arrow 39, as indicated in dotted lines. With this special embodiment it should be ensured that the leaf spring 34 is designed sufficiently long to be able to take up any increases in the distance between the vehicle body and the rear axle that may occur.
The linkage 33 described in the last-mentioned embodiment of the invention could, of course, be replaced by a simple cable. Although it is generally preferred that an electrical pull switch be used on account of the more favourable arrangement, an electrical pressure switch can also be used to advantage in some cases.
With the anti-theft device according to the present invention it is also possible to combine the connecting member with the resilient member, with the resilient member incorporating several tension springs exhibiting differing tensile force. A tension spring having comparatively little tensile force can be employed, for example, to take up the idle path (dead motion) between the automobile body or chassis and the wheel carrier, while at least one other tension spring serves to trip the electric switch and takes up an additional increase in the intervening distance.
In the case of the additional practical example illustrated diagrammatically in FIG. 5, the anti-theft device 40 incorporates a switch 41 in the form of a reed relay which is tripped by a movable magnet 42. The switch 41 is secured to the chassis or the automobile body 43 by means of a suitable mounting 44, while the movable actuating magnet 42 is attached to the axle tube 46 or a rigid rear axle by means of a holder 45.
When the vehicle is in its normal position, the switch 41 and actuating magnet 42 are relatively positioned approximately in the manner as illustrated in FIG. 5. Switch 41, for example, is kept open by magnetic force. Because the actuating magnet 42 is positioned laterally of the switch 41, sufficient dead motion is allowed for the vertical movements of the actuating magnet 42 which occur when the vehicle is travelling.
However, if the distance between the automobile body 43 and the axle tube 46 is increased to an unusual extent; for example, after the body has been raised for towing or in order to remove a wheel, then the actuating magnet 42 passes so far downwards with respect to switch 41 that this switch is tripped and closed. The alarm is then released.
Switch 41 can be designed as a normally closed or normally open switch. | An anti-theft device for a vehicle that is movably mounted on wheel carriers, for securing the vehicle against theft of wheels and against unauthorized towing, which comprises an alarm switch and an actuating member, one of which is mounted in a fixed position relative to the vehicle, and the other of which is mounted to move with one of the wheel carriers. The actuating member is arranged to actuate the switch, and has sufficient lost motion relative to the switch to accommodate normal relative movement of the vehicle and the wheel carrier during travel of the vehicle. The switch is actuated by relative motion of the switch and actuating member in excess of lost motion when the vehicle is raised for towing or for removal of a wheel. | 1 |
This invention relates to apparatus for molding foam bodies from expanded polymeric beads using the steam-fusion technique, and more particularly to such apparatus having a shortened cycle time.
BACKGROUND OF THE INVENTION
The molding of pre-expanded polymeric beads (e.g., expanded polystyrene--a.k.a. EPS) into foamed articles such as drinking cups, "lost-foam" molding patterns, Christmas decorations, etc., is a well known process wherein partially pre-expanded beads are blown into a mold, and therein subjected to steam to complete their expansion and fuse them together into a unitary mass. Expandable polystyrene is commercially available in the form of relatively small (e.g., 0.25 mm diameter, 40 lbs./ft. 3 density) white beads. The beads are formed of a suitable grade of polystyrene homopolymer for the intended molding purpose. Distributed throughout each polystyrene bead is an amount, usually about 5.5 to 6.5 percent by weight, of a suitable vaporizable expanding agent such as the hydrocarbon pentane. A portion of the pentane is probably dissolved in the polymer matrix of the bead, but a major portion of the pentane is distributed in microcavities throughout the polystyrene bead.
Before articles can be molded from the beads, the beads are subjected to a pre-expansion operation in which they are expanded and reduced in density by heating. Pre-expansion equipment is readily available commercially. In one pre-expansion process, a group of the beads is conveyed into a closed cavity where the beads are contacted with saturated steam at low superatmospheric pressure. The steam heat produces an expansion of the beads so that their diameter is increased, e.g., about fourfold, and some of the expanding agent, the pentane, is lost. The beads are discharged into a fluidized bed where room temperature air fluidizes, dries and cools the beads. At the conclusion of the pre-expansion step, the density of the beads is typically in the range of 1 to 1.6 lbs./ft. 3 , and the content of the pentane at this stage is suitably about four to five percent by weight of the bead. The diameter of the bead is now about 1 mm. The expanded bead has a cellular structure and is close to the size at which it can be suitably molded into a finished article, e.g., a "lost foam" foundry pattern. In another version of the pre-expansion process, the beads are drawn into a space which is evacuated, where they are heated at about 200° F. in the vacuum to accommodate the expansion of the beads. The expansion of the beads is arrested by the addition of water to the system. The water flashes in the vacuum, cooling the beads prior to discharge from the vacuum vessel. After this stage, the expanded beads are typically screened to remove any of the raw beads that fail to undergo the expansion process or any clumps of beads that are stuck together.
Molding of the beads into a finished article follows. The mold used to shape the foamed article has perforate walls defining a mold cavity and through which the steam enters the mold cavity. The mold is sandwiched between a pair of steam chests for applying the steam to the mold. The molds typically comprise separable mold segments/inserts inserted in and clamped, or otherwise affixed, to the steam chests. The use of mold inserts permits a single steam chest to be used with a variety of different molds for making a variety of different articles.
In the "flow-through" steaming technique, steam is introduced, through one of the mold segments on one side of the mold cavity, passes through the bed of beads in the mold cavity, and exits the mold cavity through the other mold segment on the opposite side of the mold cavity. An alternative steaming technique is known as "autoclaving" which involves pressurizing both steam chests at the same time so as to soak the beads in the steam for a sufficient duration to expand and fuse the beads together. Some practitioners use a combination of both the flow-through and the autoclaving techniques to insure rapid, uniform heating and bonding of the beads.
Following steaming, the molded article is cooled by spraying water onto the backside of the mold segments and/or by the application of vacuum to the steam chests until the expansion of the beads is arrested. In the case of EPS, steaming occurs at about 240° F. Thereafter, the mold is cooled to about 140° F. before bead expansion is arrested. The precise amount of time needed for steaming and cooling will vary with the size and complexity of the particular article being molded and the uninsulated mold mass. The mold is then opened, and the molded article ejected, e.g., by means of compressed air, mechanical ejection pins or the like. The mold is then closed and the cycle repeated.
In order to increase productivity of the apparatus, it is necessary to shorten the time required to complete the aforesaid operational cycle. One impediment to shortening the cycle time is the time required to heat-up and cool-down the mold segments, steam chest, and plumbing attachments thereto. In this regard, while the beads are being steamed, the surrounding metal forming the molding apparatus heats up and must then be cooled by as much as 100° F. or more before ejection of the article from the mold can occur. Another impediment to shortening the cycle time is the time required to build-up steam pressure to flow through the beads in the mold during the steaming cycle as well as to build-up a vacuum to cool down the mold and molded article.
Heretofore, the cycle time as well as the energy requirements of the molding apparatus has been reduced by: (1) reducing the mass of the systems components, (2) making the molds and steam chests from aluminum which has a relatively low specific heat for quicker heating and cooling with relatively low energy consumption; and (3) lining the steam chest with an insulating material to reduce the heat transfer from the steam cavity to the metal (e.g., aluminum) forming the steam chest. While these techniques have improved the cycle time and reduced the required energy load, further cycle-time reductions are desirable.
Accordingly, it is an object of the present invention to further reduce the operational cycle time of an expanded polymer bead molding apparatus by reducing the amount of heat conducted between the steam chests and the mold segments attached thereto.
This and other objects and advantages of the present invention will become more readily apparent from the description thereof which follows.
BRIEF DESCRIPTION OF THE INVENTION
I have found that the overall cycle time of an expanded polymer bead molding apparatus can be shortened by substantially preventing the temperature of the mold segments from rising after they have been cooled incident to conductive thermal feedback from the steam chest. Conductive thermal feedback from the steam chest can cause the mold temperature to elevate unacceptably and accordingly delay commencement of the next cycle until the mold can cool adequately. In this regard, it is important that following ejection of the molded article, and prior to commencing the next molding cycle, that the surface of the mold be kept at a sufficiently low temperature that the polymeric beads blown into the mold cavity do not soften or otherwise become significantly preheated upon contact with the mold surface. If the mold wall is too hot and the beads soften and/or fuse upon contact therewith, a low porosity skin can form on the surface of the bed of beads which inhibits steam flow into the center of the bed. To prevent the mold from undesirably reheating after cooling and before filling with beads, the invention comprehends apparatus for the molding and steam-fusion of expanded polymeric particles (e.g., EPS) which includes provisions to substantially reduce conductive thermal feedback into the mold segments from the metal forming steam chest. The apparatus includes first and second mold segments each mounted to the mouth of a steam chest. The mold segments each comprises a perforate wall defining a molding cavity which conforms to the shape of the articles being formed. The steam chest confronts the backside of the perforate walls (i.e., opposite its molding surface) and defines a steam cavity adjacent the perforate wall of its associated mold segment. In accordance with the present invention, a layer of thermal insulation is provided at the junction between the mold segment and the steam chest to reduce conductive heat transfer therebetween. By insulating the mold segments from the steam chest, less heat is conducted from the mold segment into the steam chest during steaming, and vice versa (i.e., less heat is conducted back from the steam chest back into the mold segment after it has been cooled sufficiently). In this regard once cooled and without conductive thermal feedback from the steam chest, the mold segment will remain sufficiently cool that the mold can be quickly re-closed following ejection of the previously formed article and a new molding cycle commenced sooner than would be possible without the insulation.
The benefits of the present invention are further enhanced by making the mold segments and the steam chest from aluminum, and by lining the inside surfaces of the steam chests defining the steam cavities with a layer of thermal insulation to reduce the amount of heat transferred directly into the steam chest from the steam in the steam cavity. Both contribute to keeping the steam chest cooler and hence less able to transmit heat conductivity into the mold segment. An important additional benefit derived from applicant's thermal barrier in combination with lining of the steam chests is that less condensate is formed resulting in a drier mold and higher quality drier foamed article. A still further benefit is reduction in the amount of steam and cooling water needed as well as reduced energy requirements to operate the apparatus. Finally, additional cycle time reduction may be obtained by minimizing the volume of the steam chest and locating the control valves for the various piping requirements of the apparatus as close to the steam chest as possible to minimize the time required to build up steam pressure during the steaming cycle and to build up vacuum during a vacuum cooling cycle.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will better be understood when considered in the light of the following detailed description of a specific embodiment thereof which is given hereafter in conjunction with the several figures in which:
FIG. 1 is a sectioned, view of a molding apparatus in accordance with the present invention shown in the mold-closed position;
FIG. 2 is a view in the direction 2--2 of FIG. 1; and
FIG. 3 is an exploded view of FIG. 1 shown in the mold-open position.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The Figures show molding apparatus 2 for steam-fusing expanded polymeric beads into a foamed article 4. The apparatus 2 includes first and second steam chests 6 and 8 having first and second mold segments 10 and 12 respectively anchored to the mouths thereof by retainer clips 14 secured by bolts 16. The mold segments 10 and 12 comprise aluminum and include perforate walls 18 and 20 respectively which, in the mold-closed position, define a molding cavity 22 into which the polymeric beads are blown in accordance with known prior art techniques. The openings in the perforate walls are smaller than the smallest beads so as to prevent escape of the beads therethrough into the steam chests. The mold segments 10 and 12 include peripheral walls 24 and 26 respectively, as well as intersecting ribs 28, 30, 32 and 34, for stiffening of the mold segments 10 and 12. Mounting flanges 36 and 38 project outwardly from the mold segments 10 and 12 respectively for anchoring the mold segments 10 and 12 to the respective mold chests 6 and 8. The mounting flanges 36 and 38 have sealing faces 40 and 42 thereon which confront mounting surfaces 44 and 46 on the steam chests 6 and 8 respectively.
The steam chests 6 and 8 each comprise a backwall 48 and 50 respectively which lies opposite the perforate walls 18 and 20 respectively. Preferably the backwalls 48 and 50 will be closely spaced from the mold inserts and conform substantially to the shape thereof to minimize the volume of the mold chest and consequently minimize steam pressure and cooling vacuum build-up time. Sidewalls 52 and 54 extend between the backwalls 48 and 50 and the mounting flanges 36 and 38 respectively, and define steam cavities 56 and 58 in the respective steam chests 6 and 8. Steam lines 60 and 62 screw into the backwalls 48 and 50 to admit steam into the steam cavities 56 and 58 respectively. Perforated baffle 65 positioned at the outlets from the steam lines 60 and 62 serve to deflect and diffuse the incoming steam throughout the steam cavities 56 and 58. Cooling water lines 64 and 66 provide water to spray nozzles 68 and 70 which spraying cooling water onto the backside of the perforate walls 18 during the cooling phase of the molding cycle as is common practice in the field. Similarly, cooling water lines 72 and 74 provide water to spray nozzles 76 and 78 for spraying cooling water onto the backside of the perforate wall 20 during the cooling cycle. Alternatively, cooling may be effected by drawing a vacuum in either or both steam chests. Air lines 80, 82, 84 and 86 enter the respective steam cavities 56 and 58 for pressurizing such cavities, after cooling, to eject the article 4 from the cavity 22 and to otherwise dry the mold cavity as much as possible prior to commencement of the next molding cycle. Dry molds produce better moldings as no water becomes entrapped in the surface of the foamed article to mar its finish.
The steam chests illustrated are each of the one-piece design--that is to say the backwall and sidewalls are one piece and the mold segments mount directly thereto. The invention, however, is not limited to such designs, but rather is applicable to other steam chest designs commonly found in the industry. Hence, for example, the invention is equally applicable to steam chest designs wherein portions (i.e., rails) of the press' platens form the sidewalls of the steam chest, a separate backplate carrying the utilities is secured to one side of the rails and a mold mounting plate is secured to the other side of the rail with an opening therein for receiving the mold segments. In this multi-piece design in addition to insulating the mold segment from the mold mounting plate according to the present invention, it is desirable to also provide insulation between the mold-mounting plate and the platen rail to further reduce conductive heat transfer therebetween. All such one-piece and multi-piece designs are considered to be "steam chests" in the context of the present invention. Moreover, the invention is likewise applicable to designs where the mold segment is mounted to a mold mounting plate and the steam chest mounted directly to the mold segment. In such a design it is desirable to also provide insulation between the mold-mounting plate and the mold segment in addition to providing insulation between the mold segment and the steam chest.
In accordance with the present invention, a layer of relatively rigid, thermal insulation 88 and 90 is positioned between the sealing faces 40 and 42 and mounting surfaces 44 and 46 respectively to prevent any substantial conduction of heat between the mold segments 18 and 20 and the steam chests 6 and 8 to which they are attached. Such insulation may comprise virtually any relatively rigid, high temperature insulating material compatible with steam. Examples of such materials include polytetrafluoroethylene gaskets having a thickness of about 0.030 inches, ceramic fiber gaskets (i.e., TRANSITE R ) having a thickness of about 0.25 inches, or Kaowool #822 millboard having a thickness of about 1/4 inches (supplied by K-Industries Corp.). Other acceptable insulating materials include polyamide, polyimide and high durometer silicone rubbers. In addition to the insulation 88 and 90 between the mold segments 18 and 20 and the steam chests 6 and 8, the interior surfaces of the steam chests 6 and 8 defining the steam cavities 56 and 58 are lined with a thermal insulating material 92 and 94 for reducing the amount of heat transmitted directly into the walls of the steam chests 6 and 8 by the steam. Not only is such heat transmission reduced, but the lining 92 and 94 also serves to reduce the amount of condensate that would otherwise be formed in the steam cavities 56 and 58 and on the molding surface, thereby resulting in a drier molded article and drier tooling requiring less drying time before the next cycle begins. The insulating linings 92 and 94 will preferably comprise heat-cured silicone rubber cast-in-place to a thickness of about 3/8 inches. One such material comprises type "E" silicone mold-making material with matching catalyst supplied by Tool Chemical Co., Inc. So insulating the steam chests supplements the benefits of the mold-to-chest insulation of the present invention by keeping the steam chests cooler than they would otherwise be and thereby reducing their ability to conductively elevate the temperature of the mold segments. Finally, a layer of insulation 89 is provided between the retainer clips 14 and the mounting flanges 36, 38 to minimize any heat transfer therebetween, and hence back into the sidewalls 52, 54 of the steam chests 6 and 8. The insulation 89 will preferably also be formed from a low friction material such as polytetrafluoroethylene or the like to permit ready sliding of the flanges thereon as mold segment expands and contracts at different stages of the thermal cycle of the apparatus.
The mold segments 18 and 20, as well as the steam chests 6 and 8, will preferably be formed from aluminum which has a low specific heat and accordingly will heat-up and cool-down more quickly than steel while requiring less energy to effect such heating/cooling. Low specific heat materials supplement the insulation of the present invention by making it easier to remove heat from the steam chest walls, and hence reduce the possibility of its flowing into, and raising the temperature of, the mold segments.
Operationally, the apparatus of the present invention will be utilized in the same manner as other similar apparatus for molding expanded polymeric beads has been used heretofore. In this regard, the mold segments 18 and 20 are brought together in the mold-closed position shown in FIG. 1. Partially pre-expanded polymeric beads having a density of about 1.5 lbs./ft. 3 are then blown into the mold cavity 22 in a conventional manner so as to completely fill the cavity 22 and slightly densify the mass of beads to about 1.6 lbs./ft. 3 . Thereafter, live steam is introduced into one of the steam cavities, e.g., 56, from whence it passes through the perforate wall 18, through the bed of beads 4 and exits the perforate wall 20 into the other steam cavity 58. Thereafter, the direction of steam flow is reversed such that the steam enters the steam cavity 58, passes through the perforate wall 20, the bead bed 4 and perforate wall 18 into the steam cavity 56. Alternatively, steam may be simultaneously introduced into both of the steam chests 6 and 8 so as to soak the beads in the steam, and thereby fuse them together according to the so-called "autoclave" technique rather than the "flow-through" steaming technique previously described. Some articles, owing to their shape and design, may require a combination of "flow-through" and "autoclave" steaming to effect uniform heating in the shortest possible time. After the beads have been steamed for a sufficient time to fuse them together, the steam is shut off and cold water sprayed from the nozzles 68,70,76 and 78 against the backsides of the perforate walls 18 and 20 to cool the molded article. Alternatively, the steam chests could be evacuated to effect cooling. Combinations of vacuum and water-spray cooling may also be used. One such combination found to be effective is to apply vacuum to one steam chest while water spraying the other. When the article has cooled sufficiently that no further expansion of the beads occurs (e.g., to about 140° F., cooling is stopped, the mold opened and compressed air introduced into the respectively steam cavities for ejecting the molded article from the mold cavity 22. The air also serves to dry the mold and ready it for the next cycle.
While the invention has been described primarily in terms of a specific embodiment thereof it is not intended to be limited thereto, but rather only to the extent set forth hereafter in the claims which follow. | Apparatus for molding expanded polymer beads by the steam-fusion technique including mold segments having perforate walls, steam chests confronting the mold segments, and thermal insulation located at the junction between the mold segments and the steam chests to reduce conductive heat transfer therebetween. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of sorting copy sheets and a sorter (automatic page arrangement device) which is capable of automatically classifying and arranging copied sheets when a plurality of sheets are copied from an original document, and, particularly, to a sorter for use in a copying machine which is intended to increase the number of copy sheets which can be accommodated in trays that are vertically arranged in multiple stages at predetermined intervals.
2. Description of the Prior Art
FIGS. 1A and 1B illustrate a conventional sorter which is used in a copying machine for automatically classifying and arranging a plurality of copy sheets. The copying machine-sorter arrangement of FIGS. 1A and 1B comprises a document feeding device 1 for automatically feeding an original document; a platen 2 for receiving the original document which is fed from the document feeding device in a predetermined position; an optical system 3 for projecting a picture image of the document which has been placed on the platen 2 onto an exposing station B; a photo-sensitive drum 4 which is capable of turning along its circumference past a charging station A, the above-mentioned exposing station B, a developing station C, a transferring station D and a cleaning station E (including an electrical discharger); a copy paper feeder 5; a fixing station F for fixing the picture image which has been transferred onto a sheet of copy paper; a discharge belt 6 for discharging a copied sheet into a sorter 20 with the help of discharge rollers 7; an actuating panel 8 for issuing commands for various operations; and the sorter 20 which is provided at the side of a copying machine 10. The sorter 20 comprises a first endless belt 21 for conveying a copy sheet which has been discharged through the discharge rollers 7; a second endless belt 23 for conveying a copy sheet to an indexer 22 in cooperation with the first endless belt 21; and the above-mentioned indexer 22 for classifying and delivering copy sheets to the respective multi-stage trays 24.
The operation of the conventional copying machiner-sorter arrangement will now be described. Each of the copy sheets which has been successively discharged from the copying machine 10 is deflected by the second endless belt 23 and guided by the indexer 22 so that it is introduced into the respective trays 24, one after another, successively, from the upper tray to the lower trays.
However, in this sorter 20, each of the sorted copy sheets 25, which is deflected by the second endless belt 23, guided by the indexer 22 and then received in the tray 24, is curved downward, as shown in FIG. 1C, because the sheet is supplied with uneven stress in the direction of its thickness when it is deflected. If the respective copy sheets received in the trays 24 are curved downward, the front end of a further copy sheet which next enters any one of the trays 24 will hit upon the end 25a of a previously sorted copy sheet 25 since the end 25a projects upward beyond the height of the tray 24. Accordingly, paper jams occur in the indexer 22. Even if no paper jams occur, because the end 25a projects upward, it is apparent that the copy sheet capacity of the trays 24 is reduced.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a sorter in which a curve-producing mechanism is provided in an indexer for making flat or upwardly curved ends of copy sheets curve downward as they are introduced into a tray, thereby increasing the number of sheets which can be received in the tray, as well as preventing the occurrence of paper jams.
The sorter of the present invention includes a plurality of trays which are vertically arranged in multiple stages at predetermined intervals, and means for conveying copy sheets into said plurality of trays and upwardly curving said copy sheets so that ends of said upwardly curved copy sheets curve downward with respect to a bottom surface of the trays. The conveying and curving means includes a conveyor which comprises an endless belt and a film sheet which convey the copy sheets to an indexer. The indexer then curves the sheets and conveys the curved sheets into the plurality of trays.
The sorter of the present invention further includes a plurality of flexible guide members which are provided at inlet portions of the multi-stage trays. These guide members cause a copy sheet which has been discharged from the indexer to advance accurately along a bottom surface of an upper tray, thus increasing the number of copy sheets which can be received in the trays without increasing an interval H between adjacent trays.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is an explanatory view showing a conventional copying machine and a sorter therefor;
FIG. 1B is an enlarged, partial view of the sorter of FIG. 1A;
FIG. 1C is a schematic view showing the state of copy sheets as they are received in a tray of the sorter;
FIG. 2A is an explanatory view showing an embodiment of the present invention;
FIG. 2B is an enlarged partial view of the sorter of FIG. 2A; and
FIG. 3 is an enlarged partial view of a further embodiment of the sorter of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 2A illustrates a copying machine-sorter arrangement of the present invention, and FIG. 2B is an enlarged, partial view of the sorter shown in FIG. 2A. Components illustrated in FIGS. 2A and 2B which are identical to components illustrated in FIGS. 1A and 1B are identified by the same reference numerals, and, therefore, an explanation of the identical components will not be repeated. In the arrangement of FIGS. 2A and 2B, a copy sheet which has passed the fixing station E is discharged through the discharge rollers 7 by a discharge belt 6a which is provided at the lower portion of the copying machine 10, and the copy sheet is then introduced into a lower portion of the sorter 20.
The sorter 20, according to the present invention, comprises multi-stage trays 24 which are vertically arranged at predetermined intervals; an endless belt 26 which is vertically disposed along the multi-stage trays 24; a film sheet 27 for conveying a copy sheet 25 to the trays 24 in cooperation with the endless belt 26; a film sheet fixing device 29 for fixing an end of the film sheet 27; an indexer 22a which is provided with rollers 30, 31, 32 and 33 for successively delivering copy sheets to the trays from a lower tray to an upper tray; a discharging brush 34 for eliminating static electricity from each copy sheet 25; and a roller 28 for winding up/off the film sheet 27.
The operation of the sorter of the present invention will now be described. A copy sheet 25 which is introduced into the sorter 20 through the lower portion of the sorter is inserted between the endless belt 26 and the film sheet 27 from the direction indicated by an arrow A. It is then conveyed upward with the upward movement of the endless belt 26 so that it is received into one of the trays 24. The copy sheet 25 is then curved upward by the endless belt 26 and the roller 30, as shown in FIG. 2B.
The upward curve of the copy sheet 25 may be formed by the rollers 31 and 32; however, the upward curve is formed mainly by the endless belt 26 and the roller 30 in the embodiment shown in FIG. 2B. When it is desired to form the upward curve principally by using the rollers 31 and 32, the diameter of the roller 31 should be made smaller than that of the roller 32 because the amount of upward curve of the copy sheet increases as the ratio between these diameters increases. The amount of upward curve of the copy sheets also increases as the diameter of the roller 30 is reduced, assuming, of course, that other variables are maintained constant. Thus, according to the embodiment of the present invention, the extent of the upward curve of the copy sheets may be controlled as desired by properly selecting the diameter of the roller 30 and the diameter ratio between the rollers 32 and 31.
In the sorter of FIGS. 2A and 2B, in order to increase the number of copy sheets which can be received in the trays by utilizing a maximum tray interval H, it is desirable to cause a copy sheet to advance along the bottom surface of an adjacent upper tray. To this end, it is necessary to stop the copy sheet discharge outlet of the indexer 22 at a vertical position which is adjacent to the forward end portion of the bottom of each tray 24. From the viewpoint of mechanical accuracy, however, it is difficult to accurately stop the indexer 22 with respect to each of the multi-stage trays 24, and, for this reason, the number of copy sheets which can be received in the trays 24 is reduced. To increase the number of copy sheets which can be received in the trays 24 to an acceptable level, the tray interval H must be increased.
According to the present invention, a flexible guide member 40, shown in FIG. 3, is provided at an inlet portion of each of the multi-stage trays 24. This flexible guide member causes a copy sheet which has been discharged from an indexer to advance accurately along a bottom surface of an upper tray to thereby increase the number of copy sheets received in the trays without increasing the interval H between adjacent trays.
The guide member 40 is made of a flexible material and is provided at the forward end of each of the trays 24 so that a copy sheet which has been discharged from the indexer 22 is positively pressed against the bottom surface of the upper tray 24. The flexible guide member 40 may be any type, such as a brush-like guide member, a film-like guide member, etc., as long as it is flexible and able to restrict the advancing direction of the copy sheet. The flexible guide member 40 may be placed at any position, as long as it is disposed at a forward end portion of the tray 24 and in the path of the copy sheets at the inlet of the tray.
The operation of the sorter described above will now be described. A copy sheet 25 is discharged from the copy machine 10 and is introduced into the sorter 20 through the lower portion of the sorter. The sheet is then inserted between the endless belt 26 and the film sheet 27 from the direction indicated by an arrow A and conveyed upward with the upward movement of the endless belt 26 so that it is received into one of the trays 24. At this time, the copy sheet 25 is guided to the inlet portion of the tray 24 while it is curved upward by the endless belt 26 and the roller 30. It is then introduced into the tray 24 while being pressed against the bottom surface 23 of the upper tray by the flexible guide member 40.
As described above, in the sorter according to the present invention, a flexible guide member is provided at the inlet portion of each of the multi-stage trays to cause a copy sheet which has been discharged from an indexer to advance along the bottom surface of the upper tray. Thus, the number of copy sheets which can be received in the multi-stage trays can be increased without increasing the interval between adjacent multi-stage trays. | A sorter for sorting copy sheets made from an original by a copying machine includes a plurality of trays which are vertically aligned in multiple stages at predetermined intervals, an indexer for delivering the copy sheets to the trays, a conveyor for conveying the copy sheets to the indexer, and a flexible guide member which is provided at the inlet portion of each of the trays for guiding each copy sheet from the indexer into one of the trays along the bottom surface of an adjacent upper tray. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 61/752,902, filed Jan. 15, 2013, the entire contents of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the delivery of intraluminal therapy, such as treatment of vascular lesions. In some preferred embodiments, apparatus and methods are provided for treating calcified lesions in peripheral vasculature to prevent arterial dissections, atheroembolizations, perforations and restenosis following an angioplasty and/or stent procedures.
BACKGROUND OF THE INVENTION
[0003] A need exists for simple and efficacious delivery of intraluminal therapies. Such therapies range from delivery of anti-mitotic agents to reduce the restenosis following angioplasty, to delivery of angiogenic factors, delivery of therapeutic agents to reduce intravascular thrombus, delivery of therapeutic agents to improve arterial compliance through the structural alteration of intimal and medial calcification, delivery of fluent cross-linkable materials that may be hardened in situ to provide support for a vessel (e.g., as is described in U.S. Pat. No. 5,749,915 to Slepian, the entire contents of which is incorporated herein by reference), or to exclude or reduce the development of a nascent vascular aneurysms. Previously-known methods and apparatus typically involve use of multiple catheters and devices to accomplish such treatments, which adds time, cost and complexity, increased exposure to ionizing radiation and risk of morbidity to previously-known therapeutic procedures. It therefore would be advantageous to provide methods and apparatus that simplify such previously-known procedures, reduce time, cost and complexity, and improve acute procedural success and long-term patient outcomes.
[0004] Percutaneous transluminal angioplasty of coronary and peripheral arteries (PTCA and PTA, respectively) are widely accepted as the revascularization procedures of choice in patients with ischemic cardiovascular syndromes (i.e., chronic and acute coronary ischemic syndromes and chronic limb ischemia, including claudication and critical limb ischemia). However, use of these conventional percutaneous treatments has an important limitation: restenosis—the exuberant proliferation of smooth muscle cells that grow to re-occlude the treated vessel segment, causing the reoccurrence of symptoms and necessitating potential reintervention.
[0005] Various adjuncts to angioplasty seek to reduce restenosis; these include atherectomy (e.g., extractional, rotational, orbital, laser), bare metal and bare nitinol stents and, more recently, drug eluting stents (DES). The latter technology has been demonstrated to significantly reduce coronary artery restenosis when compared to angioplasty or bare metal stents, however, its use requires chronic administration of adjunct pharmacotherapies to prevent subacute stent thrombosis, the sudden and life threatening clotting of the stent. Unfortunately, not all patients tolerate these essential pharmacotherapies due to impaired tolerance, allergic reactions or contraindication to such drug use (i.e., history of previous bleeding) and/or their associated expense.
[0006] In peripheral arteries, the use of bare nitinol stents have been shown to be superior to balloon angioplasty alone and has emerged as the “default” percutaneous strategy for the treatment of chronic limb ischemic syndromes, particularly in complex disease patterns involving the femoropopliteal artery. Despite their common use, nitinol stents present a substantial concern of in-stent restenosis (ISR), the proliferation of smooth muscle cells within the stent leading to occlusion of the stent lumen. ISR poses additional risk to the patient by necessitating additional vessel reintervention to re-establish vessel blood flow.
[0007] Currently, there is no established treatment for the vexing problem of ISR, which occurs in about 30%-50% of nitinol stents over a 1-2 year follow-up period, a rate that may increase depending on the patient demographic (i.e., diabetics) and vessel morphology (small vessel diameter, length of diseased vessel treated and the presence of vessel wall calcification). Importantly, there are presently no recognized effective and durable therapies to treat ISR; as such, emerging technologies focus on preventing restenosis through the application of anti-restenotic therapeutic agents into the diseased vessel wall layers via the vessel's luminal surface.
[0008] Anti-proliferative drugs (i.e., paclitaxel, sirolimus) retard smooth muscle migration into an area of angioplasty-induced vessel injury and reduce restenosis. Drug delivery catheters have been designed to facilitate the delivery of such therapeutic agents into the vessel wall via its luminal surface. For example, U.S. Pat. No. 5,112,305 to Barath et al. describes a catheter having a single balloon including a multiplicity of protrusions. The protrusions include apertures that enable a drug to be introduced into the balloon and infused through the apertures into the vessel wall. U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat. No. 6,733,474 to Kusleika each describe a catheter having an impermeable inner balloon and an outer balloon having pores through which a drug may be infused into the vessel wall. U.S. Pat. No. 5,681,281 to Vigil et al. similarly shows a catheter having an impermeable inner balloon and an outer balloon having a multiplicity of apertured protrusions for injecting a drug into a vessel wall. U.S. Pat. No. 5,213,576 to Abiuso et al. describes a catheter having nested balloons with offset apertures, to reduce jetting and provide more uniform distribution of a drug infused into a vessel through the catheter.
[0009] All of the previously-known systems described in the foregoing patents have had drawbacks that have prevented commercialization of those designs. For example, catheters having a single apertured balloon, such as described in the above patent to Shaffer et al., cannot provide uniform distribution of a drug or other material around the circumference or along the axis of the vessel due to jetting through the apertures. Catheters with apertured protrusions, such as described in the above patents to Barath et al. and Vigil et al, are difficult to manufacture and are believed to be prone to having the apertures clogged with debris when the balloon is embedded into the plaque lining the vessel wall. Also, the use of excessively high pressures within the balloon to clear the apertured protrusions may lead to excessively non-uniform drug infusion and potential vessel dissection.
[0010] On the other hand, in a catheter such as described in Abiuso et al., nested balloons having offset apertures cause the inner balloon to serve as a baffle that reduces jetting through the apertures in the outer balloon, thereby providing a much more uniform infusion through the outer balloon. However, as the Abiuso catheter lacks an inner impermeable balloon to move the drug infusing layers into apposition with the vessel wall, there is the potential for much of the drug to be washed into systemic circulation during deployment of the nested balloons. Moreover, because Abiuso lacks a dilatation balloon, it has no ability to disrupt calcified plaque, and accordingly, must be used with a separate dilatation balloon requiring additional catheter exchanges, contrast and radiation exposure and vessel irritation.
[0011] Recent clinical data has identified a variety of atherosclerotic plaque morphologies in coronary and peripheral vessels, which prevent the effective penetration of drug therapies into the various vessel layers. Specifically, the presence of dense fibro-calcific and calcified intimal and medial plaques, are associated with peri-procedural failure (due to vessel recoil and/or vessel wall dissection) and subsequent restenosis as these plaques are effective barriers to the penetration and uptake of therapeutic drugs delivered luminally. As such, the instructions for use (IFU) of many current approved devices and inclusion/exclusion angiographic criteria of on-going regulatory trial designs specifically exclude patients from device treatment with angiographic evidence of severely calcified vessels. Given the large and growing patient population with diabetes and chronic kidney disease and conditions associated with heavy vessel wall calcification, this represents a substantial patient population in which emerging therapies may be ineffective.
[0012] In view of the many drawbacks of previously-known systems and methods, it would be desirable to provide apparatus and methods that overcome such drawbacks. In particular, it would be desirable to provide devices suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, which reduce the number of equipment exchanges needed to both disrupt intravascular plaque and to infuse an anti-stenotic agent into a vessel wall to reduce occurrence of restenosis.
[0013] It further would be desirable to provide devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, that permit a clinician to dilate a vessel to disrupt calcified plaque and then to infuse an anti-mitotic agent into the vessel wall through the disrupted plaque.
[0014] It still further would be desirable to provide devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, wherein a balloon of the catheter may include a multiplicity of apertures, such that the apertures are resistant to clogging during use of the balloon to dilate the vessel and disrupt the plaque.
[0015] Previously known systems also describe the use of various energy sources to deliver energy to fluent material infused into a vessel to pave a vessel or create an in situ stent. Such systems are described, for example, in U.S. Pat. No. 5,662,712 to Pathak et al. and U.S. Pat. No. 5,899,917 to Edwards et al. A drawback of these systems, however, is that each forms a new mechanical structure disposed within the vessel that is separate and distinct from the vessel wall. Because the arteries, and to a lesser extent, the veins, expand and contract during each cardiac cycle due to pressure pulsations, such attempts to form a rigid mechanical support that is not integrated with the vessel wall are inherently problematic.
[0016] It therefore further would be desirable to use existing vasculature structure to enhance or perpetuate the anti-mitotic effect of drugs infused via an intravascular route. In particular, it would be desirable to employ application of energy, e.g., such as ultraviolet (UV) light energy, monopolar or bipolar generated radiofrequency (RF) generated heat, or focused or unfocused ultrasonic energy, to potentiate the delivery and effectiveness of anti-mitotic agents when administered from the luminal surface into the media and adventitial layers in the presence of vascular calcification.
SUMMARY OF THE INVENTION
[0017] In view of the aforementioned drawbacks of previously-known systems and methods, the present invention provides apparatus and methods that reduce the number of equipment exchanges needed to both disrupt intravascular plaque and to infuse therapeutic agents, such as anti-proliferative drugs or regenerative therapy agents, into a vessel wall to reduce occurrence of restenosis and/or promote angiogenesis, or to exclude a weakened vessel portion or reduce enlargement of a nascent aneurysm.
[0018] The present invention further provides devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, that permit a clinician to dilate a vessel to disrupt calcified plaque and then to infuse therapeutic agents into the vessel wall through the disrupted plaque without the need to exchange catheters.
[0019] In accordance with another aspect of the present invention, a balloon catheter is provided including an outer balloon having a multiplicity of apertures for infusing one or more therapeutic agents into the vessel wall, an intermediate balloon having a multiplicity of apertures offset from the apertures of outer balloon to serve as a baffle that reduces jetting and promotes uniform distribution of therapeutic agents through the outer balloon, and an impermeable inner balloon disposed within the intermediate balloon that enables the intermediate and outer balloons to be forced into engagement with the vessel wall to dilate the vessel and disrupt plaque lining the vessel wall.
[0020] The intermediate balloon optionally may include a texture, ribs or protrusions on its outer surface that contacts the inner surface of the outer balloon to prevent the intermediate and outer balloons from adhering to one another during dilation of the vessel. Such a feature ensures that an annular space is maintained between the intermediate and outer balloons to facilitate uniform distribution of therapeutic agents during use of the catheter to perform therapy.
[0021] The outer balloon also may include bumpers at its proximal and distal ends to facilitate delivery of therapeutic agents. The outer balloon optionally may include a multiplicity of protrusions and apertures, such that the apertures are interposed between the protrusions so as to reduce the risk that the apertures become clogged during use of the balloon to dilate the vessel and disrupt the plaque.
[0022] In accordance with yet another aspect of the present invention, a catheter of the present invention is constructed to include a central lumen that accommodates not only a conventional guide wire for positioning the catheter, but also permits a wire carrying an energy source, such as an ultraviolet light source (“UV”), ultrasound transducer, electrically-powered resistive heater, or monopolar or bipolar radiofrequency (RF) heating element, to be substituted for the guide wire to deliver energy to the vessel wall segment where the therapeutic agent was infused. In a preferred embodiment, the material comprising the distal end region of the catheter shaft, and preferably also the materials comprising the inner, intermediate and outer balloons, are selected to reduce absorption energy delivered to the material infused into the vessel wall.
[0023] Methods of using the apparatus of the present invention also are provided, wherein the inventive catheter is first used, by inflating the inner balloon with a conventional balloon inflation system, to dilate a vessel and disrupt calcified plaque disposed on the luminal lining. The inner balloon is then depressurized, and one or more suitable fluent therapeutic agents are infused into a space between the inner balloon and the intermediate balloon. The therapeutic agent passes through the multiplicity of apertures, designed of specific variable diameters and positioned in specific patterns along the inner-most and outer-most balloons, into the annular space between the intermediate and outer balloons, and then through the apertures in the outer balloon to uniformly contact the disrupted plaque. Immediately, or after a predetermined interval, an energy delivery source, (e.g., a wire delivering a UV light source, ultrasound transducer or resistive heater), may be exchanged for the guide wire in the central lumen of the catheter. The energy source is activated to enhance uptake of the therapeutic agent through plaque, intima, media of the vessel wall so that the therapeutic agent becomes deposited in the media, adventitia and/or vaso vasorum of the vessel wall, or to activate a property of the fluent material to cause it to harden or otherwise transition to effectuate a therapeutic or diagnostic purpose.
[0024] In accordance with one aspect of the present invention, the application of energy from the energy source to the therapeutic agent infused into the vessel wall causes the agent to polymerize in the adventitia or vaso vasorum, thereby reducing washout of the drug caused by circulation through the vaso vasorum. In this manner, the therapeutic agent will be localized within the vessel wall, and serve as a reservoir that prolongs the therapeutic effect of the agent, for example, by reducing occurrence of late-term restenosis of the vessel. Alternatively, the agent may polymerize to form a durable rigid or semi-rigid support within the vessel wall, that serves as an in situ stent that reduces reduction (restenosis) or enlargement (growth of an aneurysm) of the vessel diameter, as suited for a particular therapy. Alternatively, energy from the energy source may be delivered to the vessel media, adventitia and/or vaso vasorum prior to the application of the therapeutic agent or substance.
[0025] The apparatus and methods of the present invention therefore facilitate ease of use by reducing the number of catheters required for the effective pre-dilatation of a diseased vessel segment and facilitates the penetration and controlled, uniform delivery of one or more therapeutic agents into the vessel layers using a baffled balloon, which may include a multiplicity of bumpers or protrusions configured to disrupt calcified plaque while avoiding clogging of the infusion apertures. Finally, the catheter provides a central lumen dimensioned to accept an externally powered energy source, and the distal region of the catheter preferably comprises materials that facilitate transmission of such energy to the therapeutic agent while reducing absorption by the catheter materials.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Further features of the invention, its nature and various advantages will be apparent from the accompanying drawings and the following detailed description of the preferred embodiments, in which:
[0027] FIG. 1 is a plan view of the illustrative catheter constructed in accordance with the principles of the present invention.
[0028] FIGS. 2A and 2B are, respectively, detailed plan and sectional views of the distal region of the catheter of FIG. 1 .
[0029] FIGS. 3A and 3B are, respectively, detailed plan and sectional views of the distal region of an alternative catheter constructed in accordance with the principles of the present invention.
[0030] FIGS. 4A and 4B are, respectively, detailed plan and sectional views of the distal region of another alternative catheter constructed in accordance with the principles of the present invention.
[0031] FIGS. 5A to 5C illustrate steps of the using the catheter of FIG. 1 to dilate a plaque-lined vessel and to infuse an anti-mitotic or other therapeutic agent or drug.
[0032] FIG. 6 is a detailed sectional view of the balloons described in FIG. 5 .
[0033] FIG. 7 is a detailed sectional view corresponding to encircled region 7 in FIG. 5B .
[0034] FIG. 8 is a detailed sectional view corresponding to encircled region 8 in FIG. 5C .
[0035] FIG. 9 illustrates a step of inserting an energy delivery wire into the central lumen of the catheter of the present invention during or after the step illustrated in FIG. 5C .
[0036] FIGS. 10A and 10B are, respectively, plan and sectional views of an alternative embodiment of the catheter of the present invention.
[0037] FIG. 11 is a detailed sectional view corresponding to encircled region 11 in FIG. 10B .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] Referring to FIG. 1 , balloon catheter 20 constructed in accordance with the principles of the present invention is described. Catheter 20 includes proximal end 21 , distal region 22 and elongated shaft 23 . Proximal end 21 , which is manipulated by the clinician, preferably includes hemostatic port 24 that permits conventional guide wire 25 to be extended through a lumen of catheter 20 , balloon inflation port 26 and infusion agent port 27 . Catheter preferably has a length and diameter suitable for use in the desired cardiac or peripheral vessel, e.g., 130 to 150 cm in length with a diameter of 2.5 mm to 60 mm, in the case of an abdominal aortic or thoracic aneurysm and balloon lengths from 2 cm to 20 cm. Ports 24 , 26 and 27 are conventional elements, and together with proximal end 21 of catheter 20 may comprise materials conventionally used in the construction of intravascular catheters, e.g., polyethylene or polyterephthalate. Although catheter 20 is depicted as an over-the-wire (“OTW”) catheter, it is to be understood that the inventive aspects of the catheter of the present invention readily may be employed in a rapid exchange (“RX”) catheter or in a catheter having a working lumen and an auxiliary lumen for guidewire insertion such as that described in U.S. Pat. No. 7,018,358 to Joergensen, the entire contents of which is incorporated herein by reference.
[0039] Referring now to FIGS. 2A and 2B , distal region 22 of one embodiment of catheter 20 of the present invention is described. FIG. 2A depicts the exterior of distal region 22 with outer balloon 30 in an expanded state suitable for dilating a vessel, while for purposes of clarity, FIG. 2B depicts a sectional view of the inner components of distal region 22 with intermediate balloon 31 and inner balloon 32 in partially expanded states suitable for infusing a therapeutic agent into a vessel wall. Outer balloon 30 preferably comprises a noncompliant or semi-compliant material such as polyethylene or polyterephthalate. Outer balloon 30 is sized and shape for insertion as appropriate for the intended therapy and bodily lumen. For example, outer balloon 30 may have a diameter in an expanded state of about 2.5-4.0 mm for insertion in smaller lumens, such as coronary vessels, about 4-7 mm for insertion in larger lumens such as peripheral vessels, or as much as 4-6 cm if the catheter is designed for use in providing therapy in the thoracic or abdominal aorta. Intermediate balloon 31 and inner balloon 32 preferably comprise a semi-compliant or compliant material such as polyterephthalate or nylon. As described in further detail below, in a preferred embodiment, inner balloon 32 is configured to expand intermediate balloon 31 and outer balloon 30 until outer balloon 30 reaches its maximum designed diameter. In an alternative embodiment, outer balloon 30 also may comprise a compliant material, while intermediate balloon 31 and inner balloon 32 also may comprise a non-compliant material.
[0040] Still referring to FIGS. 2A and 2B , outer balloon 30 has exterior surface 34 and multiplicity of through-wall apertures 35 . In the embodiment depicted in FIG. 2A , apertures 35 illustratively are arranged in a pattern where each row is offset by a predetermined angle, e.g., about 45°, from an adjacent row; however, other patterns will readily occur to a person of ordinary skill in the design of balloon catheters. For example, each row or pattern of apertures on the outer balloon may be aligned uniformly with adjacent rows; there may be a single row of apertures on the outer balloon; there may be two rows of apertures on opposite sides of the outer balloon, etc. In addition, apertures 35 are depicted as being circular in shape which may vary in diameter along the length of the balloon, but could have any other desired shapes, such as rectangular, triangular or elliptical. Outer balloon 30 , intermediate balloon 31 and inner balloon 32 preferably are affixed to catheter shaft 23 at shoulders 36 and 37 via thermal bonds or glue welds.
[0041] As best shown in FIG. 2B , intermediate balloon 31 includes multiplicity of through-wall apertures 38 which may have varying diameters along the balloon length, and which preferably are offset from apertures 35 in outer balloon 30 . In this manner, a fluent therapeutic agent introduced into annular space 39 between the exterior of inner balloon 32 and interior surface of intermediate balloon 31 will pass into annular space 40 between the exterior of intermediate balloon 31 and the interior surface of outer balloon 30 without directly exiting through apertures 35 in the outer balloon. Accordingly, when a therapeutic agent is introduced into annular space 39 via infusion lumen 41 and infusion port 27 on proximal end 21 (see FIG. 1 ), the agent passes from annular space 39 to annular space 40 , from which it uniformly exits outer balloon 30 via apertures 35 . Inflation port 26 on proximal end 21 (see FIG. 1 ) is coupled to interior space 42 of inner balloon 32 via inflation lumen 43 that extends through catheter shaft 23 . Apertures 35 may be the same size or a different size than apertures 38 . Preferably, apertures 35 and 38 are laser drilled and have a diameter between about 5 μm and about 50 μm. In one embodiment, apertures 35 have a diameter of about 5 μm and apertures 38 have a diameter of about 10 μm. In addition, a subset of the multiplicity of apertures 35 or 38 may be differently sized from another subset of the multiplicity. For example, a distal portion of a row of apertures 35 each may have a first diameter and a proximal portion of the row each may have a second diameter, different from the first. In one embodiment, in a row of sixteen apertures, eight distal apertures each has a diameter of about 15-25 μm and eight proximal apertures each has a diameter of about 7-17 μm.
[0042] As depicted in FIG. 2B , after use of catheter 20 for dilating the vessel wall, inner balloon 32 may be inflated to any lower desired pressure to reduce the volume of therapeutic agent delivered into annular space 39 and to facilitate the rate of delivery to the vessel wall. Alternatively, inner balloon 32 may be deflated entirely after the vessel dilatation step.
[0043] Still referring to FIG. 2B , catheter shaft 23 includes lumen 44 , preferably centrally located in catheter shaft 23 , to permit guide wire 25 to be extended through catheter 20 to facilitate positioning of distal region 22 at a desired location in a patient's vasculature or organ. Distal region 22 also may include radiopaque markers disposed along catheter shaft 23 , for example, in the vicinity of shoulders 36 and 37 , to facilitate positioning of the catheter under fluoroscopic imaging. In accordance with one aspect of the present invention, lumen 44 preferably is sized to permit a wire containing an energy source, e.g., an ultraviolet light source (or light fiber), ultrasound transducer, or resistive heater, to be advanced into distal region 22 to deposit energy into the therapeutic agent or drug, to facilitate uptake by the vessel wall or provide another therapeutic effect, as described herein below. For such embodiments, balloons 30 - 31 and catheter shaft 23 preferably comprise materials that permit light energy of selected frequencies to pass through the catheter without significant absorption or loss of energy.
[0044] Referring now to FIGS. 3A and 3B , distal region 22 ′ of an alternative balloon catheter is constructed similarly to distal region 22 of FIGS. 2A and 2B , wherein like components are identified by like-primed reference numbers. Thus, for example, apertures 35 ′ in FIGS. 3A and 3B correspond to apertures 35 of FIGS. 2A and 2B , etc. As will be observed by comparing FIGS. 2A , 2 B and 3 A, 3 B, outer balloon 30 ′ includes proximal bumper 45 around the circumference of its proximal end and distal bumper 46 around the circumference of its distal end, and apertures 35 ′ are aligned in uniform rows. Bumpers 45 , 46 extend from exterior surface 34 ′ so as to create a pocket between bumpers 45 and 46 and between exterior surface 34 ′ and the luminal surface when bumpers 45 , 46 are urged into contact with the luminal surface. In this manner, bumpers 45 , 46 facilitate delivery of therapeutic agents to the luminal surface via the pocket such that the agents are delivered uniformly along the length of the balloon, reduce clogging of the apertures when the bumpers are urged into contact with the luminal surface, and reduce the risk that fluent material delivered to the vessel surface will be washed into systemic circulation.
[0045] Referring now to FIGS. 4A and 4B , distal region 22 ″ of yet another alternative balloon catheter is constructed similarly to distal region 22 of FIGS. 2A and 2B except that outer balloon 30 ″ further includes multiplicity of solid protrusions 47 extending from exterior surface 34 ″ and interposed between multiplicity of through-wall apertures 35 ″. In the embodiment depicted in FIG. 4A , protrusions 47 and apertures 35 ″ illustratively are arranged in a regular pattern; however, other patterns will readily occur to a person of ordinary skill in the design of balloon catheters. Preferably, apertures 35 ″ are offset from protrusions 47 so as to reduce clogging of the apertures when the protrusions are urged into contact with the luminal surface. In addition, while protrusions 47 are illustratively depicted as substantially circular cylinders having rounded extremities, other configurations, such as rectangular, conical or pyramidal structures also could be used. Protrusions 47 extend from exterior surface 34 ″ so as to create a pocket between exterior surface 34 ″ and the luminal surface when protrusions 47 are urged into contact with the luminal surface. In this manner, protrusions 47 facilitate delivery of therapeutic agents to the luminal surface via the pocket, and reduce the risk that fluent material delivered to the vessel surface will be washed into systemic circulation.
[0046] Referring now to FIGS. 5A to 5C , a method of using the catheter of FIGS. 1 and 2 to perform an interventional procedure is described. As will be readily understood to one of ordinary skill in the art, while the method is described for use with the catheter of FIGS. 1 and 2 , the alternative catheters of FIGS. 3 and 4 may be used in a similar manner to that described below.
[0047] In FIG. 5A , guide wire 25 is placed in the vessel at the location of a lesion or plaque P, or nascent aneurysm, as determined using fluoroscopic imaging, contrast agents and conventional interventional techniques. Catheter 20 then is backloaded onto guide wire 25 by inserting the proximal end of the guide wire into the distal opening of lumen 44 . Catheter 20 is advanced through the patient's vasculature until distal region 22 is disposed in the region of interest, as determined using radiopaque markers on catheter shaft 23 and fluoroscopic imaging. When so disposed in patient's vessel V, distal end 22 of catheter 20 will appear as depicted in FIG. 5A . In embodiments protrusions ( FIG. 4 ), during manufacture of the catheter, outer balloon 30 ′ or 30 ″ of the catheter may be wrapped or folded so that protrusions 47 are substantially flush with the remainder of the balloon material, thus preventing the protrusions from snagging or abrading the vessel intima during advancement along guide wire 25 to the location of interest. Alternatively, a delivery sheath (not shown) may be disposed over distal region 22 , 22 ′, or 22 ″ of the catheter to present a smooth outer surface for the catheter, and the sheath then may be retracted proximally to expose the distal region once it is at the desired location in vessel V.
[0048] Referring now to FIGS. 5B , 6 , and 7 , a conventional inflator is coupled to inflation port 26 and an inflation medium, such as saline or a saline diluted iodinated contrast agent, is delivered via inflation lumen 43 to inner balloon 32 to cause inner balloon 32 to expand intermediate balloon 31 and outer balloon 30 . As shown in FIG. 6 , inner balloon 32 may expand intermediate balloon 31 and outer balloon 30 so that pocket 48 is created between outer balloon 30 and plaque P. In such an embodiment, pocket 48 may extend between bumpers 45 and 46 ( FIG. 3 ) or protrusions 47 ( FIG. 4 ) contact plaque P and the intima of the vessel V to dilate the vessel V and crack or disrupt plaque P. In addition, as shown in FIG. 7 , inner balloon 32 may expand intermediate balloon 31 and outer balloon 30 into contact with plaque P and the intima of vessel V to dilate the vessel V and disrupt or cause cracks C in the plaque P. As inner balloon 32 expands, it contacts intermediate balloon 31 which contacts outer balloon 30 and causes outer balloon 30 to contact and crack or disrupt plaque P.
[0049] In embodiments where the outer balloon includes protrusions ( FIG. 4 ), the protrusions engage plaque at discrete locations and place the plaque in tension, causing it to fracture. One or more therapeutic agents are infused through apertures 35 , 35 ′, 35 ″ in outer balloon 30 , 30 ′, 30 ″ and contacts the plaque along fracture zones that enable the therapeutic agent to be rapidly taken up by the vessel intima. Because apertures 35 ″ are interposed between the protrusions instead of extending through the protrusions as in prior art systems, compressed plaque at the point of contact of the protrusions is expected not to clog the apertures. It is expected that the foregoing arrangement of solid protrusions and interposed apertures will enable better uptake of therapeutic agents in calcified lesions than has heretofore been achieved.
[0050] Referring to FIGS. 6 and 7 , it is observed that vessel V comprises three layers: intima I, medial M, and adventitial A, which is supplied by vaso vasorum VV. It is known that the vaso vasorum VV supplies nourishment to vessel V and removes metabolic byproducts resulting from activity of the cells making up the vessel wall. In accordance with one aspect of the present invention, a therapeutic agent is infused into the wall of a vessel V, and preferably into the adventitia A and/or vaso vasorum VV, while also locally reducing flow in the vaso vasorum VV to reduce washout of the therapeutic agent from the adventitia A and vaso vasorum VV. In this manner, the vessel wall serves as a reservoir for the therapeutic agent, so that the infused therapeutic agent or drug is released from the adventitia A back into the medial M and intimal portions I of the vessel wall over a period of months to years, thereby prolonging the therapeutic effect of the infused agent or drug.
[0051] The foregoing benefits may be achieved by a number of modes. In one embodiment, the therapeutic agent or drug may be designed so that when activated by supply of energy, e.g., irradiated by ultraviolet light, insonicated with ultrasound energy of a desired frequency, or heated by a resistive or other type of heater, the drug transitions from a fluent form to a gel-like or solid form. In this case, the therapeutic agent will assist in blocking or reducing flow through the vaso vasorum, and reduce the rate at which the therapeutic agent or drug is removed from the selected portion of the vessel wall. Alternatively or in addition, if the therapeutic agent transforms to a gel-like or solid form, it will be less susceptible to erosion. In an alternative embodiment, the deposited energy may cause a component of the therapeutic agent to heat up to cause polymerization or cross-linking of fluent bioactive materials and/or remodel or partially necrose portions of the adventitia or vaso vasorum, thereby locally blocking or reducing flow through the vaso vasorum and producing a reservoir of the therapeutic agent that provides prolonged release. As a further alternative embodiment, the deposited energy may function to enhance uptake of the therapeutic agent through the layers of the vessel wall. As a still further alternative embodiment, the energy may directly cause partial remodeling or necrosis of the adventitia and/or vaso vasorum to produce the reservoir effect noted above.
[0052] Referring now to FIGS. 5C and 8 , after inner balloon 32 has been expanded to drive intermediate balloon 31 , and outer balloon 30 (and, if present, optional bumpers or protrusions) into contact with the vessel wall, inner balloon 32 is partially or completely deflated. Next, a vial or syringe containing a desired fluent therapeutic agent or drug, (e.g., an anti-mitotic drug such as paclitaxel or sirolimus, angiogenic vector, or stem cells), is coupled to infusion port 27 on proximal end 21 and activated to inject the agent through infusion lumen 41 into annular space 39 between inner balloon 32 and intermediate balloon 31 (see FIG. 2B ). As indicated by the arrows in FIG. 5C , the agent passes through apertures 38 in intermediate balloon 31 and into annular space 40 between intermediate balloon 31 and outer balloon 30 . Inner balloon 32 may be partially or completely reinflated to cause the therapeutic agent to pass through apertures 38 and into annular space 40 between intermediate balloon 31 and outer balloon 30 before exiting through apertures 35 . Because apertures 38 are offset from apertures 35 in outer balloon 30 , the agent circulates within annular space 40 before passing through apertures 35 and exiting outer balloon 30 . Additionally, because agent moves laterally towards apertures 35 , it will be more uniformly distributed around the circumference and along the axial length of the vessel than previously-known single balloon systems. This baffling effect provided by intermediate balloon 31 is expected to reduce jetting of therapeutic agent exiting through apertures 35 of outer balloon 30 , thus reducing the potential for vessel dissection.
[0053] As depicted in further detail in FIG. 8 , the therapeutic agent exits outer balloon into pockets 48 formed between cracks C in plaque and/or between bumpers, if provided. The therapeutic agent exits apertures 35 into pockets 48 , where it is expected to gain ready access to the vessel intima through cracks and fractures formed in plaque P during the dilatation step illustrated in FIG. 5B .
[0054] As will be apparent to one of ordinary skill in interventional procedures, the rate of infusion of therapeutic agent can be adjusted by varying the pressure at which the agent is supplied from the syringe or vial through infusion port 27 , or alternatively by adjusting the degree of inflation of inner balloon 32 . By adjusting the latter, the clinician can reduce the volume of annular space 39 , reducing the volume of therapeutic agent that must be used during the procedure. In addition, after infusing the therapeutic agent into annular space 39 , the clinician may increase the pressure in inner balloon 32 to pressurize annular spaces 39 and 40 and enhance the rate at which therapeutic agent exits apertures 35 and is infused into the vessel wall. Therapeutic agent deposited in pockets 48 preferably is taken up by the cells in the various layers of the wall of vessel V by normal cellular processes, as opposed to traumatically (e.g., by cleaving intercellular connections).
[0055] In addition, as will be readily understood to one of ordinary skill in the art, while the balloon catheter is generally described as delivering a therapeutic agent, such as an anti-mitotic drug, to plaque, the disclosure is not limited thereto. The therapeutic agent may be selected to treat any condition where subintimal injection would be beneficial. For example, the therapeutic agent may be selected for treating a nascent or existing aneurysm when the balloon catheter is delivered proximate to an aneurysm. As another example, the therapeutic agent may be selected to induce angiogenesis, delivered either transluminally or into the sub-intimal space. The therapeutic agent may comprise, for example, one or more regenerative agents, anti-inflammatory agents, anti-allergenic agents, anti-bacterial agents, anti-viral agents, anticholinergic agents, antihistamines, antithrombotic agents, anti-scarring agents, antiproliferative agents, antihypertensive agents, anti-restenosis agents, healing promoting agents, vitamins, proteins, genes, growth factors, cells, stem cells, vectors, RNA, or DNA.
[0056] FIG. 9 illustrates a final optional step in accordance with the method of present invention for infusing one or more therapeutic agents into the wall of vessel V. FIG. 9 is similar to FIG. 5C , except that in this step guide wire 25 is removed or retracted, and energy delivery device 50 carrying an energy deposition element is advanced through lumen 44 of catheter 20 and disposed in distal region 22 . The energy delivery element, located in the distal region of energy delivery device 50 , preferably includes one or more radiopaque markers to indicate positioning of the distal region under fluoroscopic imaging. Energy delivery device 50 preferably has a diameter between 0.018″ to 0.035″ and may comprise an optical fiber or source for delivering ultraviolet light, ultrasonic energy, or heat. Such devices, and the energy sources that are coupled to the proximal ends of such devices, are known in the art and accordingly are not described in detail here. Of particular importance, however, if a UV light or ultrasonic energy delivery device 50 is employed, catheter 20 preferably is constructed so that a substantial part of the energy is delivered to the vessel wall without being absorbed by the catheter material, and the energy absorbed by the vessel wall has some therapeutic benefit, e.g., activates the therapeutic agent. Energy emitted by energy delivery device 50 and absorbed by vessel V is represented by the solid arrows in FIG. 9 .
[0057] As discussed above with respect to FIGS. 6 and 7 , energy delivery device 50 may provide a therapeutic effect either by facilitating uptake of the therapeutic agent by the vessel wall; by activating the therapeutic agent; by heating the therapeutic agent to effect a change to the vessel wall structure; or by directing delivering energy to selected layers of the vessel wall to cause polymerization or cross-linking of fluent therapeutic agents (e.g., as described in U.S. Pat. No. 5,749,915 to Slepian localized necrosis or remodeling of collagen contained within the vessel wall.
[0058] In one embodiment, the deposited energy enhances uptake of the therapeutic agent through the layers of the vessel wall, for example, by activating moieties bound to the effective portion (e.g., anti-proliferative portion) of the therapeutic agent, (e.g., as described in U.S. Pat. No. 4,590,211 to Vorhees). Alternatively, the therapeutic agent or drug may be designed so that when irradiated by ultraviolet light, or insonicated with ultrasound energy of a desired frequency, the drug transitions from a fluent form to a gel-like or solid form. In this case, the therapeutic agent will assist in blocking or reducing flow through the vaso vasorum, and reduce the rate at which the therapeutic agent or drug is removed from the selected portion of the vessel wall. Alternatively or in addition, if the therapeutic agent transforms to a gel-like or solid form, it will be less susceptible to erosion, thereby locally prolonging the therapeutic effect of the agent.
[0059] In a further alternative embodiment, the energy deposited by delivery device 50 may cause a component of the therapeutic agent to heat up and remodel collagen of, or partially necrose portions of, the adventitia or vaso vasorum. This effect also may cause a localized blockage that stops or reduces flow through the vaso vasorum and act to produce a localized reservoir of the therapeutic agent that provides prolonged release. As yet another alternative embodiment, the UV or ultrasonic energy may directly cause partial remodeling or necrosis of the adventitia and/or vaso vasorum to create localized blockage of the vaso vasorum to produce the reservoir effect noted above.
[0060] Referring again to FIG. 9 , energy delivery device 50 may be configured to deliver energy to vessel V during and after, or alternatively only a predetermined interval after, the therapeutic agent is delivered by catheter 20 . Once the process of delivering the therapeutic agent into the vessel wall is completed, and the appropriate amount of energy has been delivered to enhance or prolong the therapeutic effect of the therapeutic agent, energy delivery device 50 may be withdrawn. Next, suction may be drawn on infusion lumen 41 to remove any excess therapeutic agent from annular spaces 39 and 40 to collapse intermediate balloon 31 and retract outer balloon 30 away from the vessel wall. In an embodiment where the outer balloon includes protrusions, the outer balloon may be constructed so that, when deflated, the balloon preferentially will fold to enclose the protrusions and reduce the risk of abrading the vessel wall during removal. Alternatively, or in addition, an open-ended sheath (not shown) may be advanced over the exterior surface of catheter shaft 23 and the exterior of outer balloon 30 to facilitate removal of catheter 20 . Once catheter 20 is removed from the patient's vasculature, the access site may be closed using standard interventional techniques.
[0061] Referring now to FIGS. 10A , 10 B and 11 , an alternative embodiment of apparatus constructed in accordance with the principles of the present invention is described. Catheter 60 includes elongated catheter shaft 61 having distal region 62 and outer balloon 63 . The proximal end of catheter shaft 61 is similar in construction to catheter 20 and preferably includes a hemostatic guide wire port, balloon inflation port and infusion port. As shown in FIG. 10B (which corresponds to an inflation state similar to FIG. 2B ), distal region 62 includes outer balloon 63 , intermediate balloon 64 and inner balloon 65 . As for catheter 20 of the preceding embodiment, inner balloon 65 is fluid impermeable and is coupled via an inflation lumen to an inflation port on the proximal end. Likewise, intermediate balloon 64 includes a multiplicity of through-wall apertures 66 (see FIG. 11 ) and is coupled via an infusion lumen to an infusion port disposed on the proximal end of the catheter. Outer balloon 63 includes one or more spiral protrusions 67 and a multiplicity of through-wall apertures 68 .
[0062] Catheter 60 differs from the embodiment of FIG. 1 in that the exterior surface of outer balloon 63 includes protrusions 67 arranged as a spiral ridge. In addition, whereas intermediate balloon 64 of the embodiment of FIG. 1 may contain a textured surface to ensure that intermediate balloon 64 does not adhere to outer balloon 63 , intermediate balloon 64 in the embodiment of FIGS. 10 and 11 includes a macroscopic feature to prevent such adhesion. In particular, intermediate balloon 64 includes spiral rib 69 , preferably comprised of the same material and potentially integrally formed with intermediate balloon 64 , disposed on its exterior-facing surface of the intermediate balloon. In this manner, spiral rib 69 contacts the inner surface of outer balloon to ensure that annular space 70 is maintained between intermediate balloon 64 and outer balloon 63 when inner balloon 65 is inflated to urge intermediate balloon 64 and outer balloon 63 into contact with a vessel wall to dilate the vessel and disrupt plaque.
[0063] While in the embodiment of FIGS. 10 and 11 protrusions 67 are configured as a spiral ridge having a rounded extremity, it should be understood that other patterns will readily occur to a person of ordinary skill in the design of balloon catheters, such as structures having rectangular, conical or pyramidal cross-sections, as may be desirable to fracture severe calcifications. Similarly, while apertures 68 are depicted as being circular, they may have any other desired shape, such as rectangular, triangular or elliptical. Preferably, apertures 68 are offset from protrusions 67 so as to reduce clogging of the apertures when the protrusions are urged into contact with the luminal surface. Likewise, apertures 66 in intermediate balloon 64 may be offset from apertures 68 in outer balloon 63 to achieve the benefits described above.
[0064] Finally, although the macroscopic feature in intermediate balloon 64 is illustratively depicted as comprising spiral rib 69 having a substantially circular cross-section, this feature could have other cross-sections, such as rectangular, elliptical or triangular. In addition, spiral rib 69 need not form a continuous structure, but instead could comprise a multiplicity of discrete structures, similar in shape to protrusions 47 disposed on outer balloon 30 ″ of the embodiment of FIG. 4 . For example, intermediate balloon 64 and outer balloon 63 may comprise the same material having the same protrusions disposed on their respective exterior surfaces. In this manner, construction of the distal end of the catheter of the present invention could be simplified, so long as the apertures in the intermediate and outer balloons are staggered or offset to provide the baffle action discussed above.
[0065] While preferred illustrative embodiments of the invention are described above, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the invention. The appended claims are intended to cover all such changes and modifications that fall within the true spirit and scope of the invention. | A catheter and methods for luminal therapy are provided wherein a catheter has an outer balloon with a multiplicity of apertures for infusing one or more therapeutic agents into a vessel wall, an intermediate balloon having a multiplicity of apertures offset from the apertures of outer balloon to serve as a baffle that reduces jetting and promotes uniform distribution of therapeutic agent exiting through the outer balloon, and an impermeable inner balloon disposed within the intermediate balloon that enables the intermediate and outer balloons to be forced into engagement with the vessel wall to dilate the vessel and disrupt plaque lining the vessel wall and to also facilitate the uniform delivery of the therapeutic agent. The outer balloon may include protrusions that contact the vessel wall to disrupt the plaque, bumpers to reduce washout during infusion of therapeutic agents; the intermediate balloon may include a texture, ribs or protrusions on its outer surface to prevent adhesion to the outer balloon during dilation of the vessel; and the catheter may include a guide wire lumen sized to accept an energy delivery device to delivery energy that enhances uptake of the therapeutic agent or prolongs therapeutic effectiveness of the agent. | 0 |
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention is directed to vacuum or positive pressure seed meters for a seeding machine. Particularly, the invention is directed to controlling the air pressure applied to seed meters of a seeding machine.
BACKGROUND OF THE INVENTION
[0002] Modern seeding machines use plural seed meters spaced apart along a pneumatic manifold corresponding to planting rows. One such seed meter is disclosed, for example, in U.S. Pat. No. 5,170,909 assigned to the assignee of the present invention. Sophisticated seed metering systems for controlling the rate at which seeds are planted use air pressure to control the application of seed to the ground. In some systems, positive air pressure is used. In other systems, negative air pressure in the form of a vacuum is used to meter the seed.
[0003] Positive or negative air pressure is generated by an air pump in the form of a fan. This air pressure from the air pump is directed to a pneumatic manifold. The pneumatic manifold in turn is pneumatically coupled to individual seed meters by hoses.
[0004] The air pressure supplied to different row seed meters is not identical. Such a condition results in uneven seed meter performance, possibly resulting in variations in row-to-row seed population and/or seed spacing along the rows. The positive or negative air pressure is highest at those seed meters pneumatically closest to the source of pressurized air or vacuum.
[0005] The present inventors have recognized the desirability of proving an air pressure seed metering system that compensates for variations in air pressure along the pneumatic manifold to ensure a consistent row-to-row seed population and seed spacing along each row.
SUMMARY OF THE INVENTION
[0006] The present invention provides a pressure control system that is configured to precisely tune positive air pressure or vacuum to pneumatic seed meters that are located along a pneumatic metering manifold.
[0007] The system includes pressure control valves pneumatically located at plural seed meters that adjust the air pressure or vacuum at the seed meters. The system can utilize feedback pressure signals from pressure sensors at each meter to equalize positive air pressure or vacuum at the seed meters to ensure consistent row-to-row seed populations. Alternatively, the system could utilize seed population measurement as a feedback signal to adjust control valves.
[0008] A seeding machine is provided with a frame having a plurality of pneumatic seed meters. An air pump located on the frame supplies air pressure, positive or negative, depending on the seed meter type, to a pneumatic manifold. The pneumatic manifold in turn is pneumatically coupled to the seed meters by air hoses. Control valves, such as adjustable orifice valves, are pneumatically positioned between the pneumatic manifold and each air connection of the seed meters.
[0009] The pneumatic manifold is provided with radially extending tube stubs that are coupled to air hoses. The controllable pneumatic orifices can be connected to the tube stubs, can be connected at a point along the air hose, or can be connected to the seed meter.
[0010] The adjustable orifice valve of the invention comprises a substantially enclosed housing having a first air connection and a second air connection with a flow pathway therebetween. One or more baffles are arranged within the housing in the pathway between the air connections. An actuator is mounted to the housing and is operable to position the baffle to a controllable degree between the first and second air connections, to restrict flow through the orifice valve. In one embodiment three baffles are used to form an iris which can increase or decrease the orifice opening between the air connections while maintaining orifice concentricity. In another embodiment a single baffle can be used to close off the orifice in the pathway between the air connections in an eccentric manner.
[0011] As an alternative to the separate enclosed housing, the control valve of the invention could be incorporated into the seed meter housing/manifold.
[0012] Numerous other advantages and features of the present invention will become readily apparent from the following detailed description of the invention and the embodiments thereof, from the claims and from the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] [0013]FIG. 1 is a top view of a row crops planter having a plurality of individual planting units;
[0014] [0014]FIG. 2 is a semi-schematic side view of one planting unit and the pneumatic distribution system;
[0015] [0015]FIG. 3 is a perspective view of an adjustable orifice valve of the present invention;
[0016] [0016]FIG. 4 is a perspective view of the adjustable orifice valve of FIG. 3 with a front cover removed for clarity;
[0017] [0017]FIG. 5 is a perspective view of one of the baffles shown in FIG. 4
[0018] FIGS. 6 A- 6 C are fragmentary plan views of the adjustable orifice of FIG. 3 in progressive stages of closing;
[0019] [0019]FIG. 7 is a perspective view of an adjustable orifice valve according to a second embodiment of the invention with a front cover removed for clarity, but with an actuator shown in position nonetheless;
[0020] FIGS. 8 A- 8 C are fragmentary plan views of the adjustable orifice of FIG. 7 in progressive stages of closing; and
[0021] [0021]FIG. 9 is a schematic, partially sectional view of an alternate embodiment of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] While this invention is susceptible of embodiment in many different forms, there are shown in the drawings, and will be described herein in detail, specific embodiments thereof with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the invention to the specific embodiments illustrated.
[0023] [0023]FIG. 1 is a top view of a seeding machine 10 . In the illustrated embodiment, the seeding machine is a row crop planter, however, the present invention could be used on other seeding machines having pneumatic seed meters, including grain drills and air seeders. The planter comprises a frame 12 that can be extended into a working configuration illustrated in FIG. 1 and folded into a transport configuration. A plurality of row crop planting units 20 is mounted to the frame 12 .
[0024] An air pump 40 in the form of a fan creates an air pressure in two air tubes 42 and 43 . The air tube 42 extends between the air pump 40 and the pneumatic manifold 44 . The air tube 43 extends between the air pump 40 and the pneumatic manifold 45 . Each of the pneumatic manifolds 44 and 45 comprises a cylindrical tube that extends along the frame 12 . Each of the pneumatic manifolds 44 and 45 comprises two sections that are coupled together by a flapper coupling 46 . The flapper coupling 46 allows each of the manifolds to be split apart as the planter frame 12 is being folded and to be rejoined when the planter frame is unfolded into its working configuration.
[0025] [0025]FIG. 2 illustrates each of the row crop planting units 20 is provided with a seed hopper 22 that directs seed to a seed meter 24 which meters the seed. The metered seed is directed by a seed tube 26 from the seed meter 24 to a planting furrow formed in the ground by furrow opener 28 . A planting furrow is closed by angled closing wheels 30 . The planting unit may also be provided with a pesticide hopper 32 for carrying pesticides to be applied during the planting process.
[0026] The seed meter 24 , in the illustrated embodiment, is a vacuum meter of the type presently marketed by the assignee of the present application. A vacuum seed meter is disclosed for example in U.S. Pat. No. 5,170,909 herein incorporated by reference. Negative air pressure is used to attract seeds to a seeding disc as it passes through a seed pile or puddle. The seeds remain in contact with the disc until the vacuum is removed and the seeds fall into the seed tube 26 .
[0027] The present invention could also be used with positive pressure systems, wherein a positive air pressure is used to drive the seeds to a seed disc as it revolves through a seed puddle. Removing the positive air pressure releases the seeds from the disc and the released seeds then drop into the seed tube 26 .
[0028] Each of the pneumatic manifolds 44 and 45 are provided with radially extending tube stubs 50 which are coupled to air hoses 52 for directing the air pressure in the pneumatic manifold to the individual seed meters 24 .
[0029] A pressure control valve in the form of an adjustable orifice valve 60 is positioned between the pneumatic manifolds 44 and 45 and an air connection of the row crop planting unit 23 . Each orifice valve 60 comprises a housing 61 having a first air connection in the form of a tube 62 and a second air connection in the form of a tube 63 . The housing 61 includes a front cover 64 fastened to a back plate 65 . The tube 62 is fastened to the front cover 64 . The tube 63 is fastened to the back plate 65 . Within the housing 61 , one or more baffle plates are arranged as described below.
[0030] The first tube 62 is in registry with the second tube 63 . The baffle plate or plates are disposed between the first and second tubes 62 , 63 to provide an adjustable restriction of airflow between the first and second tubes. An actuator 68 is mounted by fasteners 69 (shown in FIG. 7) onto the cover 64 of the housing 61 . The actuator 68 includes an output shaft 68 a (shown for example in FIG. 7) which penetrates the housing front cover 64 and which engages one of the baffles. The actuator, depending on an input signal thereto, controls the degree of restriction caused by the baffle or baffles by controllably rotating the baffle or baffles. The actuator is preferably a servomotor, wherein the servomotor can be controlled for precise rotation.
[0031] Since the vacuum pressure is related to the flow rate, and flow rate will change as the flow area changes, changing the baffle location will change the vacuum pressure.
[0032] In the preferred embodiment, the orifice valve 60 is inserted adjacent to, or as part of the meter 24 (see FIG. 9). However, other locations for the orifice valves are possible, such as along the air hose 52 , or at the respective manifold 44 , 45 .
[0033] Preferably, an orifice valve 60 would be located at each of the seed meters 24 . However, orifice valves 60 could be located only at the seed meters 24 closest to the air tubes 42 , 43 to restrict the airflow there to more closely match the air pressure to the air pressure at the remaining seed meters 24 farther from the air tubes 42 , 43 .
[0034] Vacuum pressure can be constantly monitored by pressure sensors P for each row or group of rows. Each sensor can be signal connected to a respective valve 60 to control by feedback the position of the valve and the level of vacuum or positive pressure at the seed meter. Alternately, a controller C, such as a microprocessor, can be signal-connected to all the pressure sensors P. The controller can be signal-connected to the actuators 68 at the orifice valves 60 . The vacuum or positive pressure level at each row is adjusted by the controller C according to feedback from the sensors P and by signal communication to each actuator 68 . For example, where the actuator is a servomotor, the controller, through an appropriate input/output device, can command the servomotor to open the iris slightly by a limited rotation of the servomotor, to increase the vacuum or positive pressure at the particular seed meter 24 , ensuring equal performance of all of the seed meters.
[0035] As an alternate feedback, an optical sensor could be located at each seed meter to detect the number of seeds the meter releases to the ground. Typically, the optical sensor is an infrared light emitting diode (LED) that is used in conjunction with a photocell. The photocell emits a pulse each time the light level from the LED goes below a specified threshold. These pulses correspond to seeds. With this information, and the vehicle travel speed, the rate of seed dispensing at each meter can be sensed and the vacuum at each meter adjusted accordingly by the valve.
[0036] Although orifice valves 60 are utilized in the above-described embodiment, other types of control valves, such as butterfly valves, could be used in place of orifice valves, and are also encompassed by the invention.
[0037] [0037]FIG. 4 illustrates three baffles 82 , 84 , 86 that are inter-engaged to form an iris shaped orifice 90 at a center thereof. Each baffle includes a slotted pivot 92 , a cam slot 94 and a pin 96 . Each pin 96 is located to be positioned within a cam slot 94 of an adjacent baffle. Two of the slotted pivots 92 are rotatably received in an opening 102 in the cover 64 . One of the pivots 92 is engaged by the actuator shaft 68 a (as shown in FIG. 7) of the actuator 68 to be forcibly rotated thereby. Forceful rotation of the pivot 92 causes corresponding mutual rotation of all of the baffles via the pins 96 and cam slots 94 , to either constrict or expand the iris opening 90 . Therefore, rotation of the actuator shaft which is engaged to one of the pivots 92 will constrict the iris opening 90 when rotated in a first direction, and will expand the iris opening 90 when rotated in a second, opposite direction. The back plate 65 further includes threaded openings 106 for receiving fasteners from the cover 64 to fix the plate 65 to the cover 64 to form the enclosed housing 61 .
[0038] [0038]FIG. 5 illustrates a single baffle, such as the baffle 82 . The baffle 82 is offset in two planes which allows for the assembly of the three baffles 82 , 84 , 86 in a relatively flat profile.
[0039] As demonstrated in FIGS. 6 A- 6 C an iris-type baffle arrangement can be used to control the open orifice area 90 to conduct flow between the first tube 62 and the second tube 63 . In FIG. 6A, the iris orifice area 90 is completely open allowing full flow between the tubes 62 , 63 . In FIG. 6B, the iris orifice area 90 is closed to some extent to provide some restriction of flow through the tubes 62 , 63 . In FIG. 6C, the iris orifice area 90 is further closed to provide an even further increased restriction of flow between the tubes 62 , 63 .
[0040] [0040]FIG. 7 illustrates a second embodiment wherein the three baffles 82 , 84 , 86 of the first embodiment are replaced by a single baffle 120 . The single baffle 120 includes a pivot 92 as previously described. The baffle 120 is substantially flat and curved. The single baffle 120 is rotated by the actuator shaft 68 a of the actuator 68 in the same manner as in the first embodiment, under control from the controller C as shown in FIG. 2. In this embodiment, an open orifice area 124 is opened and closed to form an eccentric orifice compared to the pathway between the tubes 62 , 63 .
[0041] As illustrated in FIGS. 8 A- 8 C, wherein the single baffle 120 is used, upon rotation of the baffle 120 , the open orifice area 124 between the tubes 62 , 63 is progressively constricted. In FIG. 8A, the baffle 120 completely clears and exposes the pathway between the tubes 62 , 63 for a nearly negligible resistance. In FIG. 8B, a somewhat greater resistance is provided by the position of the baffle 120 . In FIG. 8C, a further flow resistance is provided by a more constricted opening 124 , caused by a further rotation of the baffle 120 .
[0042] [0042]FIG. 9 illustrates an alternate embodiment wherein the valve housing 60 ′ is combined with the seed meter 24 ′ forming one housing 150 . The seed meter 24 ′ can be as described in U.S. Pat. No. 5,170,909 herein incorporated by reference. An air assisted seed distribution device, such as a seed disk 154 distributes seed 152 . The dist 154 and the valve baffle 120 share the common housing 150 . The suction first tube 62 is used but the second tube 64 is not necessary. The single baffle 120 is shown as an example, mounted to an intermediate plate 65 ′. The iris type baffle plate arrangement of FIG. 4, or another type of control valve could be used in the housing of FIG. 9 as well.
[0043] From the foregoing, it will be observed that numerous variations and modifications may be effected without departing from the spirit and scope of the invention. It is to be understood that no limitation with respect to the specific apparatus illustrated herein is intended or should be inferred. It is, of course, intended to cover by the appended claims all such modifications as fall within the scope of the claims. | A pressure control system is configured to precisely tune positive air pressure or vacuum to pneumatic seed meters that are located along a pneumatic metering manifold. The system includes pressure control valves pneumatically located at plural seed meters that adjust the air pressure or vacuum at the seed meters. The system can utilize feedback pressure signals from pressure sensors at each meter to equalize positive air pressure or vacuum at the seed meters to ensure consistent row-to-row seed populations. | 0 |
This is a division of Application Ser. No. 08/671,537, filed Jun. 27, 1996, now U.S. Pat. No. 5,882,296.
BACKGROUND OF THE INVENTION
a) Field of the Invention
The present invention relates to an objective optical system for endoscopes, and more specifically to an objective optical system for endoscopes which is configured to allow a plurality of adapter optical systems to be attached and detached thereto and therefrom for changing a direction toward a visual field, a field angle and an observation distance.
b) Description of the Prior Art
Conventionally, medical endoscopes which permit inserting elongated insert sections into living bodies for observing organs in the living bodies and passing forceps through forceps channels for sampling tissues of living bodies for detailedly diagnosing diseased parts in detail are widely used. Industrial endoscopes which permit observation and inspections of interiors of boilers, turbines, chemical plants and so on are widely known in industrial fields.
Attached to an industrial endoscope, in particular, is a direct view type adapter for observing a diseased part which is located in the longitudinal direction before the insert section or a side-view type adapter for observing an inside wall which is located sideways in a direction perpendicular to the inserting direction. In practice, one simultaneously selects an adapter which has a field angle that is optimum for a location to be observed and another adapter which has an optimum observation distance (or a depth of field) and so on.
It is effective from an economical viewpoint to configure such an expensive endoscope as a tip adapter type endoscope which can be equipped with adapters having a direction of a visual field, a field angle and an observation distance matched with a location to be observed.
Also widely used in the industrial fields are electronic endoscopes which provide images of qualities remarkably improved owing to progress made in solid-state image pickup devices (CCD's).
A conventionally known example of such electronic endoscopes is an electronic endoscope disclosed by Japanese Patent Kokai Publication No. Hei 2-74,912 which has a composition shown in FIG. 1 . This conventional electronic endoscope has no mechanism of the tip adapter type described above and is not versatile in the industrial fields. When an attempt is made to configure this electronic endoscope as the tip adapter type by dividing a lens system thereof into a subsystem which is located before an aperture'stop S and replaceable with an adapter, and another subsystem located after the aperture stop S, for example, it is necessary to dispose a light guide to be used in an illumination system at a location of a lens unit L. A reason to select this disposition is that it is optimum to dispose a light guide G so that it turns below a side-viewing prism P as shown in FIG. 2 for attaching a side-viewing adapter.
When the light guide is disposed at the location of the lens unit L in the electronic endoscope disclosed by Japanese Patent Kokai Publication No. Hei 2-74,912, an objective optical system of this electronic endoscope has a large outside diameter at its tip. For disposing the light guide without enlarging its outside diameter, it is necessary to reduce an outside diameter of the lens unit L or a number of optical fibers which are to be used for composing a light guide. As a result, rays are eclipsed by the lens unit L or illuminating rays are reduced, thereby making brightness insufficient.
On the other hand, there is known an objective optical system for tip adapter type electronic endoscopes which has a composition shown in FIG. 3 . This objective optical system for tip adapter type endoscopes is configured to concentrate all light guides at the location of the lens unit L for correcting the defect of the electronic endoscope disclosed by Japanese Patent Kokai publication No. Hei 2-74,912.
In the recent years where images of having higher qualities and full-screen sizes are strongly demanded, it is expected that electronic endoscopes which can provide images suited for display on high definition televisions (HDTV's) will be adopted in the near future.
For obtaining images of such high qualities, however, it is necessary to configure picture elements so as to have a smaller size, or lower illuminance per picture element on an image surface, thereby making it difficult to maintain the conventional image brightness. Further, it is known that depths of field are reduced by reducing sizes of picture elements.
For correcting the defects described above, it is necessary to reserve a required depth of field by enlarging an F number of an objective lens system and compensate for brightness by increasing the number of optical fibers that are used for making the light guide.
In the field of the endoscopes which should desirably have smaller diameters, however, it is undesirable to increase the number of optical fibers that are used for making the light guide since such increase results in enlarging the outside diameters of the endoscopes. In the case of the objective optical system for the tip adapter type of electronic endoscopes illustrated in FIG. 3, the objective optical system has an outside diameter which is enlarged by increasing the number of optical fibers. When the objective optical system for tip adapter type endoscopes is configured to provide a full-size screen, it may not accept an increase the heights of rays caused by enlarging an image side and allow a visual field to be eclipsed. In FIG. 3, the reference symbol AD represents an adapter lens system and the reference symbol M designates a master lens system.
SUMMARY OF THE INVENTION
A primary object of the present invention is to provide an objective optical system for endoscopes which permits using lens elements having relatively small outside diameters and reducing outside diameters of tips of endoscopes without reducing numbers of optical fibers to be used for composing light guides, and more specifically an objective optical system for tip adapter type endoscopes.
The objective optical system according to the present invention is characterized in that it is disposed, in an object side tip of an endoscope, in parallel with an illumination optical system which is inserted in a longitudinal direction and tied up in a bundle, and that it comprises lens elements which are disposed in the object side tip of the endoscope and have an outside diameter smaller than that of lens elements located in the vicinity of an image pickup device disposed on the object side in the endoscope.
The objective optical system for endoscopes according to the present invention which has the object side tip having a small outside diameter permits reducing outside diameters of tips of endoscopes without reducing numbers of optical fibers which are to be used for composing light guides.
Further, the objective optical system for endoscopes according to the present invention is characterized in that it is configured as an adapter type objective optical system for endoscopes having a tip to and from which an adaptor comprising an aperture stop for the objective optical system can freely be attached and detached.
The objective optical system for endoscopes according to the present invention consists, as exemplified in FIG. 4, of a lens unit A which is disposed as a tip on the object side and a lens unit B which is disposed on a side of an image pickup device; the lens unit A having an outside diameter smaller than that of the lens unit B.
A tip adapter lens system AD having a small outside diameter is freely attachable and detachable, as shown in FIG. 5, to and from the object side of an objective optical system (master lens system) M which is composed of the lens unit A and the lens unit B shown in FIG. 4 .
An image of an object to be observed is allowed by the adapter lens system AD to pass through an aperture stop S 1 and fall nearly perpendicularly onto an image receiving surface of an image pickup device disposed in the objective optical system (master lens system) M. In other words, a nearly telecentric optical system is composed of the adapter lens system AD and the master lens system M.
Furthermore, the optical objective system for endoscopes according to the present invention is characterized in that it is configured so as to satisfy the following conditions (1) and (2):
1.4≦f A /f B ≦7.2 (1)
2.3≦f A /f M ≦10 (2)
wherein the reference symbol f A represents a focal length of the lens unit A, the reference symbol f B designates a focal length of the lens unit B and the reference symbol f M denotes a focal length of the objective optical system (master lens system) M.
Moreover, the objective optical system for endoscopes according to the present invention is characterized in that the lens unit A having a small diameter comprises a cemented lens component which consists of a negative lens element and a positive lens element, and is configured so as to satisfy the following conditions (3) and (4):
n 1 >n 2 (3)
ν d1 <ν d2 (4)
wherein the reference symbols n 1 and n 2 represent refractive indices of the negative lens element and the positive lens element respectively of the cemented lens component, and the reference symbols ν d1 and ν d2 designate Abbe's numbers of the negative lens element and the positive lens element respectively of the cemented lens component.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a sectional view illustrating a composition of a conventional objective optical system for endoscopes;
FIG. 2 shows a sectional view illustrating a composition of another conventional objective optical system for endoscopes;
FIG. 3 shows a sectional view illustrating a composition of still another objective optical system for endoscopes;
FIG. 4 shows a sectional view illustrating a composition of a first embodiment of the objective optical system for endoscopes according to the present invention;
FIG. 5 shows a sectional view illustrating the first embodiment of the objective optical system according to the present invention in a condition where an adapter lens system is attached to the objective optical system;
FIG. 6 shows a sectional view illustrating a composition of a master unit which comprises the objective optical system for endoscopes according to the present invention;
FIG. 7 shows a sectional view illustrating a condition where an adapter unit which comprises the adapter lens system according to the present invention is attached to the master lens unit shown in FIG. 6;
FIGS. 8A, 8 B and 8 C show views illustrating a condition of a light guide disposed in the master unit shown shown in FIG. 6;
FIGS. 9A and 9B show sectional views illustrating a composition of a light guide to be used in an endoscope which uses the objective optical system according to the present invention;
FIGS. 10 through 12 show sectional views illustrating compositions of second through fourth embodiments of the objective optical system for endoscopes according to the present invention;
FIGS. 13A and 13B show sectional views illustrating a composition of a tip of an endoscope which comprises the fourth embodiment of the present invention and a light guide;
FIGS. 14 through 19 show sectional views illustrating compositions of fifth through tenth embodiments respectively of the objective optical system for endoscopes according to the present invention; and
FIG. 20 shows a perspective view descriptive of a tip adapter type endoscope system according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The objective optical system for endoscopes according to the present invention consists, as exemplified in FIG. 4, of a lens unit A which is disposed as an object side tip and a lens unit B which is disposed on a side of an image pickup device; the lens unit A having an outside diameter smaller than that of the lens unit B.
A tip adapter lens system AD is freely attachable and detachable, as shown in FIG. 5, to and from the object side of an objective optical system (master lens system) M which is composed of the lens unit A and the lens unit B shown in FIG. 4 . Such a lens system is also referred to as an adapter type objective system.
The objective optical system (master lens system) M and the adapter lens system compose a nearly telecentric system wherein an image of an object to be observed is allowed by the adapter lens system AD to pass through an aperture stop S 1 and fall nearly perpendicularly onto an image receiving surface 12 of an image pickup device 13 .
Further, the optical system according to the present invention is characterized in that it is configured so as to satisfy the following conditions (1) and (2):
1.4≦f A /f B ≦7.2 (1)
2.3≦f A /f M ≦10 (2)
wherein the reference symbol f A represents a focal length of the lens unit A, the reference symbol f B designates a focal length of the lens unit B and the reference symbol f M donotes a focal length of the objective optical system (master lens system) M.
The condition (1) defines a ratio between the focal length of the lens unit A and that of the lens unit B. Images formed by a simultaneous type electronic endoscope which uses a color mosaic filter may be affected by color shading or luminance shading. Since such a defect is dependent on angles of incidence of rays on image pickup surfaces, it is desirable that an objective optical system for electronic endoscopes is a telecentric system.
If the upper limit of 7.2 of the condition (1) is exceeded, the lens unit B must have a short focal length for configuring the objective optical system so as to satisfy the telecentric condition and an off axial principal ray will have a large inclination angle. Accordingly, the lens unit A will have a function of a lens which refracts rays having very low heights and must use a lens element having a very short radius of curvature or a high refractive power. As a result, the lens unit A will have a small outside diameter and can hardly be manufactured in practice. Further, a strong refractive power of the lens unit A is undesirable for correction of aberrations since such a strong power degrades balance of coma. For correcting coma, it is necessary to weaken the refractive power of the lens unit A by reserving a wide airspace therein. However, such an airspace is undesirable since the airspace makes it difficult to configure the objective optical system so as to satisfy the telecentric condition and prolongs a total length thereof.
If the lower limit of 1.4 of the condition (1) is exceeded, the lens unit B will have a long focal length and the offaxial principal ray will be high on the lens unit A, whereby it must have a large outside diameter contrary to the object of the present invention. Further, when an adapter lens system is to be attached to the tip of the objective optical system for composing an adapter type electronic endoscope as described above, a sectional area of a light guide LG which is to be disposed in an objective optical system frame of the endoscope is inevitably restricted by the lens unit since it is desirable to dispose the light guide in the vicinity of the lens unit A. Accordingly, a large outside diameter of the lens unit A is undesirable since it results in insufficiency of brightness by narrowing an area allowed for a light guide or enlarges an outside diameter of the tip of the endoscope.
The condition (2) defines a ratio between the focal length of the lens unit A and that of the objective optical system (master lens system). If the upper limit of 10 of the condition (2) is exceeded, the master lens system M will have a focal length too short for obtaining the objective optical system according to the present invention. In case of a telecentric optical system, an aperture stop is disposed at a location of a front focal point of a lens unit disposed after the aperture stop, or the master lens system M. Accordingly, the master lens system has a short total length but the adapter lens system undesirably has a large outside diameter when the upper limit of the condition (2) is exceeded. When an attempt is made to lower rays by strengthening a refractive power, for example, of a cemented lens component consisting of lens elements L 2 and L 3 disposed in the adapter lens system shown in FIG. 5, it is necessary to impart a very strong refractive power to this cemented lens component since rays are high on this lens component which is disposed close to the aperture stop. As a result, it will be difficult to manufacture this cemented lens component in practice and spherical aberration will undesirably be aggravated. When the cemented lens component is disposed apart from the aperture stop and has a weakened refractive power, in contrast, the adapter lens system will undesirably have a large outside diameter and a long total length.
If the lower limit of 2.3 of the condition (2) is exceeded, the master lens system M will have a long focal length for configuring the objective optical system so as to satisfy the telecentric condition. As a result, the master lens system will have a large total length. Accordingly, an endoscope which has a tip bending mechanism will have a remarkably prolonged non-flexible distal end which is a fatal defect for an endoscope. Further, the offaxial principal ray will have too small an inclination angle and the lens unit A will undesirably tend to have a large outside diameter.
It is desirable that the lens unit A which comprises at least one cemented lens component and has a positive refractive power as described above is configured so as to have a composition described below. Speaking concretely, it is desirable to compose the lens unit A, in order from a side of the aperture stop, of a negative lens element L 4 and a positive lens element L 5 which has at least one surface convex toward an image surface.
In FIG. 5, asymmetry of strong coma produced by the negative lens element L 1 disposed in the adapter lens system is corrected favorably by the surface of the lens element which is convex toward the image surface (r 12 in FIG. 5 ). Further, spherical aberration and curvature of field which are produced by the positive lens element disposed in the adapter lens system AD and the master lens system M are corrected to practically allowable levels by a negative function of the cemented surface (r 11 in FIG. 5) formed between the lens elements L 4 and L 5 of the cemented lens component disposed in the lens unit A.
Further, it is desirable, for the cemented lens component L 4 , L 5 or the lens unit A comprising at least one cemented lens component and having a positive refractive power, to compose the cemented lens component, in order from the side of the aperture stop S 1 , of the negative lens element L 4 and the positive lens element L 5 having at least one surface convex toward the image surface so as to satisfy the following conditions (3) and (4):
n 1 >n 2 (3)
ν d1 >ν d2 (4)
wherein the reference symbols n 1 and n 2 represent refractive indices of the negative lens element and the positive lens element respectively of the cemented lens component, and the reference symbols ν d1 and ν d2 designate Abbe's numbers of the negative lens element and the positive lens element respectively of the cemented lens component.
The conditions (3) and (4) are required for correcting chromatic aberration produced by a front lens unit disposed before the aperture stop, longitudinal chromatic aberration in particular practically favorably, with the cemented lens component described above. Though this chromatic aberration can be corrected to a certain degree with the cemented lens component disposed in the front lens unit, it is difficult to correct the chromatic aberration sufficiently favorably since the cemented lens component is disposed in the vicinity of the aperture stop. For this reason, correction of the chromatic aberration is aided by the cemented lens component used in a rear leas unit disposed in the image side of the aperture stop.
When the conditions (3) and (4) are satisfied by the cemented lens component, it is possible to Configure the master lens system M so as to have a small outside diameter, and correct practically favorably aberrations which are produced by the objective optical system as a whole consisting of the adapter lens system AD and the master lens system M.
Now, description will be made of the tip adapter type endoscope according to the present invention. Shown in FIGS. 6 and 7 are sectional views illustrating a composition of the tip adapter type endoscope according to the present invention: FIG. 6 showing only the master unit M, whereas FIG. 7 showing a combination of the master unit M′ and a tip adapter unit AD′ comprising an adapter lens system AD. The master unit M′ shown in FIG. 6 consists of the above-mentioned master lens system M which is disposed in a master unit frame 13 and a light guide 14 which passes therethrough. The master unit M′ is further equipped with a focus adjusting frame 15 which is adjustably fitted, for example by screwing, in a master lens system receiving frame 16 . Further, integrally fitted in the focus adjusting frame 15 is a focus adjusting lens unit (the lens unit A in FIG. 1) which is movable back and forth in a direction along an optical axis together with the focus adjusting frame 15 which is moved relatively to the master lens receiving frame 16 by a moving means, for example, of a screw type. By this focus adjusting mechanism, the master unit M′ is adjusted to optimum focused conditions. For this adjustment, it is generally desirable to focus the master lens system on infinite distance so as to minimize a variation in focused condition between the master lens system M and the adapter lens system AD. For this reason, it is effective to select a finite distance for adjusting a focused condition of the master unit M′ by using a jig lens or the like (not shown). When variations of focused conditions are too large among adapter lens systems AD which are to be used in combination with the master lens system M, the focused conditions can be adjusted as described below. A means for moving adapter lens systems in the direction along the optical axis is disposed in an adapter unit AD′ and the variations of the focused conditions are adjusted by this moving means. For example, the focused conditions can be adjusted by reserving an adjustable airspace between the negative lens element L 1 and the cemented lens component consisting of the lens elements L 2 and L 3 shown in FIG. 5 and moving the lens elements in the axial direction of the endoscope. Since the airspace reserved between the lens element L 1 and the cemented lens component consisting of the lens elements L 2 and L 3 has a very large correction coefficient for the positions of focus, these positions can be moved by slightly moving this airspace in the axial direction.
An adapter unit for observing an object located at a short distance or a long distance can be prepared by adjusting the airspace for intentional change of a position of focus. A more adequate observation range can be obtained by selecting different apertures of the aperture stop for the short distance and the long distance.
A desired direction toward a visual field, a desired field angle and a desired observation distance can be obtained by integrating the master unit M′ having an adjusted position of focus with the adapter unit AD′ as shown in FIG. 7 . Disposed in the adapter unit AD′ are the adapter lens system and an adapter side illumination system 23 , 24 . The adapter unit AD′ having such a composition is freely attachable and detachable to and from the master unit M′ with an adapter fitting frame 22 or the like. The adapter fitting frame 22 is attached to the master unit M′ by a means such as a knurling tool and the adapter unit AD′ is equipped with a means for preventing it from coming off.
It is desirable that an illumination system for leading illumination light from a light source to the tip adapter type endoscope is configured as shown in FIGS. 8A, 8 B, 8 C, 9 A and 9 B. Speaking concretely, the illumination system for the tip of the endoscope according to the present invention is characterized in that a light guide is divided, in a tip frame of an endoscope, into at least two branches each passing in the axial direction of the endoscope and having at least one bending in the tip frame of the endoscope, and that the two branches are formed again into a single light guide. Speaking concretely with reference to FIG. 8 A and FIG. 9A, a light guide for leading illumination light from a light source (not shown) is branched into two light guides 26 a and 26 b in the tip of the endoscope as shown in FIG. 8 A and FIG. 9 A. As shown in FIG. 8C (sectional view taken along the C—C line in FIG. 8 A), the branched light guides 26 a and 26 b pass through spaces which are not occupied by an image pickup device having a relatively large diameter (spaces between the image pickup device and the outer frame of the endoscope), are bent to have bendings 27 as shown in FIG. 8 A and FIG. 9B, and are integrated with each other so as to form a light guide 28 as shown in FIG. 8B (sectional view taken along the B—B line in FIG. 8 A).
By configuring a light guide as described above, it is possible to pass a large number of light guides through the tip of the endoscope and use an image pickup device which has a large image size corresponding to the full screen size. Further, by attaching cover glass plates 30 to end surfaces of the branched light guides 26 a and 26 b as shown in FIG. 9B, it is possible to assure a watertight condition for the lens system, absorb variations of the light guides 16 a and 16 b in the longitudinal direction and facilitate assembly of the light guides.
Now, the preferred embodiment of the objective optical system for endoscopes according to the present invention will be described below with reference to the accompanying drawings.
The objective optical system for endoscopes according to the present invention uses lens elements having a small diameter as lens elements to be disposed in a tip out of lens elements adopted for composing the optical system, thereby making it possible to pass a large number of optical fibers through light guides composing an illumination optical system, or obtaining a bright illumination optical system. Further, the objective optical system according to the present invention is characterized in that it is configured as the adapter type permitting attaching and detaching adapter units comprising adapter lens system having different field angles, directions toward visual fields, and so on.
Therefore, each of the embodiments described below is an adapter type objective optical system for endoscopes in which an adapter is attached to the optical system according to the present invention (master lens system).
FIGS. 4 through 9 show a first embodiment of the present invention: FIG. 4 showing a composition of a master unit M′ (FIG. 6) comprising an objective optical system (master lens system) M, whereas FIG. 5 showing an adapter unit AD′ (FIG. 7) comprising an adapter lens system AD, and freely attachable and detachable to and from the master unit M′.
The first embodiment is an example wherein a direct viewing adapter lens system AD having a field angle of 120° is attached to the master lens system M.
In the first embodiment illustrated in FIG. 4, the objective optical system (master lens system) M consists of a lens unit A which is composed of a cover glass plate C 2 , and a cemented lens component consisting of a negative lens element L 4 and a positive lens element L 5 , and a lens unit B which is composed of a field lens FL. Further, disposed in the objective optical system (master lens system) M are a low pass filter F 1 , an infrared cut filter F 2 , a CCD cover glass plate C 3 and a CCD image pickup surface 12 . The cover glass plate C 2 is used for maintaining the objective optical system in a watertight condition, whereas the cover glass plate C 3 is adopted for preventing the CCD image pickup surface from being deteriorated. It may be considered, as represented by the reference symbol B in FIGS. 4 and 5, that the lens unit B comprises the field lens FL, the low pass filter F 1 , the infrared cut filter F 2 and the cover glass plate C 3 . These optical elements have a diameter which is substantially equal to that of the image pickup surface, whereas the lens unit A has a diameter smaller than that of the lens unit B.
The adapter lens system AD which is freely attachable and detachable to and from the objective optical system (master lens system) M in FIG. 5 is composed of a negative lens element L 1 , a cemented lens component which consists of a positive lens element L 2 and a negative lens element L 3 , and a cover glass plate C 1 . This adapter lens system AD uses, in addition to the negative lens element L 1 , the cemented lens component consisting of the lens elements L 2 and L 3 for correcting chromatic aberration, curvature of field and astigmatism to levels at which these aberrations pose no problem in practical use of the objective optical system. Further, the cover glass plate C 1 is disposed for maintaining the adapter lens system in a watertight condition, thereby preventing a visual field from being dimmed by water vapor, etc. The adapter lens system has a small diameter like the lens unit A.
In the first embodiment, the adapter lens system AD is attached to the objective optical system (master lens system) M for obtaining a wide field angle of 120° so that the objective optical system is efficiently usable for a far visual field or an object located at a relatively long distance. For this embodiment, an illumination system is to be composed as already described above with reference to FIGS. 8A, 8 B, 8 C, 9 A and 9 B.
The first embodiment has numerical data listed below:
first embodiment
f = 0.582, image height = 0.5055,
object distance = −8.0860
r 1 = ∞
d 1 = 0.0886
n 1 = 1.88300
ν 1 = 40.78
r 2 = 0.3372
d 2 = 0.1440
r 3 = 0.7794
d 3 = 0.3988
n 2 = 1.76182
ν 2 = 26.55
r 4 = −0.3285
d 4 = 0.1130
n 3 = 1.60342
ν 3 = 38.01
r 5 = −1.9389
d 5 = 0.0066
r 6 = ∞ (stop)
d 6 = 0.0886
n 4 = 1.88300
ν 4 = 40.78
r 7 = ∞
d 7 = 0.0576
r 8 = ∞
d 8 = 0.0886
n 5 = 1.51633
ν 5 = 64.15
r 9 = ∞
d 9 = 0.0443
r 10 = −2.1850
d 10 = 0.0665
n 6 = 1.78472
ν 6 = 25.71
r 11 = 0.5047
d 11 = 0.3434
n 7 = 1.69680
ν 7 = 55.53
r 12 = −0.8824
d 12 = 0.2437
r 13 = 1.1630
d 13 = 0.9260
n 8 = 1.72916
ν 8 = 54.68
r 14 = ∞
d 14 = 0.1772
n 9 = 1.54814
ν 9 = 45.78
r 15 = ∞
d 15 = 0.3545
n 10 = 1.51400
ν 10 = 75.00
r 16 = ∞
d 16 = 0.1661
n 11 = 1.49700
ν 11 = 81.61
r 17 = ∞
d 17 = 0.0410
r 18 = ∞ (image)
f M =1, f A =2.856, f B =1.594, f A /f B =1.792 f A /f M =2.856
A second embodiment of the objective optical system according to the present invention has a composition illustrated in FIG. 10, wherein an adapter lens system is attached to a master lens system as in FIG. 5 . An objective optical system (master lens system) M used in the second embodiment is the same as that adopted in the first embodiment. The second embodiment adopts an adapter lens system AD which is composed of a negative lens element L 1 , a cemented lens component which consists of lens elements L 2 and L 3 , and an aperture stop. The adapter lens system used in the second embodiment is different from that adopted for the first embodiment in that the former is composed of a negative lens element L 2 and a positive lens element L 3 which are disposed in order from the object side. The reference symbol C 1 used in FIG. 10 represents a cover glass plate. The adapter lens system has a field angle of 80° and is configured for direct viewing.
The second embodiment has the following numerical data;
second embodiment
f = 0.794, image height = 0.5055,
object distance = −21.0456
r 1 = ∞
d 1 = 0.0886
n 1 = 1.51633
ν 1 = 64.15
r 2 = 0.3932
d 2 = 0.1329
r 3 = 3.4298
d 3 = 0.0665
n 2 = 1.51633
ν 2 = 64.15
r 4 = 0.4338
d 4 = 0.4209
n 3 = 1.88300
ν 3 = 40.78
r 5 = −7.9322
d 5 = 0.0066
r 6 = ∞ (stop)
d 6 = 0.0886
n 4 = 1.88300
ν 4 = 40.78
r 7 = ∞
d 7 = 0.0576
r 8 = ∞
d 8 = 0.0886
n 5 = 1.51633
ν 5 = 64.15
r 9 = ∞
d 9 = 0.0443
r 10 = −2.1850
d 10 = 0.0665
n 6 = 1.78472
ν 6 = 25.71
r 11 = 0.5047
d 11 = 0.3434
n 7 = 1.69680
ν 7 = 55.53
r 12 = −0.8824
d 12 = 0.2437
r 13 = 1.1630
d 13 = 0.9260
n 8 = 1.72916
ν 8 = 54.68
r 14 = ∞
d 14 = 0.1772
n 9 = 1.54814
ν 9 = 45.78
r 15 = ∞
d 15 = 0.3545
n 10 = 1.51400
ν 10 = 75.00
r 16 = ∞
d 16 = 0.1661
n 11 = 1.49700
ν 11 = 81.61
r 17 = ∞
d 17 = 0.0410
r 18 = ∞ (image)
f M =1, f A =2.886, f B =1.594, f A /f B =1.792, f A /f M =2.856
A third embodiment of the objective optical system according to the present invention has a composition shown in FIG. 11, wherein an adapter lens system AD is attached to an objective lens system M. This master lens system selected for the third embodiment is also the same as that used in the first or second embodiment.
Further, the adapter lens system AD is composed, in order from the object side, of a negative lens element L 1 , a positive lens element L 2 and an aperture stop, and is configured as a direct-viewing adapter lens system having a field angle of 80°. This adapter lens system corrects aberrations to practically allowable levels and uses a single lens element in place of the cemented lens component used in the second embodiment. Further, an image side surface of the positive lens element L 2 is configured as a planar surface for enhancing adherability to the aperture stop and eliminating the necessity of a cover glass plate which would otherwise be used for maintaining the adapter lens system in a watertight condition. The third embodiment requires a smaller number of parts and uses no cemented lens component, thereby eliminating a cementing step and remarkably lowering a manufacturing cost of the objective optical system.
This adapter lens system may be configured so as to intentionally tilt an image surface on the positive side so that the objective optical system is used exclusively for observing pipes. Further, the adapter lens system may be adjusted so that the third embodiment is to be used exclusively for observing objects located at short distances or long distances as described above. In other words, it is possible to change a location of focus and an observation range by adjusting an airspace reserved in the adapter lens system (airspace d 2 between the lens elements L 1 and L 2 ) and varying a diameter of the aperture stop at the same time.
Listed below is numerical data of the third embodiment:
third embodiment
f = 0.817, image height = 0.5055,
object distance = −21.045
r 1 = ∞
d1 = 0.0886
n 1 = 1.51633
ν 1 = 64.15
r 2 = 0.4836
d 2 = 0.2039
r 3 = 0.8595
d 3 = 0.2127
n 2 = 1.78472
ν 2 = 25.71
r 4 = ∞ (stop)
d 4 = 0.1817
r 5 = ∞
d 5 = 0.0886
n 3 = 1.51633
ν 3 = 64.15
r 6 = ∞
d 6 = 0.0443
r 7 = −2.1850
d 7 = 0.0665
n 4 = 1.78472
ν 4 = 25.71
r 8 = 0.5047
d 8 = 0.3434
n 5 = 1.69680
ν 5 = 55.53
r 9 = −0.8824
d 9 = 0.2437
r 10 = 1.1630
d 10 = 0.9260
n 6 = 1.72916
ν 6 = 54.68
r 11 = ∞
d 11 = 0.1772
n 7 = 1.54814
ν 7 = 45.78
r 12 = ∞
d 12 = 0.3545
n 8 = 1.51400
ν 8 = 75.00
r 13 = ∞
d 13 = 0.1661
n 9 = 1.49700
ν 9 = 81.61
r 14 = ∞
d 14 = 0.0410
r 15 = ∞ (image)
f M =1, f A =2.856, f B =1.594, f A /f B =1.792, f A /f M =2.856
An objective optical system preferred as a fourth embodiment of the present invention has a composition shown in FIG. 12, wherein an adapter lens system configured for side-viewing is attached to an objective optical system (master lens system) M. The adapter lens system is composed, in order from the object side, of a negative lens element L 1 , a visual field changing prism P, a positive lens element L 2 and an aperture stop S 1 . The objective optical system (master lens system) M is the same as that used in the first, second or third embodiment.
The fourth embodiment is an optical system in which a side-viewing adapter lens system having a field angle of 120° is attached to the objective optical system (master lens system) M. The fourth embodiment which comprises the visual field changing prism P and permits side viewing is suited in particular for observing inside surfaces of pipes, outside surfaces of heat exchange pipes of nuclear reactors and so on.
FIGS. 13A and 13B show an example wherein the tip illumination system described above is applied to the optical system preferred as the fourth embodiment. A light guide 42 used in an adapter lens system shown in FIG. 13A may be formed by molding. Further, it is desirable that the light guide 42 has an end surface 42 ′, on a side of a light source, which has a shape substantially matched with that of a light guide disposed in a master lens system M as shown in FIG. 13B (sectional view taken along the B—B line in FIG. 13A) for minimizing loss of illumination light coming from a master unit when the adapter lens unit is attached. This shape of the light guide is applicable also to an optical system to which a direct-viewing adapter lens system is attached. Further, it is desirable that the light guide has a nearly circular end surface on the object side. Since a circular end surface is capable of minimizing loss of the illumination light and ununiformity of illumination, the end surface should desirably have a nearly circular shape.
Selected for the fourth embodiment is the following numerical data:
fourth embodiment
f = 0.563, image height = 0.5055,
object distance = −5.0953
r 1 = ∞
d 1 = 0.0997
n 1 = 1.51633
ν 1 = 64.15
r 2 = 0.4218
d 2 = 0.2193
r 3 = ∞
d 3 = 0.6868
n 2 = 1.84666
ν 2 = 23.78
r 4 = ∞
d 4 = 0.0222
r 5 = 1.0326
d 5 = 0.1772
n 3 = 1.78472
ν 3 = 25.71
r 6 = ∞ (stop)
d 6 = 0.1108
r 7 = ∞
d 7 = 0.0886
n 4 = 1.51633
ν 4 = 64.15
r 8 = ∞
d 8 = 0.0443
r 9 = −2.1850
d 9 = 0.0665
n 5 = 1.78472
ν 5 = 25.71
r 10 = 0.5047
d 10 = 0.3434
n 6 = 1.69680
ν 6 = 55.53
r 11 = −0.8824
d 11 = 0.2437
r 12 = 1.1630
d 12 = 0.9260
n 7 = 1.72916
ν 7 = 54.68
r 13 = ∞
d 13 = 0.1772
n 8 = 1.54814
ν 8 = 45.78
r 14 = ∞
d 14 = 0.3545
n 9 = 1.51400
ν 9 = 75.00
r 15 = ∞
d 15 = 0.1661
n 10 = 1.49700
ν 10 = 81.61
r 16 = ∞
d 16 = 0.0410
r 17 = ∞ (image)
f M =1, f A =2.856, f B =1.594, f A /f B =1.792, f A /f M =2.856
A fifth embodiment of the present invention has a composition illustrated in FIG. 14 wherein an adapter lens system is composed of a negative lens element L 1 , a field stop S 2 , a positive lens element L 2 , an aperture stop S 1 and a cover glass plate C 1 . The fifth embodiment is an example wherein a direct-viewing adapter lens system having a field angle of 120° is attached to a master lens system M. In this embodiment, a focal length of an objective optical system is shortened by restricting only a portion of an entire image area. The fifth embodiment therefore makes it possible to obtain a range of observation depth which is broader than that obtainable with any one of the first through fourth embodiments. The first or fourth embodiment provides a field angle of 120° in a diagonal direction of an image area but has a field angle as narrow as approximately 70° in a direction along a shorter side.
The fifth embodiment which restricts the image area in a direction nearly matched with the shorter side of a monitor screen provides a merit that it permits observing a tubular object such as a pipe in all directions nearly at the same time within a circular visual field having a field angle of 120°.
Listed below is numerical data selected for configuring the fifth embodiment:
fifth embodiment
f = 0.323, image height = 0.2880,
object distance = −1.7058
r 1 = ∞
d 1 = 0.0886
n 1 = 1.88300
ν 1 = 40.78
r 2 = 0.3152
d 2 = 0.1196
r 3 = ∞ (field stop)
d 3 = 0.4896
r 4 = −2.9903
d 4 = 0.1772
n 1 = 1.84666
ν 2 = 23.78
r 5 = −0.6927
d 5 = 0.0066
r 6 = ∞ (stop)
d 6 = 0.0886
n 3 = 1.88300
ν 3 = 40.78
r 7 = ∞
d 7 = 0.0576
r 8 = ∞
d 8 = 0.0886
n 4 = 1.51633
ν 4 = 64.15
r 9 = ∞
d 9 = 0.0443
r 10 = −2.1850
d 10 = 0.0665
n 5 = 1.78472
ν 5 = 25.71
r 11 = 0.5047
d 11 = 0.3434
n 6 = 1.69680
ν 6 = 55.53
r 12 = −0.8824
d 12 = 0.2437
r 13 = 1.1630
d 13 = 0.9260
n 7 = 1.72916
ν 7 = 54.68
r 14 = ∞
d 14 = 0.1772
n 8 = 1.54814
ν 8 = 45.78
r 15 = ∞
d 15 = 0.3545
n 9 = 1.51400
ν 9 = 75.00
r 16 = ∞
d 16 = 0.1661
n 10 = 1.49700
ν 10 = 81.61
r 17 = ∞
d 17 = 0.0410
r 18 = ∞ (image)
f M =1, f A =2.856, f B =1.594, f A /f B =1.792, f A /f M =2.856
A sixth embodiment of the present invention has a composition illustrated in FIG. 15 . In this embodiment, an adapter lens system is composed, in order from the object side, of a negative lens element L 1 , a field stop S 2 , a visual field changing prism P, a positive lens element L 2 , an aperture stop S 1 and a cover glass plate C 1 .
The sixth embodiment is configured as a side-viewing objective optical system by adding the visual field changing prism P to the adapter lens system which is used in the fifth embodiment. Since the adapter lens system selected for the sixth embodiment has an observation range broader than that of the side-viewing adapter lens system used in the fourth embodiment, it provides a merit that the sixth embodiment can be placed closer to an object for observation.
The sixth embodiment has numerical data listed below:
sixth embodiment
f = 0.321, image = 0.2880,
object distance = −1.7058
r 1 = ∞
d 1 = 0.0886
n 1 = 1.88300
ν 1 = 40.78
r 2 = 0.3152
d 2 = 0.1196
r 3 = ∞ (field stop)
d 3 = 0.0443
r 4 = ∞
d 4 = 0.6868
n 2 = 1.84666
ν 2 = 23.78
r 5 = ∞
d 5 = 0.0775
r 6 = −2.9903
d 6 = 0.1772
n 3 = 1.84666
ν 3 = 23.78
r 7 = −0.6927
d 7 = 0.0066
r 8 = ∞ (stop)
d 8 = 0.0886
n 4 = 1.88300
ν 4 = 40.78
r 9 = ∞
d 9 = 0.0576
r 10 = ∞
d 10 = 0.0886
n 5 = 1.51633
ν 5 = 64.15
r 11 = ∞
d 11 = 0.0443
r 12 = −2.1850
d 12 = 0.0665
n 6 = 1.78472
ν 6 = 25.71
r 13 = 0.5047
d 13 = 0.3434
n 7 = 1.69680
ν 7 = 55.53
r 14 = −0.8824
d 14 = 0.2437
r 15 = 1.1630
d 15 = 0.9260
n 8 = 1.72916
ν 8 = 54.68
r 16 = ∞
d 16 = 0.1772
n 9 = 1.54814
ν 9 = 45.78
r 17 = ∞
d 17 = 0.3545
n 10 = 1.51400
ν 10 = 75.00
r 18 = ∞
d 18 = 0.1661
n 11 = 1.49700
ν 11 = 81.61
r 19 = ∞
d 19 = 0.0410
r 20 = ∞ (image)
f M =1, f A =2.856, f B =1.594, f A /f B =1.792, f A /f M =2.856
The objective optical system (master lens system) M is common to all the first through sixth embodiments described above.
A seventh embodiment of the present invention has a composition illustrated in FIG. 16, wherein an objective optical system (master lens system) M is composed, in order from the object side, of a lens unit A which is composed of a cemented lens component consisting of a negative lens element L 4 and a positive lens element L 5 and a lens unit B which is composed of a field lens FL. Further, the seventh embodiment additionally comprises a cover glass plate C 1 , a low pass filter F 1 , an infrared cut filter F 2 , a CCD cover glass plate C 3 and a CCD image pickup surface.
An adapter lens system adopted for the seventh embodiment is composed, in order from the object side, of a negative lens element L 1 , a positive lens element L 2 and an aperture stop S 1 .
In the seventh embodiment, the objective optical system (master lens system) M is configured so as to have an outside diameter as small as possible while satisfying the conditions (1) and (2) so that an increased number of light guides can pass therethrough. It is undesirable to configure the lens unit A so as to have a smaller outside diameter since such an outside diameter will allow eclipse of a visual field, production of flare, etc. and aggravation of aberrations to unallowable levels. Attached to the objective optical system (master lens system) M is an adapter lens system having a field angle of 80°.
The seventh embodiment has the following numerical data:
seventh embodiment
f = 0.727, image height = 0.4567,
object distance = −19.0114
r 1 = ∞
d 1 = 0.0800
n 1 = 1.51633
ν 1 = 64.15
r 2 = 0.4400
d 2 = 0.2239
r 3 = 0.5969
d 3 = 0.1990
n 2 = 1.78472
ν 2 = 25.71
r 4 = ∞ (stop)
d 4 = 0.0155
r 5 = ∞
d 5 = 0.0800
n 3 = 1.51633
ν 3 = 64.15
r 6 = ∞
d 6 = 0.0400
r 7 = −0.7168
d 7 = 0.0600
n 4 = 1.78472
ν 4 = 25.71
r 8 = 0.2927
d 8 = 0.2882
n 5 = 1.69680
ν 5 = 55.53
r 9 = −0.5898
d 9 = 0.3002
r 10 = 1.0095
d 10 = 0.8185
n 6 = 1.72916
ν 6 = 54.68
r 11 = ∞
d 11 = 0.1601
n 7 = 1.54814
ν 7 = 45.78
r 12 = ∞
d 12 = 0.3202
n 8 = 1.51400
ν 8 = 75.00
r 13 = ∞
d 13 = 0.1501
n 9 = 1.49700
ν 9 = 81.61
r 14 = ∞
d 14 = 0.0370
r 15 = ∞ (image)
f M =1, f A =9.484, f B =1.010, f A /f B =9.885 f A /f M =9.984, outside diameter of lens unit A=2.4 mm, outside diameter of lens unit B=5.4 mm, (outside diameter of lens unit A)/(outside diameter of lens unit B)=0.44
An eighth embodiment of the present invention has a composition illustrated in FIG. 17 . In the eighth embodiment, an adapter lens system AD is composed of a negative lens element L 1 , a positive lens element L 2 and an aperture stop S 1 , whereas an objective optical system (master lens system) M is composed of a lens unit A which is composed of a cover glass plate C 2 , a cemented lens component consisting of a negative lens element L 4 and a positive lens element L 5 , and a lens unit B which is composed of a field lens FL, a low pass filter F 1 , an infrared cut filter F 2 , a CCD cover glass plate C 3 and a CCD image pickup surface.
In the eighth embodiment also, the lens unit A disposed in the master lens system M is configured so as to have an outside diameter as small as possible while satisfying the conditions (1) and (2). In the eighth embodiment, it is undesirable to configure the lens unit A so as to have a smaller outside diameter since such an outside diameter will enhance rays on the lens unit B. As a result, it is necessary to enlarge an outside diameter of the lens unit B, thereby producing inconvenience of a necessity to enlarge an outside diameter of a tip of the endoscope or reduce a number of optical fibers to be disposed in light guides. The eighth embodiment is an example wherein an adapter lens system AD which has a field angle of 80° is attached to the master lens system M.
Selected for the eighth embodiment is numerical data which is listed below:
eighth embodiment
f = 0.825, image height = 0.5228,
object distance = −21.7640
r 1 = ∞
d 1 = 0.0916
n 1 = 1.51633
ν 1 = 64.15
r 2 = 0.4946
d 2 = 0.2108
r 3 = 0.9964
d 3 = 0.2199
n 2 = 1.78472
ν 2 = 25.71
r 4 = ∞ (stop)
d 4 = 0.1983
r 5 = ∞
d 5 = 0.0916
n 3 = 1.51633
ν 3 = 64.15
r 6 = ∞
d 6 = 0.0458
r 7 = −3.2009
d 7 = 0.0687
n 4 = 1.78472
ν 4 = 25.71
r 8 = 0.5537
d 8 = 0.3551
n 5 = 1.69680
ν 5 = 55.53
r 9 = −0.9075
d 9 = 0.2978
r 10 = 1.2448
d 10 = 0.9576
n 6 = 1.72916
ν 6 = 54.68
r 11 = ∞
d 11 = 0.1833
n 7 = 1.54814
ν 7 = 45.78
r 12 = ∞
d 12 = 0.3666
n 8 = 1.51400
ν 8 = 75.00
r 13 = ∞
d 13 = 0.1718
n 9 = 1.49700
ν 9 = 81.61
r 14 = ∞
d 14 = 0.0424
r 15 = ∞ (image)
f M =1, f A =2.3, f B =1.707, f A /f B =1.347, f A /f M =2.3, outside diameter of lens unit A=3 mm, outside diameter of lens unit B=4.4 mm, (outside diameter of lens unit A)/(outside diameter of lens unit B)=0.68
In each of the seventh and eighth embodiments, it may be considered that the lens unit B used in the master lens system comprises the field lens FL, the low pass filter F 1 , the infrared cut filter F 2 and the cover glass plate C 3 .
In the numerical data of the first through eighth embodiments described above, the reference symbols r 1 , r 2 , . . . represent radii of curvature on respective lens surfaces, the reference symbols d 1 , d 2 , . . . designate thicknesses of respective lens elements and airspaces reserved therebetween, the reference symbols n 1 , n 2 , . . . denote refractive indices of the respective lens elements, and the reference symbols ν 1 , ν 2 , . . . represent Abbe's numbers of the respective lens elements. Further, the reference symbol f designates a focal length of the optical system as a whole comprising the adapter lens system and the reference symbol f M denotes a focal length of the master lens system only. The numerical data is normalized to f M =1.
Out of the embodiments described above, the seventh embodiemnt is configured to have a ratio (outside diameter of lens unit A)/(outside diameter of lens unit B) of 0.44 which is the smallest of all the ratios or a largest difference between the outside diameters of all the differences selected for the embodiments and the eighth embodiment is configured to have a ratio of 0.68 between the outside diameters which is the largest of all the ratios or a smallest difference between the outside diameters of all the differences selected for the embodiments. Ratios between the outside diameters selected for the other embodiments are between the values adopted for the seventh and eighth embodiments.
When an adapter lens system type objective optical system such as that according to the present invention uses an adapter lens system having a wider field angle, a lens element which is to be disposed on the object side in the optical system tends to have a large outside diameter. For this reason, it is desirable to select for an endoscope tip such a composition as that adopted for a ninth embodiment of the present invention illustrated in FIG. 18 . Schematically shown in this drawing is an adapter lens system which is seen from a side of its tip and has a partially cut objective optical system. Since an image pickup device generally has a rectangular shape, it is unnecessary to shape lens elements circular. Accordingly, a ray which is incident highest on the image pickup device (in a diagonal direction in a visual field) is not eclipsed when an objective optical system 72 is partially cut as shown in FIG. 18 . Further the lens element may be rectangular.
When lens elements cannot be laid within a tip frame or when it is desired to configure an endoscope tip thinner, an illumination lens 73 may be composed of parts which are integrated after shaping as shown in FIG. 18 . An illumination lens having such a shape may be manufactured by shaping or molding a material such as a resin.
Since the image pickup device is rectangular as described above, circular lens elements are apt to allow flare to be produced by detrimental rays (rays outside a visual field). Accordingly, it is possible to select a composition such as that shown in FIG. 19 illustrating a tenth embodiment of the present invention. Shown in this drawing is a side-viewing adapter lens system as seen from a side of its end surface (from above) which is not circular unlike the ordinary flare stop. Detrimental rays to be incident on an image pickup surface can be eliminated by using a flare stop 75 which has a partially cut circular shape. A plurality of portions of a flare stop may be cut off and a flare stop having such a shape may be used in an objective optical system.
FIG. 20 is a perspective view schematically showing an endoscope system which uses the tip adapter lens system type objective optical system for endoscopes according to the present invention. In this drawing, an adapter that is optimum for an object to be observed is selected from among a group of adapters 77 and attached to an endoscope body 78 . In this condition, an image of the object is imaged on a light receiving surface of an image pickup device disposed in the endoscope through the attached adapter lens system and the objective optical system for endoscopes, transferred as image data through a universal cord 80 to a camera control unit 82 for required conversion of the image data, and output to a monitor for display. An illumination light beam emitted from a light source is led through light guides (not shown) so that an illuminator lens disposed in a tip of the endoscope will irradiate the object at proper distribution and intensities. | An illumination system for endoscopes has a light guide bundle constructed and arranged to illuminate an object to be observed. The light guide bundle is extended in an axial direction of the endoscope and branched into a plurality of branch portions in a frame which is adapted to be disposed inside of the endoscope. Each of the branch portions have a crescent-shaped cross-section at a mid-portion along the axial direction of the endoscope and each of the branch portions have at least one bent portion in which a protective glass plate is disposed on each exit surface of the branch portions. An endoscope system includes the above illumination system. | 0 |
BACKGROUND OF THE INVENTION
1. The Field of the Invention
This invention relates to expandable pouches and more particularly to that class of pouch or bag which facilitates containing items therein of extremely large size when the pouch is in an expanded condition and permits the pouch to be utilized in a partially folded up condition, at all other times.
2. Description of the Prior Art
The prior art abounds with foldable and collapsible bags and pouches of many varieties. U.S. Pat. Nos. 2,447,940 issued Aug. 24, 1948 to I. Holland and 2,431,030 issued Nov. 18, 1947 to E. L. Edwards each teach a self-closing or foldable handbag wherein a string-like attachment is threadingly engaged with the side walls of the bag adjacent the open mouth regions thereof such that when the string-like attachment is pulled taut the open mouth portion of the bag is shrunk into a closed condition thereby maintaining the contents of the bag locked therewithin, permitting the string-like attachment to act as a handle therefor. Unfortunately, such apparatus is restricted in the size of the articles that may be contained within the bag and is not otherwise foldable so as to permit the bag size to be collapsed when carrying small articles therewithin.
U.S. Pat. Nos. 676,659 issued June 18, 1901 to M. E. Mogg (No. 1) and 676,659 issued the same date to the same inventor, (No. 2) both teach a flexible pouch-like bag having a handle attachment affixed to the sides of the bags and extending upwardly from the open mouth portions thereof. Such handles may not be used when attempting to grasp them together with one hand of the user when a large package is inserted within the container such that a portion of the package extends outwardly from the open mouth region of the bag.
SUMMARY OF THE INVENTION
A primary object of the present invention is to provide a collapsible and expandable shopping bag which may be utilized to carry large or small packages with equal ease.
Another object of the present invention is to provide an expandable shopping bag wherein the otherwise usable small gathering-like handle disposed in the marginal edges thereof, are not required for purposes of carrying the bag when large articles are disposed carried within the bag.
Still another object of the present invention is to provide a girth encircling strap which permits the bag to be utilized in a collapsed or folded up condition whilst carrying articles, serving as a shoulder strap, if desired, when the bag or pouch is permitted to be expanded to full size whilst carrying larger articles.
Yet another object of the present invention is to provide a shopping bag or pouch which may be carried about utilizing hand grasping handles and a shoulder strap carrying means.
A further object of the present invention is to provide a girth encircling strap which may be utilized to secure articles within the bag when such strap is maintained in a tightened condition therearound.
Another object of the present invention is to provide a pouch or bag expansion limiting strap which adds greater strength to the bag when installed wrapped around the girth of such bag.
Still another object of the present invention is to provide a pouch-like shopping bag having a pair of opposed hand grasping handles serving to close the open mouth portion of the pouch when such handles are grasped and utilized to lift the bag upwardly.
Yet another object of the present invention is to provide an expandable shopping bag having a storage location for shoulder straps, when such shoulder straps are not being utilized for the bag carrying operation.
Heretofore, shopping bags were predominantly fabricated having a generalized sack or bag-like shape in which a pair of inverted U-shaped handles were affixed to opposed marginal edges of the bag upstanding from the open mouth regions thereof. However, when it is desired to carry large articles within the bag or pouch, such handles tended to reside on the sides of such articles provided the length of such articles extended outwardly from the open mouth regions of the pouch, thereby preventing efficient carrying about of the pouch with the large package therewithin. Furthermore, large shopping bags represented an inconvenient carrier when carrying about small items within the bag. Hence, it is highly desirable to provide an expandable shopping bag capable of having small storage capacity therewithin when carrying small articles and a larger storage capacity when carrying large articles, coupled with carrying handles or straps which extend well above the top of large items carried about within the bag. Furthermore, when carrying small articles it is highly desirable to maintain the open mouth region of the pouch in a semi-closed condition. In addition, it is desirable to add to the strength of the bag by utilizing a strap portion wrapped about the girth of the bag thereby preventing heavy items from bulging the sides of the bags outwardly tending to rupture them. The present invention recognizes these needs and provides a ready solution therefor by utilizing a girth encircling strap which tends to maintain the bag in a small shape, suitable for carrying about small items therewithin. The strap may be loosened so as to accommodate larger articles of commerce within the bag, as desired. Finally, the strap may be removed from its waist encircling position and be disposed extending upwardly and outwardly from the open mouth portion of the bag so as to form thereby a shoulder strap for carrying the bag, or alternatively, an extended or lengthy hand grasping handle. A pair of short string-like handles are attached to opposed loop-like channels disposed on opposite surfaces adjacent the marginal edges of the pouch occupying a length somewhat less than half the perimeter of the bag. In this position, portions of the exposed string-like attachments act as handles and when so used, tend to pull together, in a semi-gathering type arrangement, the majority of the perimeter of the open mouth portion of the bag, when the handles support the bag. The remaining ungathered portions of the perimeter of the open mouth portion of the bag may be folded inwardly intermediate the gathered portions when the bag is in a semi-folded up condition or extended outwardly when the bag encircling strap is loosened, in a large item carrying mode. When the string-like attachments are relaxed, the bag mouth may be fully opened and the bag may be carried about utilizing the girth encircling straps in a shoulder strap mode or a hand-held carrying strap mode such that items may be carried within the bag absconsed totally within the bag or partially passing through the fully open mouthed portions thereof. It this manner, the bag may be folded up, enlarged, carry small parcels or large, be carried utilizing a short pair of opposed hand-held straps or a single elongated strap in either a hand-held mode or a shoulder carrying mode. Since the bag is flexible, the entire apparatus may be rolled up or folded, occupying a small space when not in use.
These objects as well as other objects of the present invention will become more readily apparent after reading the following decription of the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front elevation view of the present invention shown in an expanded mode.
FIG. 2 is a front elevation view of the present invention shown in a semi-folded up mode.
FIG. 3 is a side elevation view of the present invention shown in an expanded mode, having the waist encircling strap being utilized in the shoulder carrying mode thereof.
FIG. 4 is a side elevation, cross-sectional view, taken along lines 4--4, viewed in the direction of arrows 4--4, of the apparatus shown in FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The structure and method of fabrication of the present invention is applicable to a flexible pouch, fabricated from a fabric-like material, such as canvas, having a pair of opposed side walls, sewn together on the lowermost and side marginal edges thereof, a portion of the uppermost marginal edge, of each of the side walls, are turned back on themselves, so as to form a pair of passageways therein, carried within each of the passageways is a string-like attachment, preferably fabricated from a rope-like material, such as leather welting or if desired, cording. A pair of loops are disposed on each of the sheets defining the pouch extending having their open mouth portions disposed about a waist encircling line and located adjacent the open mouth regions of the pouch. A flexible strap, preferably fabricated from leather or the like, is disposed residing within the loops and is provided with a pair of snap fastener components secured on one surface, adjacent the end of such strap, the other surface of the strap is provided having a pair of complementary shaped snap fasteners disposed in spaced apart relationship and secured thereto. Each sheet comprising the bag or pouch is also provided with a complementary snap fasteners disposed adjacent the open mouth portions thereof and intermediate the ends of the passageways. Binding may be disposed adjacent the edges of each of the sheets forming the bag and extending from the open mouth portions of the bag, passing beneath the loops, and downwardly towards the lowermost seam of the pouch. Such binding serves to reinforce the pouch and act decoratively thereon. When the bag is disposed into a folded up condition, the seams extending upwardly from the lowermost bottom seam and the open mouth portion of the bag, may be folded inwardly within the confines of the bag, retained thereat by cinching the girth encircling strap into a tightened position, by having such strap pass through the loops and utilizing one of the snap fastener components into preferred engagement with one of the plurality of complementary snap fastener components. When it is desired to have the bag contain somewhat larger items, the girth encircling strap may be expanded, by allowing the same snap component to engage another complementary snap component, thereby allowing the girth encircling strap to have a greater length. In either position, grasping the string-like attachments, comprising each endless band of flexible string-like material, causes the passageways to gather up tending to seal together the mouth of the pouch in a puckered up condition. When it is desired to utilize the girth encircling strap as a shoulder strap, such strap is removed from the loops, allowing the snap fastener components disposed at the ends thereof to engage the complementary snap fastener components secured to the sides of the bag or pouch. In this location, the shoulder carrying strap extends outwardly from the string attachments which may be either maintained in a taut condition or may be relaxed so as to permit large articles to be placed within the bag extending outwardly from the open mouth region thereof. Obviously, buckles or other fasteners may be substituted for the snap fasteners thereby permitting such bag to carry articles of great weight with relative ease.
Now referring to the figures, and more particularly to the embodiment illustrated in FIG. 1 showing the present invention 10 comprising a sheet 12, superimposed over another sheet 14 therebehind. Dotted lines 16 simulate stitching disposed adjacent lowermost marginal edge 18. Dotted lines 20, disposed on each side of sheet 12 and 14, simulate stitching adjacent marginal edges 22, of sheet 12 and 14. Dotted lines 24 simulate stitching disposed adjacent marginal edges 26 of sheet 12, forming a finished edge thereby. Dotted lines 28 serve the same purpose as dotted lines 24, for sheet 14. Open mouth region 30 is exposed when marginal edges 22 are located outwardly from decorative binding 32. Loops 34 are similar to loops not shown, located similarly on sheet 14. Girth encircling strap 36 is shown carried within loops 34 and has end 38 thereof overlaying region 40, being secured thereto, utilizing snap fastener element 42 therefor. Complementary snap fastener element 44 is shown secured to sheet 12 on external surface 156 thereof. Another complementary fastener, now shown, is located on sheet 14, in an equivalent location to complementary fastener 44. String-like attachment 46 is shown carried within a passageway 150, denoted by dotted lines 48, occupying a position adjacent a portion of the length of marginal edge 26. Passageway 150 is formed by folding such portion of the length of marginal edge 26 over onto external surface 156 of sheet 12 and securing such portion to sheet 12 as by stitching. Another string-like attachment, not shown, extends behind attachment 46 and is carried within another passageway, not shown, similar to that depicted by passageway 150 and is carried adjacent the marginal edge, not shown, of sheet 14. It is to be noted that girth encircling strap 36 extends around the entire external surfaces of sheets 12 and 14, adjacent the uppermost marginal edges of such sheets and is removable from loops 34 and the loops, not shown, carried by sheet 14.
FIG. 2 illustrates string attachment 46 shown emerging outwardly from openings 50 disposed at the ends of sheet 12, adjacent the open mouth portion 52, formed opposite the marginal edge 18 thereof. In this position, snap fastener component 42 is installed to the right of dotted lines 54, denoting unused complementary snap fasteners carried by strap 36, located behind end 38 of girth encircling strap 36. When string attachment 46 is pulled upwardly, at point 56, in the direction of arrow 58, ends 60, of the passageway in which string attachment 46 resides, move inwardly towards each other, in the direction of arrows 62. In this condition, open mouth portion 52 is collapsed, thereby permitting present invention 10 to carry small articles within the confines between sheet 12, and sheet 14, shown in FIG. 1.
FIG. 3 illustrates string attachment 46 and its mated string attachment 64. Both string attachments emerge outwardly from openings 50 located in sheets 12 and 14, adjacent open mouth region 52, shown in a collapsed condition, due to disposing string attachments 46 and 64 in close engagement. Waist encircling strap 36 is shown removed from loops 34 and companion loops 66, carried on sheet 14. Marginal edge 22 is shown extending intermediate sheets 12 and 14 and is formed thereby. Such marginal edge is not shown tucked behind sheet 12, as in FIG. 2, but may extend outwardly from decorative binding 32, as shown in FIG. 1. Snap fastener 42, disposed at end 38 of girth encircling strap 36, is shown snappingly engaged with complementary snap fastener 44. Another snap fastener 68, is shown carried adjacent end 70, of girth encircling strap 36, and is secured to another complementary snap fastener 72, secured to sheet 14, in a similar position to complementary snap fastener 44. In this position, complementary snap fasteners 54 are shown disposed on an outermost surface 74 of girth encircling strap 36. In the position shown in FIG. 1, girth encircling strap 36 has snap fastener 68 disposed in touching engagement with an exterior surface of either sheet 12 or sheet 14 shown thereat. Another complimentary snap fastener, not shown, similar to complementary snap fastener 44, may be located on such surface, at a convenient location, facilitating the storage of end 70 on such surface, when girth encircling strap 36 is stored in a girth encircling position, as shown in either FIGS. 1 or 2.
FIG. 4 illustrates a cross-sectional view of a portion of the apparatus shown in FIG. 3, disposed defining passageway 150 in which string attachment 46 resides. It should be noted that holes 50, shown in FIGS. 2 and 3, define the ends of passageway 150. Free end 152, of sheet 12 is secured to external surface 156, of sheet 12, utilizing stitches 154 thereof. Bight 158 thus defines passageway 150. The same construction is utilized to form a passageway in which string attachment 64, shown in FIG. 3, resides.
One of the advantages of the present invention is a collapsible and expandable shopping bag which may be utilized to carry large or small packages with equal ease.
Another advantage of the present invention is an expandable shopping bag wherein the otherwise usable small gathering-like handle disposed in the marginal edges thereof, are not required for purposes of carrying the bag when large articles are disposed carried within the bag.
Still another advantage of the present invention is a girth encircling strap which permits the bag to be utilized in a collapsed or folded up condition whilst carrying articles, serving as a shoulder strap, if desired, when the bag or pouch is permitted to be expanded to full size whilst carrying larger articles.
Yet another advantage of the present invention is a shopping bag or pouch which may be carried about utilizing hand grasping handles and a shoulder strap carrying means.
A further advantage of the present invention is a girth encircling strap which may be utilized to secure articles within the bag when such strap is maintained in a tightened condition therearound.
Another advantage of the present invention is a pouch or bag expansion limiting strap which adds greater strength to the bag when installed wrapped around the girth of such bag.
Still another advantage of the present invention is a pouch-like shopping bag having a pair of opposed hand grasping handles serving to close the open mouth portion of the pouch when such handles are grasped and utilized to lift the bag upwardly.
Yet another advantage of the present invention is an expandable shopping bag having a storage location for shoulder straps, when such shoulder straps are not being utilized for the bag carrying operation.
Thus, there is disclosed in the above description and in the drawings, an embodiment of the invention which fully and effectively accomplishes the objects thereof. However, it will become apparent to those skilled in the art, how to make variations and modifications to the instant invention. Therefor, this invention is to be limited, not by the specific disclosure herein, but only by the appending claims. | An expandable shopping bag utilizes an open mouth pouch, fabricated from a flexible material, having a girth encircling strap removably secured thereto which permits the pouch to be utilized in small and large item receiving capacities. The strap ends are removably affixed to the pouch adjacent the open mouth portion thereof facilitating its use as a shoulder strap, complementing a pair of string-like handles partially contained within opposed passageways shorter than half the perimeter of the marginal edges of the pouch. | 0 |
BACKGROUND OF THE INVENTION
The invention relates to a closure for a container such as a cap for a bottle or the like.
Bottle stoppers are injection molded by many various methods. EP Patent No. 0 056 469 describes single-piece stoppers with snap hinges that have proven to be very reliable. A plastic closure of similar construction, but that does not have a snap hinge, is known from French patent No. FR-2 309 425. The present invention is based on the technical problem of making a generic stopper with a snap hinge, that is both less expensive to produce and safe and easy to use. This technical problem is solved by the present invention as will be described below.
The known closures of the kind referred to above are injection molded in a position open to approximately 180°. The opening to a complete 180° is necessary in order to achieve a simple mold opening without transverse stresses. The inverse shapes of the interior contours of the cap and base portions are situated side by side in one half of the injection mold. The hinges must be chosen so that they allow for an opening of around 180°, an opening angle that afterwards is not normally in use at all.
SUMMARY OF THE INVENTION
The closure according to the present invention makes possible a process with which, in contrast to the conventional method of manufacture, the closure can be manufactured in a closed position in the injection molding process. This results in a number of remarkable advantages.
The cross-sectional area of the injection mold parts is reduced to somewhat less than half, so that double as many closures can be produced on the same injection mold press per cycle than with conventional processes and conventional tools. Because the closures are already closed after the injection molding, the isolated closing operation required for conventional closures is no longer required. For the foregoing reasons the closures according to the invention can be produced at a significantly lower cost.
Because the closure is injection molded in a closed position, it can quite easily be made tamper proof, i.e. secure against unintentional premature opening, by attaching safety tabs to the snap hinge between the top and the lower portion. These safety tabs contribute to filling the die cavity during injection molding.
In contrast to conventional closures, it is not necessary in this process for the cap to swivel 180° from the closed position relative to the base portion.
BRIEF DESCRIPTION OF THE DRAWINGS
The advantages of the present invention will become more fully understood from the following description in conjunction with the attached drawings, in which:
FIG. 1 is an axial view through a bottle closure according to the present invention;
FIG. 2 and FIG. 3 are sectional views in the direction of the arrows II and III in FIG. 1 respectively;
FIG. 4 and FIG. 5 are sectional views along lines IV--IV and V--V in FIG. 3 respectively;
FIG. 6 is an enlarged view in the direction of arrow VI in FIG. 4;
FIG. 7 is a sectional view along lines VII--VII in FIG. 6;
FIG. 8 is a schematic axial view through a portion of an injection mold part; and
FIG. 9 and FIG. 10 are plan views of two alternate embodiments of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Bottle closure 1 as shown in FIG. 1 is a single piece of plastic, e.g. of polypropylene, injection molded and consisting of a pipe shaped base portion 2 and a cap portion 3. Insert 4 is snapped into base portion 2, which with cylindrical insert 5 is inserted as a seal into the cylindrical neck 6 of bottle 7. By means of a circular ring 8, insert 4 is snapped over rim 9 of the bottle neck 6. Clamping rim 10 of base portion 2 holds the insert 4 in the base portion 2. In the embodiment presented here a circular cylindrical, tubular insert 15 of cap 3 seals against a cylindrical interior surface 16 of insert 4. Surface 16 and insert are coaxial to axis 17 of the tubular base portion 2.
Cap 3 is connected to base portion 2 by a snap hinge 20, as shown in FIG. 2. This consists of a main bending juncture 21, which directly connects cap 3 to base portion 2 and runs vertical to axis 17 and defines the main pivotal axis of closure 1, and two intermediate elements 22 arranged on both sides, that are each connected by two secondary or auxiliary bending junctures 23, 24 to base portion 2 or cap 3. Main bending juncture 21 and secondary bending Junctures 23 and 24 are suitably designed as plastic film snaps and are all preferably straight. In the embodiments presented the intermediate elements 22 are triangular tension elements. Their points are turned against one another and collapse with the ends of main bending juncture 21. In the closed position the surface defined by the secondary bending junctures 23, 24 of the same intermediate element 22 is slanted both toward the main bending juncture 21 and toward axis 17. This enables the sectional view in the area of snap hinge 20 to be formed in such a way that in spite of the appropriate narrow belted thin points for bending junctures 21, 23, 24 the mold part 70 for formation of the interior wall of the die cavity of the injection mold illustrated in FIG. 8 can be opened in the direction of axis 17. Main bending juncture 21 and secondary bending junctures 23, 24 are arranged on an approximately cone-shaped or cylinder-shaped surface, whose generatrix form in conjunction with axis 17 a sharp angle of preferably more than 20°. Flat surfaces 25, 26, 27 (see FIG. 6) connect downward, in the direction of opening, to bending Junctures 21, 23, 24 parallel to the axis 17. In contrast, the connecting surfaces 28, 29, 30 from the opposite side pass almost radial to axis 17. In cap 3 there is one slot 31 at each side of the snap hinge 20. The intermediate elements 22 have a free rim 32 against this slot 31.
The approximately conical outer surface 35 of snap hinge 20 continues in the downward direction beyond slots 31 as a conical end face 36 of base portion 2 and as cone 37 of cap 3. On its periphery extending from slots 31 connecting to cone 37, cap 3 has a cylindrical surface 38 whose diameter is less than the smallest internal diameter of base portion 2. Narrow slot 39 formed from this is bridged at several points by safety tabs 40 extending from the main hinge 21. Diametrically opposite to snap hinge 20, cone 37 of cap 3 terminates into a radial, inwardly displaced cylindrical wall 41, so that a grip attachment 42 is formed thereon. The upper frontal area 43 of base portion 2 and the lower frontal area 44 of the outer area of cap 3 are in a single plane 45.
The lower portion of cone 37 and the cylindrical section 38 of cap 3 are reinforced by several radial ribs 46 (see FIG. 2), which also are connected to frontal area 44. This frontal area 44 reinforces ribs 46 in closed position on a flat frontal area 47 of insert 4 (FIG. 1), in order to transfer the outward forces and loads of cap 3 to insert 5.
As is apparent from FIG. 2 the outer diameter of cap 3 is smaller by twice the width of slot 39 than the smallest internal diameters of base portion 2.
In FIG. 8 a mold part 70 of an injection mold is schematically presented in sectional view. The section provides for a completed mold in the die cavity above the separating plane 45 a wall 71 for formation of the internal contour of cap 3 and below the separating plane 45 a wall 72 for formation of the interior contour of base portion 2. The two walls 71, 72 are coaxial to each other and to axis 17. In the projection parallel to axis 17, wall 71 is located completely within wall 72.
The described closure 1 is well suited for expedient mechanical assembly on bottle neck 6. It is tamper proof, i.e. the final user can immediately determine if closure 1 has been opened after placement on the bottle 7 because then the safety tabs 40 are broken. The safety tabs 40 are broken when the bottle is opened for the first time. This is both visible and audible. For additional opening the tension elements 22 are stressed, and pressure or traction forces that because of the eccentric traction forces lead to an elastic bending of these closure components are transferred to the walls of base portion 2 and cap 3 next to the bending junctures 21, 23, 24. As soon as dead center is exceeded, in which all bending junctures 21, 23, 24 lie in a single plane, the cap snaps into the open position. The described closure 1 is also appropriate when correspondingly adapted for container openings other than round ones, e.g. for oval openings. Given appropriate adaptation of neck 6 of bottle 7 insert 4 can also be dispensed with. Instead of the described snap hinge 20, which presents a particularly aesthetically pleasing solution, other hinge designs can also be used, for example snap hinges for which the secondary hinges are parallel to the main hinge and/or for which the intermediate elements are spiral springs.
Two alternate applications are presented in FIGS. 9 and 10 in which like reference numerals denote like elements of FIGS. 1-8, and in which the snap hinge 20 is constructed on flat surfaces angled towards one another, for example on adjoining surfaces 35a, 35b and 35c of a truncated pyramid. That way the bending junctures 21, 23, 24 can be constructed perfectly straight. As FIG. 10 shows, the slots 31 can also run skewed towards closure axis 17 and the intermediate elements 22 asymmetrically arranged relative to the main axis defined through the main bending juncture 21. In this way the tension of intermediate elements 22 can be reduced for a specified dead-center angle.
The invention having thus been described, it will be apparent to those of skill in the art that the same may be varied in many ways without departing from the spirit of the invention. All such variations are intended to be covered by the following claims. | The closure (1) consists of a tubular base portion (2) and a cap (3). Considered in the direction of the axis (17) of the base portion (2), in the closed position the outer contour of the cap (3) is within the interior contour of the base portion (2). Cap and base portion are connected to each other in a single unit by a snap hinge and injection molded in a closed position. Extending from the snap hinge, cap and base portion are additionally connected together by a safety strap (40), which is to safeguard against unintentional premature opening of the closure (tamper evidence). The closure enables a marked productivity increase during manufacture. | 1 |
This is a division of application Ser. No. 830,240 filed, Sept. 2, 1977, now U.S. Pat. No. 4,145,466, issued Mar. 20, 1979.
BACKGROUND OF THE INVENTION
I. Field of the Invention
This invention relates to compositions and processes for thermoplastic processing of PET, more particularly extrusion/melt shaping of PET.
II. Description of the Prior Art
Until now, linear thermoplastic polyesters such as PET have found no utility in extrusion/melt shaping and related thermoplastic fabrication techniques that require dimensional stability in the melt because such techniques require high melt viscosity and a high degree of melt strength and elasticity. PET generally has an intrinsic viscosity of about 0.5 to 1.1 dl. per gm. and insufficient melt strength and elasticity for such applications. Furthermore, PET exhibits a fast rate of crystallization at temperatures above 140° C. which makes the achievement of clear amorphous articles by such thermoplastic fabrication techniques difficult. Therefore, until now, articles produced from PET had to be made by injection blow-molding techniques in which a parison or perform is injection molded, cooled rapidly and then reheated to a temperature above the T g but below the crystalline melting point and then blown to the desired shape. See U.S. Pat. Nos. 3,733,309; 3,745,150; and 3,803,275. While amorphous articles would be preferred because of their clarity and toughness as compared to crystalline articles, until now such processing required very specialized equipment such as is shown in U.S. Pat. No. 3,803,275 wherein a hollow slug was extruded directly into a mold maintained at less than 0° C.
It has been previously suggested by Dijkstra et al, U.S. Pat. No. 3,553,157, to prepare thick-walled shaped articles of improved impact strength from PET and a compound capable of reacting with hydroxyl or carboxyl end groups, for example polyanhydrides. "Thick-walled" is defined by Dijkstra et al as "shape and/or dimensions are such that they are not readily conducive to orientation of the polymer by drawing." Dijkstra et al prefer crystalline articles reinforced by glass fibers, and teach nothing with regard to methods of producing blow-molded articles, blown film or foam from PET, nor anything regarding enhancement of melt characteristics of PET.
Extrusion/melt shaping of poly(butylene terephthalate) (PBT) at intrinsic viscosities at least 1.05 dl./gm. has been accomplished by a variety of techniques. See U.S. Pat. Nos. 3,814,786 and 3,931,114. Borman et al, Ser. No. 382,512 of July 25, 1973 (Netherlands 74,07268) attempt to solve this melt strength problem by the use of branched polyesters. The branching necessarily must be conducted in the polyester kettle and thus there is an upper limit as to how much viscosity Borman et al can achieve while still being able to handle the branched polyester.
The object of the present invention is to provide a method of thermoplastic processing of PET to form amorphous articles. It is a further object to provide amorphous extrusion/melt shaped PET articles. A still further object is to provide clear PET bottles by extrusion blow-molding.
SUMMARY OF THE INVENTION
These and other objects as will become apparent from the following disclosure are achieved by the present invention which comprises in one aspect a composition for improving the thermoplastic processing characteristics of PET comprising (A) a polyanhydride selected from the group consisting of pyromellitic dianhydride, mellitic trianhydride, tetrahydrofuran dianhydride, and polyanhydrides containing at least two unsubstituted or substituted phthalic anhydride radicals; and (B) a fatty acid or N-substituted fatty acid amide having at least 10 carbon atoms in the acid portion of the molecule. In another aspect the invention comprises a composition for thermoplastic processing to form amorphous articles comprising PET, the polyanhydride, and the fatty acid or N-substituted fatty acid amide. In another aspect, the invention comprises a process for preparing noncrystalline shaped articles comprising adding about 0.1 to 5% by weight of a polyanhydride, selected from a defined group, to PET before processing. A still further aspect of the invention comprises films, pipes, foams, containers, profiles, or other articles prepared in accordance with the above-mentioned process.
DETAILED DESCRIPTION OF THE INVENTION
The PET used with this invention contains terminal hydroxyl groups and possesses relatively low melt strength and elasticity before modification. The PET generally has an intrinsic viscosity of about 0.5 to about 1.1 dl./g., preferably about 0.6 to 0.8 dl./g.
The polyanhydride used is selected from the group consisting of pyromellitic dianhydride, mellitic trianhydride, tetrahydrofuran dianhydride, and polyanhydrides containing at least two unsubstituted or substituted phthalic anhydride radicals such as the reaction product from two moles of pyromellitic dianhydride or trimellitic anhydride with one mole of a glycol or other active hydrogen-containing compound.
It has been found that certain types of polyanhydrides do not function in this invention. These include maleic anhydride copolymers, cyclopentane tetracarboxylic acid dianhydride, 1,4,5,8-naphthalene tetracarboxylic acid dianhydride, 3,4,9,10-perylenetetracarboxylic acid dianhydride, and bicyclo (2:2:2) oct-7-ene-2,3,5,6-tetracarboxylic acid dianhydride.
Optimum results are achieved by use of 0.1 to 5% by weight of the polyanhydride, preferably 0.2 to 1.5 percent and most preferably about 0.3 to 1.0 percent by weight based on PET. The most preferred polyanhydride is pyromellitic dianhydride.
The maximum melt visocity is achieved with stoichiometric equivalence of anhydride groups and terminal hydroxyl groups in the polyester after making allowances for possible side reactions. The higher the processing temperature, the higher the concentration of the modifier composition required for high melt strength at that processing temperature up to the stochiometric equivalence of anhydride and terminal hydroxyl groups.
The optical fatty acid or N-substituted fatty acid amide has at least 10 carbon atoms in the acid portion of the molecule. By the term "fatty acid" is meant to include fatty acids and other materials which generate fatty acids under the processing conditions used. Preferred compounds are palmitic acid, lauric or stearic acid, N-alkyl stearamide, N-N-dialkyl stearamide or alkylene bis(stearamide). Surprisingly other types of lubricants which would be expected to function equivalently in this process have been found to be unsuitable. The lubricants found to be unsuitable were metal stearates, unsubstituted fatty acid amides, paraffin waxes, ester waxes, polyethylene, and oxidized polyethylenes.
From about 0.1 to 5% by weight of fatty acid of N-substituted fatty acid is suitable, with a preferred amount being about 0.25 to 1.5 percent by weight.
The polyanhydride and the optional fatty acid or N-substituted fatty acid amide are suitably incorporated in the composition by mixing at some time prior to melt blending in the extruder. The melt blending step may be separate and distinct or identical with the processing step to produce the finished article.
It is important that no crystallization promoter is present in the composition since this invention is directed to compositions suitable for producing amorphous, non-crystalline articles. If substantial crystallization occurs in the process the resultant articles become opaque and brittle. In some cases, such as with pipe, foam and profile extrusion, a small degree of crystallinity may be acceptable and can be achieved by control of the cooling cycle. However, in most cases it is preferred to prepare amorphous articles on standard extrusion equipment with no special cooling device. The type of article to be produced, whether it be bottles, films, foams, pipes or profile, will govern the auxiliary equipment to be employed. For instance, to produce bottles, blow-molding equipment is necessary. To produce film, blown film equipment is necessary.
The PET, polyanhydride, and optional fatty acid or N-substituted fatty acid amide are extruded to a molten self-supporting preform which is subsequently shaped into a final form and then allowed to cool to a shaped article.
The shaping step can be accomplished by either injecting a fluid into the molten composition, or by means of a die. In the case where a fluid is used, air or inert gas are the preferred fluids, and bottles, foams, films, and containers can be made. By "blow-molding" is meant shaping by inserting the molten self supporting preform (or "parison") in a mold and injecting a gas such as air into the parison to form the shaped article. In the case of films, shaping is accomplished by extruding a hollow tube and expanding to a larger diameter while still molten by gas pressure within the tube. The film "bubble" is cooled and subsequently collapsed to a film. Clear film can be made by the latter process.
Shaping is also accomplished by extrusion blow-molding, wherein a hollow tube or parison of molten resin is extruded vertically downward until a prespecified length has been achieved. The length of the parison depends upon the size of the bottle to be produced. The tube of molten resin is cut and carried to the blow-molding equipment where it is clamped into a mold having a shape of the bottle to be produced. It is then blown with fluid, usually air, to conform to the mold shape, and then is cooled and ejected. The mold walls are usually cooled with tap water. Unmodified PET is unsuitable for these types of operations because it does not have sufficient melt strength to prevent sagging. Although melt strength varies with viscosity of PET, it is not solely a function of viscosity or of molecular weight.
The shaping operation is meant to also include drawing or stretching below the melting point of the polymer to achieve orientation.
Thin-walled articles are produced by the present invention. By "thin-walled" is meant articles of shape and/or dimensions such that they are readily conducive to orientation of the polymer by drawing. Drawing, and the resultant orientation, is entirely optional, however.
Blow-molded bottles are usually only about 20 to 30 mils thick, and blown film is generally only about 0.5 to 10 mils thick.
Conventional additives such as antioxidants, thermal stabilizers, fillers, pigments and flame retardant additives can be used in the composition of this invention provided they do not exert any adverse effect on the melt strength.
It is preferred not to have glass fiber reinforcement.
It is highly preferred that clear articles are produced.
The following examples are presented to illustrate but a few embodiments of the invention. Comparative examples are also presented.
All parts and percentages are by weight unless otherwise indicated.
EXAMPLE 1
Poly(ethylene terephthalate), 1000 gms, having an intrinsic viscosity of 0.67 dl/g and moisture content below 0.02%. and pyromellitic dianhydride, 3.0 gms. were mixed and melt blended in a 1-inch extruder at 260°-275° C. The extrudate was in the form of a clear, molten, hollow tube that was blow-molded into a clear 4 oz. bottle. There was no evidence of parison sag. The intrinsic viscosity of the walls of the bottles was 0.86 dl/g and was found to be completely amorphous by DSC measurements. The bottle mold temperature was 10° C. and the time in the mold was 30 to 40 seconds.
The parison or molten, hollow tube, exhibiting only moderate die swell and some die lip sticking, was produced at a smooth, steady rate allowing continuous production of bottles. No additional cooling was needed to achieve clear bottles other than the tap water cooled mold. The air pressure for blow molding was about 90 psig.
The bottle had properties characteristics of amorphous unoriented poly(ethylene terephthalate); tensile strength (yield/break)=6489/4536 psi; tensile modulus=254918 psi; elongation (yield/break)=3.1/281%, water vapor transmission=6.9 gm-mil/100 in 2 /24 hrs. at 38° C. and 90% R.H., wall thickness=20-25 mils.
EXAMPLE 2
Example 1 was repeated except that the pyromellitic dianhydride was replaced with 7.6 g of the ethylene glycol bis(4-trimellitate anhydride) which is the ester adduct of trimellitic anhydride and ethylene glycol. Clear selfsupporting parisons were formed which could be blow-molded into clear bottles.
EXAMPLE 3
EXAMPLE 1 was repeated except that pyromellitic dianhydride was replaced by 9.0 gms. of 3,3'4,4'-benzophenonetetracarboxylic dianhydride. Clear, selfsupporting parisons were formed which could be blown into clear bottles.
EXAMPLE 4
Poly(ethylene terephthalate), 1000 gms. having an intrinsic viscosity of 0.67 dl/g and a moisture content below 0.02%, pyromellitic dianhydride, 5.0 gms., and ethylene bis(stearamide), 10.0 grams, were mixed and melt blended in a 1-inch extruder at 260°-275° C. The extrudate was in the form of a clear, molten, hollow tube that was blow-molded into a clear 4 oz. bottle. There was no evidence of parison sag or capacity even when the molten tube was 12 to 16 inches in length. The walls of the bottles had an intrinsic viscosity of 0.84 dl/g and were found to be completely amorphous by DSC measurements. The bottle mold temperature was about 10° C. and the dwell time in the mold was 30 to 40 seconds.
The parison or molten, hollow tube, exhibiting only moderate die swell and no die lip sticking, was produced at a smooth, steady rate, allowing continuous production of the bottles. No additional cooling was required to achieve clear bottles other than the tap-water cooled mold. The air pressure for the blow-molding operation was about 90 psig.
The bottles had properties characteristic of amorphous, unoriented poly(ethylene terephthalate); tensile strength (yield/break)=6263/4929 psi, tensile modulus=243,149 psi, % elongation (yield/break)=2.9/237%, water vapor transmission=6.5 gm-mil/100 in 2 /24 hours at 39° C. and 90% R.H., bottle weight =15 gms, wall thickness=25-30 mils.
EXAMPLE 5
Example 4 was repeated except the ethylene bis(stearamide) was replaced with 5.0 gms of stearic acid. Stable molten parisons that were redily blow-molded into clear bottles, were produced at a smooth steady rate. The intrinsic viscosity of the bottle walls was about 1.1 dl/g, and there was no evidence of crystallization in the body walls by appearance or DSC measurements.
EXAMPLE 6
Example 4 was repeated except the ethylene bis(stearamide) was replaced with 10.0 gms of N,N-dibutyl stearamide. No evidence of parison sag was encountered and clear bottles were readily produced.
EXAMPLE 7
Example 4 was repeated except the pyromellitic dianhydride was replaced with the reaction product from two moles of pyromellitic dianhydride and one mole of 1,5-pentanediol. Stable, clear, molten parisons were produced that could be blow-molded into clear bottles.
EXAMPLE 8--Comparative
For comparative purposes, unmodified poly(ethylene terephthalate) having an intrinsic viscosity of 0.67 dl/g and a moisture content of less than 0.02% was extruded under conditions similar to Example 1. The extrudate exhibited excessive sagging and formed a very thin rod rather than a hollow tube. A stable, molten parison or hollow tube could not be formed under any conditions and the intrinsic viscosity of the extrudate was 0.65 dl/g. The melt strength was not great enough to allow bottles to be blow-molded.
EXAMLE 9--Comparative
Example 8 was repeated except poly(ethylene terephthalate) with an intrinsic viscosity of 1.04 dl/g was employed. Excessive parison sag occurred and it was impossible to maintain a stable, molten parison long enough to allow bottles to be blow-molded.
EXAMPLE 10
This Example illustrates the manufacture of blown film in accordance with the invention.
Poly(ethylene terephthalate), 1000 gms. having an intrinsic viscosity of 0.67 deciliters/gm. and a moisture content below 0.02%, pyromellitic dianhydride, 4.0 grams, and ethylene bis(stearamide), 10.0 grams, were melt blended in a 1" extruder at 260°-275° C. through a vertical film blowing die with a 2 inch diameter and a 30 mil die land into a 5 ft. bubble tower. A stable film bubble was made by introducing air into the interior of the extruded tube. The melt was cooled with a circular jet of air as it emerged from the die. The extrudate had sufficient melt strength that a stable film bubble could be maintained without difficulty. The thickness of the film could be varied from 0.5 to 6.0 mils. It was completely clear and had tensile properties characteristic of unoriented, amorphous PET; tensile strength (break)=7500 psi, tensile modulus=350,000 psi, % elongation (break)=2.5%.
EXAMPLE 11--Comparative
Example 10 was repeated except the pyromellitic dianhydride and ethylene bis(stearamide) were deleted. A stable bubble could not be maintained due to low melt strength. The extrudate continually collapsed on the die or holes developed in the tube. | Composition and method for improving the thermoplastic processing characteristics of poly(ethylene terephthalate) (PET) in amorphous form are disclosed, as well as PET with improved melt strength. | 2 |
CROSS REFERENCED TO RELATED APPLICATIONS
[0001] Not Applicable
FEDERALLY SPONSORED RESEARCH
[0002] Not Applicable
SEQUENCE LISTING OR PROGRAM
[0003] Not Applicable
FIELD OF INVENTION
[0004] This invention generally relates to a batter training apparatus utilizing a vertically and horizontally adjustable tee to allow a user to learn and practice proper technique for hitting a ball with a bat.
BACKGROUND
Prior Art
[0005] A batting tee is used by baseball players and coaches in teaching, learning and practicing the skills involved in hitting a baseball. A ball placed upon a tee that can be moved horizontally to spots on and around the home plate area coupled with vertical tee adjustment, allows the users to simulate the various pitches a batter must learn to hit. The player, through repetition and instruction, can develop consistent proper technique required to hit the various pitches thrown in a game.
[0006] During instruction or practice it is desirable for the player or coach to be able to make quick, easy and spontaneous adjustments to the tee. It is desirable that the tee be capable of unlimited horizontal adjustability on and around the home plate area and also have ample vertical adjustability. It is also desirable that this adjustability be accomplished instantly and easily without the use of cumbersome adjustment devices such as pins, clips, brackets, tracks, pivots, holes, pegs, rails or legs. Furthermore, it is advantageous for the tee to have adequate stability to prevent nuisance tipping or other movement as this causes the user to spend an inordinate amount of time resetting the tee, thereby disrupting the efficiency and rhythm of practice. Finally, it is desirable that the tee be able to tip in the instance of a mishit to prevent damage to the tee and that the tee can be quickly reset to the desired spot.
[0007] An added benefit is a tee that is portable and useable in a variety of locations on a variety of substrates (such as sand, gravel, wood or artificial turf) regardless of the availability of an existing home plate and that this same tee require no extra weighting, shims, blocking or bracing.
[0008] A typical batting tee consists of base, which is often in the shape of a baseball home plate but sometimes square or round. Attached vertically to the base, (usually centered), is a set of telescoping tubes on top of which a ball can be placed. The top of the ascending tube may act as the ball holder or the ascending tube might be fitted with a ball holding device. Ball height adjustment is made utilizing the telescoping action of the vertical tubes. If the tee is permanently attached to the base, horizontal adjustment is made by moving the entire apparatus to a different area of the ground. Other tees use integrated tracks, brackets, sockets, pins, pivots or legs. Several tees of the former description are known in the prior art. U.S. Pat. No. 3,883,138 to Chorey and U.S. Pat. No. 6,358,163B1 to Tanner disclose such designs. Tees of this type suffer from a lack of stability especially on uneven substrates or when placed on the borders of an elevated home plate. These tees are also prone to nuisance tipping and movement. While some allowance for tipping can be beneficial to prevent tee damage on mishits, a tee that tips too easily must be reset even when the batter strikes the ball within an acceptable range of accuracy. This tipping movement creates an annoyance and detracts from the teaching, learning or practice objective. Users frequently are forced to stack auxiliary weights on the base of the tee to gain stability.
[0009] Another tee with a with a permanently attached base is disclosed in U.S. Pat. No. 5,386,987 to Rodino, Jr. This device uses a larger heavier base and rigidly connected telescoping rubber pipes for vertical adjustment. Because of the large intrusive base such a tee is very limited in horizontal adjustability. The rubber pipe ball holder is too bulky and creates excessive interference with the batters swing. This type of tee has no built in protection from mishits. Thus, it is susceptible to damage, tumbling and nuisance shifting.
[0010] An effort at adding some horizontal adjustability to the Rodino design is disclosed in U.S. Pat. No. 4,227,691 to Lefebvre, et, al. The options available for adjustment are limited to a few predetermined choices as dictated by locating holes installed through the base. Also, the adjustment requires the inconvenient process of unscrewing the telescopic pipe ball holder assembly from a threaded disc located under the base of the tee and reassembling it at another hole location. The bulky rubber pipe ball holder creates excessive interference with the batters swing and also has no built in protection from mishits making it vulnerable to damage, tumbling and nuisance shifting.
[0011] U.S. Pat. No. 5,556,091 to Lin discloses an attempt to improve horizontal adjustability by attaching the vertical telescoping pipe assembly to a pivoting swivel mount. The mount rotates on a centrally located bolt on the base and engages locating holes in the base surface via a spring loaded bolt. The location options are restricted by the range of the pivot and the limited number of locating holes. The tee's design makes no allowance for being struck by the bat on mishits and is susceptible to damage, nuisance shifting and tumbling.
[0012] Yet another attempt to improve the range of horizontal adjustment is disclosed in U.S. Pat. No. 7,354,360 B1 to Eckstein. This tee design utilizes a steel base consisting of two legs secured at 90 degree angles in regard to each other, forming an X. The X base is set on the ground centered over an existing home plate. The tee element has a magnet attached at the bottom end that allows it to be coupled to various locations on the steel X base. To reposition the tee the user must step on the X base to disengage the magnet for repositioning. Horizontal adjustment is limited to the area upon the X base. The design's chosen magnet is of a strength that prevents disengagement on mishits and thus the tee design is susceptible to damage and nuisance shifting. The X base design is prone to stability issues especially when the tee is positioned on the outer ends of the X legs.
[0013] Prior art discloses batting tees that use a track or channel system to facilitate horizontal adjustment, as is disclosed in U.S. Pat. No. 6,099,418 to Owen. The tee is secured to a channel installed in the base with the use of a track follower that slides in the track and is secured to the bottom of the tee with the use of a threaded shank. This creates a rigid connection that will be very susceptible to damage, as well as nuisance shifting and tumbling on mishits. Horizontal adjustability is limited to locations made available by the layout of the installed track.
[0014] U.S. Pat. No. 4,445,683 to Cardieri discloses a tee design that utilizes a tube and aperture arrangement for horizontal adjustment. The vertical adjustable tee member is inserted into vertically aligned apertures supported by a bi-level base with the bases divided by spacers. Horizontal adjustments are limited to the provided apertures. The design does not offer any protection from the force of mishits which will result nuisance movement and damage to the vertical tee member.
SUMMARY
[0015] It is an object of the present invention to provide a readily adjustable batting tee apparatus that has an expanded range of horizontal positioning and is unencumbered by limiting adjustment devices. In addition, horizontal positioning is achieved and maintained in a way that allows for tee stability while simultaneously limiting susceptibility to damage on mishits. The apparatus includes a batting tee platform component with a perimeter appreciably larger than a standard sized home plate and an independent vertically adjustable tee component. The tee platform's surface is magnetically attractive and furnished with a home plate applique. The tee is equipped with a magnetic base that allows it to be securely positioned without limitation upon the batting tee platform. The tee base's magnetic force is sufficient to hold the tee in place on reasonable bat contact but will release when subjected to mishits. Because the tee platform is substantial enough to maintain position if the tee is dislodged, it is a simple matter to reset the tee and resume activity. Desired horizontal adjustment is made by tipping the tee in any direction to break the magnetic bond and setting the tee on the desired spot. Vertical tee adjustment is achieved through simple manipulation of a set of telescoping tubes, with the adjustment held in place by friction contact made at several points within the tubes assembly. A ball holder suitably sized and made of a resilient material allows bat to ball contact to occur with minimal interference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a front perspective view of the batting tee platform and batting tee of the present invention.
[0017] FIG. 2 is a front perspective view of the present invention in use.
[0018] FIG. 3 is an exploded view of the batting tee platform of the present invention.
[0019] FIG. 4 is an elevation view of the batting tee of the present invention.
[0020] FIG. 5 is a cut away view of the batting tee of present invention
[0021] FIG. 6 is an overhead view of the tee platform of the present invention with a sample array of possible tee positioning.
[0022] FIG. 7 is a perspective view of the batting tee of the present invention attached to an alternate platform.
[0023] FIG. 8 is a perspective view of the batting tee of present invention alternately attached to a dumb bell weight.
[0024] FIG. 9 is a perspective view of the batting tee platform and batting tee of the present invention.
[0025] FIG. 10 is an elevation view of the batting tee platform and batting tee of the present invention with the tee vertically adjusted to a low position.
[0026] FIG. 11 is an elevation view of the batting tee platform and batting tee of the present invention with the tee vertically adjusted to a middle position.
[0027] FIG. 12 is an elevation view of the batting tee platform and batting tee of the present invention with the tee vertically adjusted to a high position.
[0028] FIG. 13 is an elevation view of the batting tee of the present invention highlighting the sliding tube within the base tube.
[0029] FIG. 14 is a perspective view of the sliding tube assembly of the present invention.
[0030] FIG. 15 is a perspective view the ball holder and the ball holder attachment to the sliding tube of the present invention.
[0031] FIG. 16 is a cut away view of the attachment of the magnet base to the base tube of the present invention.
[0032] FIG. 17 is an exploded view of the base tube and base magnet assembly of the present invention.
[0033] FIG. 18 is a perspective of the tee platform and pitch zone markers of the present invention.
[0034] FIG. 19 is a perspective view of the pitch zone marker of the present invention.
[0035] FIG. 20 is a cut away view of the pitch zone marker of the present invention.
[0036] FIG. 21 is an exploded view of the pitch zone marker of the present invention.
DESCRIPTION
[0037] Presented in the drawings is a preferred embodiment of a batting tee platform and accompanying tee. FIG. 1 shows a perspective view of the present invention batting tee platform 8 and batting tee 10 . FIG. 2 is also a perspective view showing the present invention being used in a typical fashion by user/batter (A) striking ball (C) with bat (B). FIG. 3 shows an exploded view of batting tee platform 8 of the preferred embodiment being constructed of a section of exterior grade plywood which has been coated with exterior wood primer. The predominately square plywood section is ideally noticeably larger than a regulation size home plate to provide a surface 18 with adequate area to simulate various horizontal pitch locations as well as facilitate ball placement for various drills. The plywood should be of sufficient thickness to provide material stability as well as provide the mass required to keep batting tee platform 8 in place during use without being too heavy so as to detract from intended portability. Other materials may be used such as plastic, fiberglass or various composite materials. To platform base 20 is attached a layer of sheet steel 21 .
[0038] Attachment of sheet steel 21 to plywood base 20 is preferably accomplished using contact cement. The sheet steel could be attached with other adhesives or with mechanical fasteners such as screws. Alternative embodiments might replace the use of sheet steel 21 with the use of steel strips attached across platform base 20 or steel rods inlayed into platform base 20 . However, maximum horizontal adjustment capability is achieved when the entire surface 18 area is magnetically attractive. Also a flat, smooth surface 18 provides a superior finish and an uncluttered appearance.
[0039] When attachment of sheet steel 21 to platform base 20 is complete all sides are sanded and edges eased to eliminate any sharp surfaces and prepare for finishing. Tee platform 8 is then painted with a durable exterior grade paint or comparable durable coating. Surface 18 painting includes a representation of home plate 19 in a contrasting color, preferably white. Surface 18 painting or home plate 19 painting might be replaced by the use of decals or other coating application techniques. Finishing not only protects batting tee platform 8 from environmental damage but also enhances aesthetic appeal. Color selection could match various field surface types.
[0040] Handle 22 attachment is undertaken upon completion of final finish coating. Preferred handle material is strong and flexible such as nylon web strap. This type of material is abrasion resistant, won't break if stepped on and will allow tee 10 and platform 8 to be carried together in one hand. Other materials such as rope or vinyl or plastic strap could be used. A shoulder strap might also be used for carrying purposes. Handle 22 is attached to tee platform 8 with mechanical fasteners such as screws 23 with finishing washers 24 .
[0041] Tee 10 of the present invention is seen in FIGS. 4 and 5 . The tee assembly utilizes as the tee base 17 a round base ferrite magnet with a nickel plated cap and a manufacturer's listed pull strengths of 190 lbs. Magnet base 17 allows tee 10 to be attached to any point on the magnetically attractive surface 18 of batting tee platform 8 FIG. 6 shows a sample array of horizontal adjustments available with tee 10 upon the surface 18 of batting tee platform 8 . The magnetic strength of magnet base 17 is adequate to keep the tee upright during reasonable bat to tee 10 contact but will release from tee platform 8 on severe mishits to prevent tee damage. Potentially the magnet base could be accomplished by using a set of magnets attached to a base frame. To make horizontal tee adjustments the tee is grasped at friction cap 14 and tipped at in any direction to break the magnetic bond between surface 18 of platform 8 and tee 10 and repositioned to a new spot as desired by the user or reset to a the prior position if knocked over on a mishit. As seen in FIGS. 7 and 8 batting tee 10 can be used independently from batting tee platform 8 by magnetic attachment to magnetically attractive objects. FIG. 7 shows batting tee 10 magnetically attached to a downsized version (D) of batting tee platform 8 . FIG. 8 . shows magnetic attachment to iron dumbbell weight (E). FIG. 9 shows batting tee 10 attached to a full sized batting tee platform 8 .
[0042] As seen in FIGS. 10 , 11 and 12 , batting tee 10 is vertically adjustable. Referring again to FIG. 5 , a cutaway view discloses that vertical height adjustability is achieved utilizing a set of tubes. Sliding tube 13 slides inside base tube 15 and can be adjusted vertically in a telescopic manner. This arrangement is also seen in FIG. 13 . Adjusted height is held using friction force applied to sliding tube 13 by friction cap 14 and bushing 28 to base tube 15 . Bushing 28 is pressed onto sliding tube 13 and held by friction. An application of all purpose glue to the connection between sliding tube 13 and bushing 28 will aid in holding bushing 28 in place. FIG. 14 discloses a separate view of sliding tube 13 . The applied friction force is enough to hold sliding tube 13 in place during use while still allowing the user to manually adjust sliding tube 13 up or down to set ball holder 12 to the desired height. The diameter of the sliding tube hole in friction cap 14 is smaller than the diameter of sliding tube 13 . Friction cap 14 is ideally made of rubber. Rubber has the characteristics needed to allow the sliding tube hole in friction cap 14 to suitably expand and grip sliding tube 13 . The diameter of bushing 28 is about the same as the inside diameter of base tube 15 . Bushing 28 also provides lateral stability for sliding tube 13 . Rubber is the preferred material for friction cap 14 and bushing 28 . Bushing 28 could be made of vinyl, plastic or a fibrous material. Alternate of attachment of bushing 28 could be made by using mechanical fastener such as a screw and attaching bushing 28 to the bottom of sliding tube 13 . Optionally, height adjustment could be held by the use of an interior twist lock cam or a hand tightened compression nut and sleeve assembly. Ideally sliding tube 13 should be made of an impact and shatter resistant material such as fiberglass or some type of reinforced plastic. A solid rod of the same material could be used. A material of a smaller diameter is preferred to prevent visual obtrusiveness.
[0043] Ball holder 12 attaches to the top of sliding tube 13 as can be seen in FIG. 15 . The preferred embodiment shows a conical shaped ball holder 12 that is formed of a durable resilient material with enough rigidity to support the ball without collapsing such as rubber, vinyl or suitable derivatives. The ball holder must be flexible enough not to impede the user's swing. The ball holder should be as compact as possible so as not to be visually obtrusive. As seen in FIG. 15 sliding tube 13 is pressed into ball holder 12 . The flexible properties of the material of which ball holder 12 is formed allows sliding tube 13 to a slightly larger diameter than the receiving socket of ball holder 12 . When pressed together a friction fit is created that secures ball holder 12 to sliding tube 13 . An all purpose glue is applied to the socket of ball holder 12 before joining sliding tube 13 and ball holder 12 . The glue aids in the joining of the two parts and will also aid in preventing ball holder 12 from detaching from sliding tube 13 .
[0044] Base tube 15 is best constructed of painted steel or similar rigid, impact resistant thin walled material. As seen in FIGS. 16 and 17 magnet base 17 is rigidly connected to base tube 15 by means of a rigid mechanical connection. The preferred embodiment utilizes coupling nut 27 which is pressed into base tube 15 . Magnet base 17 is secured to base tube 15 by use of bolt 26 and washer 25 connected via a mounting hole in magnet base 17 . Thread lock compound is applied to bolt 26 to prevent loosening during use. The connection between base tube 15 and magnet base 17 is covered by a rubber, plastic or vinyl trim piece 16 .
[0045] FIG. 18 shows an alternate use embodiment for tee platform 8 where pitch zone markers 29 as seen in FIG. 19 , are magnetically attached to batting tee platform 8 . As seen in FIG. 20 the preferred embodiment is shown using the same fiberglass tube material as is used for sliding tube 13 . As seen in FIGS. 21 and 22 a smaller magnet base 32 with a listed pull strength of 15 lbs. is attached to indicator tube 30 using screw 34 and washer 33 via a mounting hole in magnet base 32 . The top of indicator tube 30 is fitted with vinyl cap 31 but a small ball or other top could be used to provide a finished appearance and prevent injury. Pitch zone indicators are used when batting tee platform 8 is used as a home plate and a batter is having pitches thrown to him/her and tee 10 is not in use. Pitch zone indicators 29 can help the pitcher better see the zone into which the ball is to be thrown and can help the batter to see where pitches are being thrown in relation to home plate. The magnetic attachment allows pitch zone indicators 29 to be positioned as desired to highlight different pitch zones. Should pitch zone indicators 29 be struck by a ball they will tip and can be reset. The impact resistant tubes will reduce the chance of damage to pitch zone indicators 29 . | A device for use in the instruction and practicing of hitting a baseball with a bat and consisting of a platform component and a tee component. The platform has a surface area appreciably larger than a regulation size home plate providing adequate area surrounding home plate needed to duplicate horizontally various pitch locations. The platform's surface is made of magnetically attractive material. The tee utilizes a magnetic base that allows it to be affixed to any point on the platform surface giving the user maximum choices for horizontal tee placement. The base's magnetic force is sufficient to hold the tee in place for reasonable bat contact and will release when subjected to mishits. The tee component is vertically adjustable to replicate pitches of various heights. | 0 |
This invention relates to an improved method and apparatus for applying foliar spray of aqueous-solution fertilizer, and/or herbicide, and/or pesticide.
BACKGROUND TO THE INVENTION
In the development of the present invention, it has been discovered that many previous mechanisms for applying foliar spray material do not effectively contribute to the obtaining of good coatings and to obtaining well-distributed coatings on foliage, with regard to each of the tops and bottoms of leaves. In other words, teachings from the prior art, so to speak, have proven to be ineffective for precise application. In the present invention, for example, it has been discovered that what works for a flattened stream of spray is not equally true for a conical spray pattern. Likewise, it has been found that a non-solid stream does not have the required spray characteristics, and that very specific controls are required to obtain a successful result by method and apparatus thereof.
Prior to the present invention, application of liquid composition by foliar spraying has been inconsistent, producing poor results. Inconsistent results were obtained by Garcia and Hanway, 1966--"Foliar Fertilization of Soybeans During the Seed-Filling Period"; Agronomy Journal 68(4): 635-657. Himel stated that the efficiency rate for pesticide is usually less than one percent, 1982--Himel, C. M., "Analytical Systems for Pesticide Spray Transport and Impingement"; American Society of Agricultural Engineers Paper No. 82-1001.
Prior also to the present invention, there has been some experimentation involving various apparatuses and blowers for application of spray in foliar spraying, but as noted above, with limited success. For example, air blast sprayers have been used on row crops in some experimental work, by Kahn, A. S., T. G. Carpenter and D. L. Reichard, 1981--"Variables Affecting Spray Deposit Efficiency of a Row Crop Airblast Sprayer", American Society of Agricultural Engineers Paper No. 68-149. These row crop row blast sprayers spray several rows at one time from one air and fluid outlet point. A type of single row air blast applicator was developed by farmer Bruce Viker and has been tested with herbicides in terms of percent control--Roehl, L. J. 1982, "Row Crop Spray Evaluation", American Society of Agricultural Engineers Paper No. 82-1007. Other sprayers have used an air stream to atomize the spray material--(1) Wilkes, L. H. 1961--"Effects of Nozzle Types and Spray Application Methods on Cotton Insect Control", Transactions of the ASAE 4: 166-169; and (2 ) A. Zucker and N. Zamir, 1984--"Air Carriers Sprayers for Cotton", Journal of Agricultural Engineering Research 9: 188-193. In contrast to spray method and apparatuses thereof, the present invention has taken a novel approach in its method and apparatus.
Prior to describing the present invention, it is noted that for entirely different and unrelated fields and for different purposes having no relationship nor bearing on specific beneficial results achieved in this invention in foliar spray application, there have been apparatuses for spraying and applying paints, varnishes and the like, such an U.S. Pat. No. 1,897,173 by R. Long et al. granted Feb. 14, 1933, and U.S. Pat. 2,051,210 by E. Gustafsson granted Aug. 18, 1936, and U.S. Pat. No. 3,252,657 by D. D. Winegar granted May 24, 1966, and U.S. Pat. No. 4,236,674 by George Dixon granted Dec. 2, 1980. A mere air-nozzle that is non-spraying is covered by U.S. Pat. 4,050,632 to Harold G. Wyse granted Sept. 27, 1977.
OBJECTS OF THE INVENTION
A primary object of the present invention is to obtain a method and apparatus for applying a liquid composition to foliage of vegetation by spraying, and in so doing to achieve a major and significant increase in amount of coating of spray particles on foliage of vegetation as contrasted to poor low levels of deposition heretofore.
Another major object is to obtain by the novel method and apparatus, a major and significant increase in spray-coating of undersides of leaves of vegetation sprayed, in contrast to heretofore most deposited spray being on the top surface of the leaves.
Another major object is to obtain improved efficiency in spray application of liquid composition to foliage of vegetation, to achieve a major and significant reduction in required volume of liquid composition required to obtain not only equivalent results but improved deposition in spray-coating of foliage of vegetation, as contrasted to large volumes thereof heretofore required which when heretofore applied achieved poor levels of deposition.
Another object is to obtain improved distribution, to obtain a more homogeneous application of spray particles to foliage of vegetation by the present spray method and apparatus.
Another object is to obtain a method and apparatus therefore, that avoids damaging of vegetation as the apparatus moves through the vegetation being sprayed.
Other objects become apparent from preceding and following disclosure.
One of more objects of the invention are obtained by the invention as described herein, and illustrated in the accompanying Figures which are intended to improve understanding, but to not unduly limit the invention to the illustrative example, the invention including variations and modification and mechanical-equivalents for substitution within ordinary skill.
BROAD DESCRIPTION OF THE INVENTION
Broadly the invention may be defined in terms of each of the method and apparatus, respectively, described hereinafter.
The method includes step of first spraying a liquid composition from a flat, solid-stream spray nozzle at a pressure of about 10 to about 75 pounds per square inch producing at the nozzle-outlet a spray stream having a cross-sectional area (of the orifice(s)) of from about 0.0000948 to about 0.0323000 square inches, in a direction laterally and/or rearwardly toward vegetation foliage to be coated with the spray, while concurrently as a second step directing gas(es) in substantially the same or a common direction as the spray stream but from opposite non-circumscribing positions on opposite sides of the spray nozzle or spray stream therefrom, such that the gas(es) intersect and impinge on the spray stream of the sprayed liquid composition at a distance (range) of about five to fifteen inches, while the support structure therefore and the vehicle carrying the support structure advance forwardly at a speed of from about one to about ten mile per hour. Guiding baffles on each of opposite sides of the directed-gas, extend from about one to eight inches, and as measured from an axis of the directed-gas longitudinally, each baffle is angled divergingly at angle(s) ranging from zero to about 20 degrees, and that axis of directed-gas relative to a second axis extending from the directed-gas outlet and parallel to a longitudinal axis of the spray stream, is at a converging angle toward the spray stream at from about zero degrees to about 50 degrees.
Preferred results are obtained by narrower limits: with liquid spray pressure of from about 35 pounds per square inch to about 60 pounds per square inch; and the steam orifice cross-section (and stream at the orifice) being between about 0.0001152 and 0.0008640 square inches; and the directing-angle for the gas(es) being from about 10 to 35 degrees; and the baffle lengths being between about 2 and 5 inches and the baffle angles each being about 5 to 15 degrees; and the point of gas(es) impingement onto the spray stream being at from about 6 to about 10 inches outwardly from the orifice of the spray stream; and the speed of forward advancement being between about 3 and 6 miles per hour. The locations and directions of the opposing oppositely-spaced gas vents and gases thereof cause the gases to intersect and impinge upon the outer peripheries of the gas stream to form a partial, incomplete, non-circumscribing shroud of the spray stream.
As above-noted, the longitudinal axis of direction of the directed gas is not necessarily toward nor even parallel with the spray stream's longitudinal axis of direction thereof, but in fact preferred results above-noted and as set-forth in the objects, are obtained when the direction of the directed gas's axis (from side of the opposite two or more sources/locations and vents thereof) is at an angle converging on the spray-stream's longitudinal axis within an angle of from about ten to about thirty-five degrees, above-noted. This is contrary to what might have been expected on the theory that total spray concentration would be better placed as would be obtained if gas-directing streams totally surrounded, or circumscribed, and impelled from all circumscribing locations against the spray stream. Alternatively, one might expect better distribution and coverage from a conical nozzle. Neither of these approaches work however, the invention requiring a flat-spray solid-stream type nozzle, and requiring that the impinging directed-gases being solely from substantially two opposite sides, together with all the other limitations already set-forth in preceding paragraphs.
Moreover, it has proven to be true that preferred results are obtained when the gas-shrouded (as above described for this invention) spray stream is impinged by directed-gas--i.e. the shroud, of which the shroud at the outlet-port of the directed-gas vent is of a thickness of from about 0.20 inch to about 0.30 inch, thereby maximizing and optimizing results set-forth in preceding objects.
Also the length of the baffles of the gas-directing vents, i.e. the second dimension versus distance between oppositely positioned baffles, ranges from about one inches to about twelve inches, preferably from about two to about nine inches.
Also, while moving the spray nozzle along normally below the level of the top of the vegetation and its foliage, the preferred and optimum and maximized results in deposition of coating, and of homogeneous distribution, together with equalizing coverage on the top and bottom of leaves, are obtained when the spray nozzle and associated gas-directing structures, are all directed substantially commonly upwardly preferably within a range of about 25 to about 35 degrees relative to a horizontal, during the spraying.
Likewise, while moving the spray nozzle(s) along normally below the level of the top of the vegetation foliage, the prefer and optimum and maximized results in deposition, homogeneous distribution and improved coverage of both bottom and top of foliage, together with other such above-noted objects, are obtained when the spray nozzle and structure(s) directing the gas(es) from the plurality above-noted, are all directed substantially laterally relative to a direction of forward or advancing movement of a moving vehicle on which support structure and the spray nozzle(s) and associated gas-directed apparatus(es) and supported and/or mounted. Maximum preferred results are achieved when the later angle is within about 75 and about 105 degrees relative to an axis extending along a direction of movement of the support vehicle.
Results are further enhanced together with avoidance of damage to plants and foliage thereof, by mounting the nozzles spaced-apart along an open boom or boom-like structure such that the nozzle(s) and their associated gas-directing apparatus(es) may be optimally positioned as above-noted, at a level preferably below the top of the vegetation with spray streams meeting or overlapping at the point of contact with the foliage.
In further prevention of damage to the plants and foliage thereof, and/or in altering position(s) of foliage to be sprayed, fender structure or the like is mounted on the apparatus(es) of the spray nozzle and/or associated gas-directing structure and/or on the support structure thereof, positioned ahead of the spray nozzle(s) and gas-directing structure(s) such that and adapted to shielding is provided to divert the plant foliage from its normal growing position, aside upwardly or laterally, or downwardly.
Preferred optimal results in achieving above-noted objects are achieved by spraying the liquid spray stream under substantial pressure as noted above. Likewise, the rate of flow of the directed-gas assists in accelerating and/or maintaining spray-suspension and preferably ranges between about 40 cubic feet to about 75 cubic feed per minute for optimal results of above-noted objects.
While preferably the directing-gas is air, it may be any other convenient gas such as nitrogen, carbon dioxide, or some insecticidal or herbicidal or growth-stimulating gas or suspension, or mixture(s) thereof. Likewise, it could be a gas entrained in or a part of the liquid composition being sprayed from the nozzle(s); such gas(es) may be any one or more of the above-noted gas(es).
The overall spraying and gas-directing mechanism(s) are typically mounted on a boom, as noted-above, and in any event on a support structure with or without a boom, and such support structure is mounted on and conveyed by a vehicle that is motorized for the advancing forwardly substantially horizontally during spraying. As used herein, motorized vehicle is intended to include a trailor device taken together with a truck, tractor or the like that would pull the device or have the device mounted thereon.
The motorized vehicle optimally and preferably during spraying moves fowardly (advances) at a reasonable rate as above-noted.
The liquid composition sprayed by and as a part of the method and apparatus(es) of this invention, may be any conventional pesticide such as insecticide, herbicide and/or aqueously-soluble fertilizer and/or growth stimulant ingredient(s) and/or composition(s), and/or mixtures thereof, in a suitable liquid medium such as water.
A major purpose of the invention was to improve the performance of liquid application of agricultural materials, specifically, to improve the control of spray particle placement and increased deposition in a given target area over the level obtained with conventional hydraulic spraying nozzles. The problem associated with conventional nozzle arrangement and spraying methods is the inability to accurately direct spray particles to a desired target area when the target consists of plant foliage or is obstructed by plant foliage or crop stubble. Examples of these problems situations are the application of foliar fertilizers to soybeans or herbicides to soil through wheat stubble. Conventional nozzle arrangements have been found to provide less than desirable spray placement control to the target area in these situations. This lack of spray droplet control with conventional applications results in low spray coverage on the target areas, excessive particle drift and ineffectively applied spray material, together with excessive waste of spray material.
The method and apparatus therefor of the present invention, typically referred to as the air stream assisted spraying method, improve(s) the performance of conventional nozzle spraying by using air streams to accelerate droplets, providing better directional control and confining the spray particles to the target area. These characteristics of the invention increase spray coverage in the target area of the plant and reduce spray particle drift, together with other benefits set-forth in the preceding objects.
The invention may optimally be practiced with ground spraying equipment.
An air supply for the air vents can be provided from a fan mounted on the spraying equipment and ducted to the air vents through tubing. The air-vent nozzle units can be mounted in various configurations within a spray shroud structure or open boom, depending on the spray target area. Spraying would then take place with conventional hydraulic atomization nozzles with air vents accelerating, directing, and confining the spray particles. The placement of an air vent adjacent to or around a conventional nozzle enhances spray particle deposition through its acceleration of droplets within the discharge pattern of the air vent, thereby confining the spray particles to the target area and reducing drift.
The invention may be better understood by making reference to the following Figures.
THE FIGURES
FIG. 1 illustrates a perspective view of a tractor-vehicle mounting a liquid-containing tank, fan conduits, boom(s), nozzle, and associated gas-directing structure.
FIG. 2 diagrammatically illustrates the flat-spray nozzle and associated gas-directing structure, spray inlet conduit and air-inlet conduit, and spray and air-shroud patterns are formed.
FIG. 3 diagrammatically illustrates a top view of FIG. 2.
FIG. 4 symbolically also illustrates the same view as FIG. 3.
FIG. 5 illustrates diagrammatically an in-part view of the boom(s) structures and spray-nozzles and gas-directing apparatuses mounted thereon, showing data regarding overlap of spray patterns.
FIG. 6 illustrates a conical spray nozzle having a central air space, i.e. non-solid stream, with totally circumscribing air-shroud, diagrammatically.
DETAILED DESCRIPTION
It is to be noted that the term "preferred" as utilized herein connotes that the particular characterized embodiment or limitation is considered to be critical for achieving the benefical results associated herewith, based on experimentation by the present inventors.
The air stream assisted spraying system consists of two major components. These components are the air supply fan and tubing and the air-vent nozzle units. These components were installed on a Hahn Hi-Boy sprayer, model H-312. The air-vent nozzle units were used within a spray shroud structure and on an open boom.
The air source for the air stream was provided by a hydraulically driven centrifugal fan (Buffalo Forge model BL-445) mounted on the Hahn Hi-Boy sprayer with tubing to route the air to the air vents. The hydraulic fan drive system allowed for convenient testing of various fan speeds. Air flow to the air vents at the highest fan speed of 1500 revolutions per minute was 69 cubic feet per minute at 3175 feet per minute velocity for the hollow cone unit. The airflow to each of the air vents of the flat fan was 44 cubic feet per minute at 2031 feet per minute air speed.
To route the air flow to the air vent nozzle units a manifold chamber was constructed and mounted on the fan outlet. This manifold reduced the air outlet size from one opening of 2.83 square feet to eight openings of 1.5 inches in diameter.
The routing of air from the manifold to the air vent consisted of semi-rigid tubing, plastic pipe, and flexible tubing. Semi-rigid polyvinyl chloride reinforced plastic tubing was used to duct the air flow from the manifold to the custom spray boom drops. This plastic tubing was chosen because of its smooth inner surface and its availability in two inch inside diameter. Each piece of tubing was 9.5 feet in length. Two inch inside diameter schedule polyvinyl chloride plastic pipe in five foot lengths were secured to the spray boom drops in a vertical position. At the upper end of each piece of plastic pipe a two inch coupling was glued in place. The semi-rigid tubing was then secured to the coupling with sheet metal screws.
For air supply to the flat fan units, a four inch length of 1.5 inch inside diameter plastic pipe was attached to the lower ends of the two inch plastic pipe to serve as a union. Silicone rubber caulking was used to seal the joints of the plastic pipe union and the larger plastic pipe. A more flexible tubing was required to make the 120 degree band from the custom boom drop to the air vents, so flexible automotive heater duct tubing was chosen. The heater tubing was of wire reinforced cloth construction with an inside diameter of 1.88 inches. One end of the hose was connected to the plastic pipe and the other end to the air vent. For the hollow cone type units, 2.25 inch inside diameter heater duct tubing was used to connect the lower end of the plastic pipe and the air vent. The air supply tubes were routed to each flat fan unit, whereas each hollow cone unit required only one air supply.
The flat fan type air vent unit consisted of an adjustable mounting base constructed from sheet steel and hinges. The mounting base provided a mounting point for conventional flat fan nozzle in the center and hinged mounting points for a vacuum formed plastic air vent on each side of the nozzle. The plastic air vents were designed to emit a flat fan type air pattern. The air vents were formed using an Emco model 810 vacuum forming machine and a positive type die made from wood. The plastic used for the air vents was 0.13 inch polystyrene. The hinging mechanism was adjusted so that the air stream from both sides would intersect the fluid pattern six inches from the nozzle tip. The air vents were secured to the mounting base with foam rubber weatherstripping and hose clamps. The angle of the air vent pattern was eighty degrees and the opening size was approximately two square inches. The eighty degree air vent pattern corresponded to the eighty degree spray pattern of the flat fan nozzle.
The hollow cone type air vents were constructed using 28 gauge galvanized sheet steel to form inner and outer cones. Galvanized pipe fittings were brazed to the cones to provide the fluid source for the hydraulic nozzles mounted within the inner cone. Design was such that air did not enter the inner cone but only flowed through the gap between the two cones to form an air shield or shroud around the spray pattern. Silicone rubber caulking was used to seal the inner cone from the outer cone. The hollow cone unit was designed for use with a hollow cone nozzle spraying a seventy degree pattern, thus the air pattern was a seventy degree cone. The width of the air outlet around the inner cone was 0.25 inches.
A Hahn Hi-Boy, model H-312, high clearance sprayer with a six foot clearance was used as the prime mover for the field testing. Custom spray boom drops were attached to the mounting frame. The custom spray boom drops had an adjustable mounting point for the air bent nozzle units, which allowed variable positioning in the horizontal and verticle planes. An air vent nozzle unit was mounted on each side of the row and the nozzles were directed perpendicular to the direction of travel and upward at a thirty degree angle. This two nozzle per row arrangement was used in an attempt to maximize coverage on the undersides of leaves in the upper half of the soybean plant. Curved sheet metal fenders were mounted in front of the air vent nozzle units to funnel the soybean foliage between the units and minimize the tendency for the leaves to be torn on the air vent nozzle units.
The spray shroud structure was designed to cover the top and both sides of one crop row. The shroud was initially constructed to test recirculation feasibility of conventional nozzle spraying, and subsequently used with the air assist spraying method. Construction of the shroud structure was accomplished using a 22 gauge sheet aluminum and 3/4 inch galvanized conduit. The conduit served as the frame of the shroud structure on which the aluminum sheeting was mounted with rivets. Each shroud structure consisted of five sections. These sections were a top section, a left and right bottom section and a left and right removable section. The middle sections were installed when spraying corn and removed for the shorter soybeans. The shroud structure was suspended from a rectangularly-shaped mounted frame secured to the hydraulic lift points of the sprayer and directed-gas/fan apparatuses. The air-vent nozzle units were attached to the shroud structure in the desired position for each test of the sprayer performance. Accordingly, the presence of the air vents for directing the air to impinge upon the spray stream provide acceleration and direction and control for placement of the deposition of the liquid composition being sprayed.
To date, the air stream assist spraying method of this invention has been tested on corn and soybean plants, for example. The coverage values obtained on plants with the air assist treatments were compared coverage values obtained with conventional (two and three nozzle per row) treatments evaluated on both corn and soybeans in 1981. The method and apparatus in this spraying test resulted in better and improved spray coverage than conventional nozzles alone. In addition to increasing coverage on the top portion of the plant, there was considerably better overall plant coverage, including the underside of the foliage leaves.
The inventive method and apparatus were tested within the spray shroud structure, during 1982 and compared to conventional nozzle arrangements which were evaluated using the same spray shroud structure. A two nozzle per row, ten gallon per acre treatment by the inventive method and apparatus, on corn increased spray coverage from 0.26 to 0.53 percent overall, and from 0.09 to 0.94 percent on the bottom surface of the leaves, compared to the best conventional treatment. The inventive method and apparatus improved spray coverage over the conventional treatments by approximately 50 percent overall. The coefficient of variation values, which are an indication of the uniformity of application, were improved by the inventive method and apparatus with a resulting reduction of over 25 percent in the coefficient of variation value.
The inventive method and apparatus also demonstrated improvement over conventional spraying methods and apparatuses. One air assist treatment resulted in 3.11 and 0.82 percent coverage for the top and bottom surfaces respectively of the leaves in the upper portion of the plant. The percent coverage value for the entire plant was 1.37 percent. The inventive method and apparatus improved spray overall coverage by 334 percent while concurrently also improving the uniformity.
In another test of the inventive method and apparatus, higher spray coverage on the bottom surface of the leaves resulted, with coverage values of 0.05 percent for the top and 2.26 percent for the bottom surfaces of the leaves in the upper portion of the plant. Table I lists the percent coverage values for the conventional and air assist treatments. The air streams, which intersected the fluid nozzle pattern and accelerated the droplets, allowed better controlled deposition of spray material to the target area of the plants, than had previously been found with conventional methods. The air vent nozzle unit could be arranged to deposit spray on the desired target area of the plant. Coverage on the underside of leaves which was minimal and difficult to obtain with conventional methods was improved with the inventive method and apparatus.
TABLE I__________________________________________________________________________Mean Percent Coverage Values Resulting from Conventional andInventive Method & Apparatus-treatments Conducted within theSpray Shroud Structure on Corn and Soybeans UPPER HALF OF PLANT ENTIRE TOP LEAF BOTTOM LEAFCROP TREATMENT PLANT SURFACE SURFACE BOTH SURFACES__________________________________________________________________________Corn Conventional 0.26 0.63 0.09 0.30Corn Inv. Method 0.53 0.79 0.94 0.81SoybenasConventional 0.41 1.58 0.44 0.28SoybeansInv. Meth./1st 1.37 3.11 0.82 1.69SoybeansInv. Meth./2nd 1.04 0.05 2.26 0.95__________________________________________________________________________
Tests were performed during 1983 to evaluate the inventive method and apparatus without the shroud enclosure structure. Additionally a hollow cone type air vent nozzle unit was tested. Tests of the hollow cone type air unit revealed that the addition of the air stream did not significantly improve deposition and provide other advantages. Accordingly, the improved and preferred method is best characterized by the gas/air-directing locations and streams of gas/air there from begin on opposite sides of flat fan spray nozzle, resulting in a spray-pattern having an oblong appearance, but with the directing gas/air coming from a sufficient number of different locations or positions as to cause the directing gas/air to substantially sandwich and shield the spray stream, and this method and apparatus are characteristically termed to be the flat-fan method and apparatus, because such tend to flatten-out the cross-sectional appearance of the spray stream as above-noted into a flattened oblong appearance.
The method and appearance may be better understood by now making reference to the preceding Figures. Common or similar indicia are utilized for parts that are substantially the same on different figures and embodiments.
First, however, it should be noted that the above-stated cross-sectional areas were calculated; for example, the areas of 0.0000949 square inches to 0.0323000 square inches, correspond to a flat-type solid-stream commercially-available nozzle having orifice diameter(s) (distance across) from 0.011 inch to 0.203 inch.
For all limitations and ranges of angles, dimensions and locations described and/or shown in the illustrations, they have been found by field experimentation to be critically essential in order to achieve the objects of this invention as stated above. The table involving and contrasting conventional non-inventive structure in the preceding Table I, are typical of such observations.
FIGS. 1 through 5 all illustrate different views and features of the same preferred embodiment, and accordingly indicia to the extent shown in one or more of the Figures are the same. FIG. 6 illustrates a unit that does not embody the invention, but is included to illustrate criticality of the inventive limitations, the FIG. 6 structures or apparatus having likewise been field tested.
FIG. 1 shows an actually built and successfully operated motorized vehicle 6 mounting each of: a spray liquid-tank 9; compressed-air-source-fan 10a; a liquid-pressurizing pump 10b for pressurizing the liquid being sprayed; boom(s) and boom-support structure(s) 7 (collectively); the several separate spray nozzles (not visible) 12 and their associated baffles 15; fenders 35; and a showing of the nozzle and baffle combinations being directed slightly upwardly, laterally and rearwardly.
FIG. 2 is a diagrammatic face-on view of the flat-solid stream-spray-type nozzle 12 and slotted-outlet ports 12a and 12b thereof, and spray-liquid inlet conduit 11, and flat-solid spray-pattern 13, and air-inlet conduits 14a and 14b, and directed-gas vents 20a and 20b, and baffles 15a, 15b, 15aa, and 15bb thereof, and the sandwiching air-shrouds 16a and 16b, the non-shrouded (non-circumscribed) spray-mists 17a and 17b, and the baffles's length-dimension 18, and the baffles's diverging-angle 19. While the support structures are not shown in this FIG. 2, the illustrated elements are factually mounted in the positions and orientations shown, such as the nozzle and air-directing apparatuses being angled slightly upwarded as shown.
FIG. 3 illustrates diagrammatically a top-view of FIG. 2. There are shown the gas-directing vents 20a and 20b, spray nozzle 12 (shown in phantom), support pivots 29a and 29b, imaginary first axis 21, imaginary second axis 22, imaginary third axis 26, imaginary linear-line direction 24, angle 25, angle 23, and baffle 15a. Basically the same view is FIG. 4 showing imaginary areas 21 and 23 and 26, and the intersecting and target-distance 27, and baffle-distance dimension 28 that the baffles each extend along their respective imaginary axes 26, and the pivots 29a and 29b revolvable in either and each of opposite directions 29a', air unit-mounting clamp 30. It is to be understood that FIG. 4 illustrations are diagrammatically presented.
FIG. 5 diagrammatically illustrates an in-part view of boom(s) 7x, 7y, and 7z mounting nozzles (not visible) 12 and their respective associated gas-directing apparatuses 12x, 12y, and 12z, and support structure(s) 7a thereof, illustrating the preferred arrangements of the spray streams 16x, 16y, and 16z meeting or over-lapping each other as they strike the target(s) typically diagrammatically represented as target 34. Spaces 33 exist before directed-air shroud impinges the spray-stream(s).
FIG. 6 diagrammatically illustrates a conical spray nozzle 31 and fully conical and circumscribing gas-directing baffles 15c and 15d, resulting in a hollow annular spray having an annular air shroud 16a fully circumsribing the spray steam. In the illustration, space 33 exists (as shown) at the illustrated location at which the air-shroud has not yet impinged upon the inner conical spray stream 31a.
FIG. 2 angle 19 is the earlier mentioned diverging angle of the baffles. Width dimension 20x represents the air-shroud thickness at the distal ends of opposing baffles. Length dimension 18 represents the length of the baffles at their distal ends, and likewise, of the air shroud at that point (location). FIG. 3 angle 25 discloses the converging angles of the baffles (such as 15a) relative to imaginary axis 24 that is parallel to the imaginary axis 26 that is the longitudinal axis of the direction in which the directed-air is moving. Angle 23 is defined between imaginary axis 26 and the imaginary axis 22 that is parallel to imaginary axis 21 that is longitudinal axis of the direction of movement of the spray stream from nozzle 12.
FIG. 4 angle 23 (described-above) is the angle at which the directed air is adjusted to converge downwardly toward the imaginary longitudinal axis 21, as measured between imaginary axis 26 and imaginary axis 22. Distance dimension 27 represents the distance to points (locations) of the target and approximately of the impingement on the spray stream by the oppositely inwardly-directed sandwiching air-shrouds 16a and 16b of FIG. 2.
There is no relevant prior art with regard to spray-particles distribution homogeneously on both top and bottom surfaces of foliage nor having to do with foliar spraying.
Non-analagous patents dealing with spray paint nozzles and the spray patterns therefrom, include: Long et al. U.S. Pat. No. 1,897,173, and Gustafsson U.S. Pat. No. 2,051,210, and Winegar U.S. Pat. No. 3,252,657, and Dixon U.S. Pat. No. 4,236,674. None of the patents relate to nor teach anything in regard to foliar spraying nor to the many critical limitations of the present invention. | A method and apparatus for foliar spraying liquid composition such as pesticide, aqueous fertilizer solution, and/or herbicide, onto foliage of vegetation. In a preferred embodiment, while spraying a spray stream of liquid composition at 10 to 75 pounds per square inch pressure from an orifice having a cross-sectional area of from about 0.0000948 to about 0.0323000 square inches to strike vegetation foliage within from about 5 to about 15 inches, with a plurality of gas-directing vents spaced-apart on opposite sides of the orifice but not circumscribing the orifice, the gas-directing vents each being directed to impinge air upon the spray stream within the 5 to 15 inches, the gas-directing vents being angled toward the spray stream at angles from about 0 to about 50 degrees relative to a second axis extending from the gas-directing vent that is parallel to a first axis following the spray stream, with baffles on opposite sides of the gas-directing vent for each thereof, the baffles being angled divergingly outwardly from the axis in which directed at angle ranging from 0 to about 20 degrees, a plurality of spray orifices each with its plurality of gas-directing vents, are mounted and spaced-apart from one another along an open boom and adapted to spray laterally and/or backwardly, while a support structure mounting the boom(s) moves the spray vents substantially horizontally forwardly by way of a vehicle advancing at a speed of from about 1 to 10 miles per hour. | 0 |
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Ser. No. 60/765,984, filed Feb. 7, 2006, the content of which is hereby incorporated herein by reference as if recited in full herein.
FIELD OF THE INVENTION
[0002] The invention relates to spinal implants.
BACKGROUND OF THE INVENTION
[0003] The vertebrate spine is made of bony structures called vertebral bodies that are separated by relatively soft tissue structures called intervertebral discs. The intervertebral disc is commonly referred to as a spinal disc. The spinal disc primarily serves as a mechanical cushion between the vertebral bones, permitting controlled motions between vertebral segments of the axial skeleton. The disc acts as a joint and allows physiologic degrees of flexion, extension, lateral bending, and axial rotation. The disc must have sufficient flexibility to allow these motions and have sufficient mechanical properties to resist the external forces and torsional moments caused by the vertebral bones.
[0004] The normal disc is a mixed avascular structure having two vertebral end plates (“end plates”), an annulus fibrosis (“annulus”) and a nucleus pulposus (“nucleus”). Typically, about 30-50% of the cross sectional area of the disc corresponds to the nucleus. Generally described, the end plates are composed of thin cartilage overlying a thin layer of hard, cortical bone that attaches to the spongy cancellous bone of the vertebral body. The end plates act to attach adjacent vertebrae to the disc.
[0005] The annulus of the disc is a relatively tough, outer fibrous ring. For certain discs, particularly for discs at lower lumbar levels, the annulus can be about 10 to 15 millimeters in height and about 10 to 15 millimeters in thickness, recognizing that cervical discs are smaller.
[0006] Inside the annulus is a gel-like nucleus with high water content. The nucleus acts as a liquid to equalize pressures within the annulus, transmitting the compressive force on the disc into tensile force on the fibers of the annulus. Together, the annulus and nucleus support the spine by flexing with forces produced by the adjacent vertebral bodies during bending, lifting, etc.
[0007] The compressive load on the disc changes with posture. When the human body is supine, the compressive load on the third lumbar disc can be, for example, about 200 Newtons (N), which can rise rather dramatically (for example, to about 800 N) when an upright stance is assumed. The noted load values may vary in different medical references, typically by about ±100 to 200 N. The compressive load may increase, yet again, for example, to about 1200 N, when the body is bent forward by only 20 degrees.
[0008] The spinal disc may be displaced or damaged due to trauma or a degenerative process. A disc herniation occurs when the annulus fibers are weakened or torn and the inner material of the nucleus becomes permanently bulged, distended, or extruded out of its normal, internal annular confines. The mass of a herniated or “slipped” nucleus tissue can compress a spinal nerve, resulting in leg pain, loss of muscle strength and control, and even paralysis. Alternatively, with discal degeneration, the nucleus loses its water binding ability and deflates with subsequent loss in disc height. Subsequently, the volume of the nucleus decreases, causing the annulus to buckle in areas where the laminated plies are loosely bonded. As these overlapping plies of the annulus buckle and separate, either circumferential or radial annular tears may occur, potentially resulting in persistent and disabling back pain. Adjacent, ancillary facet joints will also be forced into an overriding position, which may cause additional back pain. The most frequent site of occurrence of a herniated disc is in the lower lumbar region. The cervical spinal disks are also commonly affected.
[0009] There are several types of treatment currently being used for treating herniated or degenerated discs: conservative care, discectomy, nucleus replacement, fusion and prosthesis total disc replacement (TDR). It is believed that many patients with lower back pain will get better with conservative treatment of bed rest. For others, more aggressive treatments may be desirable.
[0010] Discectomy can provide good short-term results. However, a discectomy is typically not desirable from a long-term biomechanical point of view. Whenever the disc is herniated or removed by surgery, the disc space will narrow and may lose much of its normal stability. The disc height loss may cause osteo-arthritis changes in the facet joints and/or compression of nerve roots over time. The normal flexibility of the joint is lost, creating higher stresses in adjacent discs. At times, it may be necessary to restore normal disc height after the damaged disc has collapsed.
[0011] Fusion is a treatment by which two vertebral bodies are fixed to each other by a scaffold. The scaffold may be a rigid piece of metal, often including screws and plates, or allo or auto grafts. Current treatment is to maintain disc space by placement of rigid metal devices and bone chips that fuse two vertebral bodies. The devices are similar to mending plates with screws to fix one vertebral body to another one. Alternatively, hollow metal cylinders filled with bone chips can be placed in the intervertebral space to fuse the vertebral bodies together (e.g., LT-Cage™ from Sofamor-Danek or Lumbar I/F CAGE™ from DePuy). These devices have disadvantages to the patient in that the bones are fused into a rigid mass with limited, if any, flexible motion or shock absorption that would normally occur with a natural spinal disc. Fusion may generally eliminate symptoms of pain and stabilize the joint. However, because the fused segment is fixed, the range of motion and forces on the adjoining vertebral discs can be increased, possibly enhancing their degenerative processes.
[0012] Some recent TDR devices have attempted to allow for motion between the vertebral bodies through articulating implants that allow some relative slippage between parts (e.g., ProDisc®, Charite™). See, e.g., U.S. Pat. Nos. 5,314,477, 4,759,766, 5,401,269 and 5,556,431. As an alternative to the metallic-plate, multi-component TDR (total disc replacement) designs, a flexible solid elastomeric spinal disc implant that is configured to simulate natural disc action (i.e., can provide shock absorption and elastic tensile and compressive deformation) is described in U.S. Patent Application Publication No. 2005/0055099 to Ku, the contents of which are hereby incorporated by reference as if recited in full herein.
[0013] Other parts of the spine may also deteriorate and/or need repair and implants for various portions of the spine may be desirable.
SUMMARY OF EMBODIMENTS OF THE INVENTION
[0014] Embodiments of the present invention are directed to anchoring spinal implants in bone using suture anchors.
[0015] Some embodiments are directed to spinal implants with cooperating suture anchors. The devices include a spinal implant and at least one suture anchor comprising a threaded bone anchor holding at least one suture. In position, the at least one suture extends outwardly from the threaded bone anchor and attaches to the spinal implant while the threaded bone anchor is anchored in a vertebral body.
[0016] Other embodiments are directed to medical spinal implant kits. The kits include; (a) a total disc replacement (TDR) spinal implant comprising a bone attachment material; and (b) a plurality of suture anchors configured to define suture knots against an outer surface of the bone attachment material with the threaded anchors configured and sized to reside in at least one vertebral body above or below the TDR implant to secure the TDR implant in position.
[0017] Still other embodiments are directed to methods of attaching a total disc replacement (TDR) implant to at least one vertebral body. The methods include: (a) implanting a TDR; (b) anchoring at least one bone anchor in at least one vertebral body proximate the TDR; and (c) tying at least one suture set attached to the bone anchor to the TDR to thereby secure the TDR in position in the body.
[0018] Some embodiments are directed to TDR implants. The implants include: (a) a flexible implant body; and (b) a bone attachment member with at least one outwardly extending plug configured and sized to reside in a cavity formed in a vertebral body.
[0019] The TDR implant may optionally include at least one threaded bone anchor with at least one suture set attached to the bone attachment member. A single anchor can be sized and configured to reside in the vertebral cavity with a respective plug.
[0020] Further features, advantages and details of the present invention will be appreciated by those of ordinary skill in the art from a reading of the figures and the detailed description of the embodiments that follow, such description being merely illustrative of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is an anterior view of an implantable spinal disc prosthesis with cooperating suture anchors according to embodiments of the present invention,
[0022] FIG. 2A is an anterior view of another implantable spinal disc prosthesis with cooperating suture anchors according to embodiments of the present invention.
[0023] FIG. 2B is an anterior view of another implantable spinal disc prosthesis with cooperating suture anchors according to embodiments of the present invention.
[0024] FIG. 3 is an anterior view of a vertebral body with exemplary locations for suture anchors according to embodiments of the present invention.
[0025] FIGS. 4A and 4B are lateral views of a portion of a suture anchor held in vertebral bone according to embodiments of the present invention.
[0026] FIG. 5 is a side view of an exemplary suture anchor with a plurality of suture sets according to some embodiments of the present invention.
[0027] FIG. 6 is an exploded anterior view of a suture anchor with two suture sets and an implant according to embodiments of the present invention.
[0028] FIG. 7A-7E are sequential views of implantation steps that can be used to anchor a spinal implant according to embodiments of the present invention. FIGS. 7A-7C and 7 E are lateral views and FIG. 7D is an anterior exploded view.
[0029] FIG. 8 is an anterior view of implantable spinal discs using several exemplary different suture anchor configurations according to embodiments of the present invention.
[0030] FIG. 9 is a schematic illustration of a medical kit according to embodiments of the present invention.
[0031] FIG. 10A is a lateral view of a bone attachment material comprising a plug configuration according to embodiments of the present invention.
[0032] FIG. 10B is a side perspective view of an exemplary bone cavity plug according to embodiments of the invention.
[0033] FIG. 11A is a lateral view of a spinal implant with bone attachment material comprising plugs or inserts according to embodiments of the present invention.
[0034] FIG. 11B is an anterior view of the device shown in FIG. 11A .
[0035] FIG. 12 is a side perspective view of a spinal implant with keels according to some embodiments of the present invention.
[0036] FIG. 13A is a side view of a portion of the spine illustrating an implant on a spinous process with a cooperating suture anchor according to embodiments of the present invention.
[0037] FIG. 13B is a side view of an exemplary spinous process cuff suitable for use with cooperating suture anchors according to some embodiments of the present invention.
[0038] FIG. 14 is a side view of a spine illustrating a wide range facet prosthesis secured using a cooperating suture anchor according to some embodiments of the present invention.
DETAILED DESCRIPTION
[0039] The present invention now is described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
[0040] Like numbers refer to like elements throughout. In the figures, the thickness of certain lines, layers, components, elements or features may be exaggerated for clarity. Broken lines illustrate optional features or operations unless specified otherwise.
[0041] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. As used herein, phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y. As used herein, phrases such as “between about X and Y” mean “between about X and about Y.” As used herein, phrases such as “from about X to Y” mean “from about X to about Y.”
[0042] Unless otherwise defined, all terms (including 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 belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.
[0043] It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.
[0044] It will be understood that, although the terms first, second, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the present invention. The sequence of operations (or steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise.
[0045] The terms “spinal disc implant” and “spinal disc prosthesis” are used interchangeably herein to designate total disc replacements using an implantable total disc replacement (TDR) prosthesis (rather than a nucleus only) and as such are configured to replace the natural spinal disc of a mammalian subject (for veterinary or medical (human) applications). In contrast, the term “spinal implant” refers to both TDR spinal disc implants and alternative spinal implants, such as, for example, a spinal annulus implant, a spinal nucleus implant, a facet implant, and a spinous process implant as well as implants for other portions of the spine.
[0046] The term “keel” means an implant component, feature or member that is configured to be received in a recess or mortise in an adjacent bone to facilitate short and/or long-term fixation and/or to provide twist or torsion resistance in situ.
[0047] The term “flexible” means that the member can be flexed or bent. In some embodiments, the implant can include a keel, which may be flexible but has sufficient rigidity to be substantially self-supporting so as to be able to substantially maintain a desired configuration outside of the body. If flexible, the keel can include reinforcement to increase its rigidity.
[0048] The term “mesh” means any flexible material in any form including, for example, knotted, braided, extruded, stamped, knitted, woven or otherwise, and may include a material with a substantially regular foramination pattern and/or irregular foramination patterns.
[0049] The term “macropores” refers to apertures having at least about a 1 mm diameter or width size, typically a diameter or width that is between about 1 mm to about 3 mm, and more typically a diameter or width that is between about 1 mm to about 1.5 mm (the width dimension referring to non-circular apertures). Where mesh keels are used, the macropores are larger than the openings or foramina of the mesh substrate. The macropores may promote bony through-growth for increased fixation and/or stabilization over time.
[0050] The term “loop” refers to a shape in the affected material that has a closed or nearly closed turn or figure. For example, the loop can have its uppermost portion merge into two contacting lower portions or into two proximately spaced apart lower portions. The term “fold” means to bend and the bend of the fold may have a sharp or rounded edge. The terms “pleat” or “fold” refer to doubling material on itself (with or without sharp edges). The term “attachment point” and derivatives thereof refers to a common attachment location and is not meant to restrict the attachment to a geometric point.
[0051] Referring now to the figures, FIG. 1 illustrates an example of a spinal implant 10 with cooperating suture anchors 20 . The suture anchors 20 include at least one suture 22 that is attached to a bone anchor 20 b ( FIGS. 4A, 4B ). Typically, the suture 22 is provided as a suture set 22 s , in which each leg of the set is tied together such as using a knot 22 t to secure the spinal implant 10 in location. The knot 22 t can reside proximate to and/or against the outer surface of the implant 10 . It is also noted that in lieu of, or with, the knot 22 t , the ends of the sutures 22 may be attached to the implant 10 via other attachment means. For example, the two end portions of the suture 22 can be separately or jointly adhesively attached to the implant 10 such with an adhesive, heat-melt process, staple, clip or other anchor member.
[0052] The implant 10 can include a bone attachment member or material 11 that receives the suture 22 . As shown, the bone attachment material 11 can reside above and below the primary body of the implant 10 . However, the bone attachment material 11 may be configured to reside only above, only below, or to be substantially coextensive with the primary implant body (not shown). Each suture set 22 s can be closed so that the respective knot 22 t resides against or proximate an exterior surface of the bone attachment material 11 , above or below the primary body of the implant 10 . In some embodiments a unitary layer of bone attachment material can form a skirt that defines both an upper and lower bone attachment material 11 . The bone attachment material 11 can comprise any biocompatible material suitable to provide the attachment and/or stabilization. The bone attachment material 11 may comprise a flexible substrate. In some embodiments, the bone attachment material 11 comprises a mesh substrate. The mesh can be metallic, fabric, polymeric or comprise combinations of materials.
[0053] The bone attachment material 11 can include one or more relatively small preformed apertures (not shown) at the respective target indicia markings 122 that can be sized and configured to receive the needle 23 and suture 22 . The preformed apertures may be molded in or introduced at a manufacturing site to reduce clinician preparation time. Alternatively, the substrate can be configured to allow the needle to be inserted through the substrate in the target attachment regions in situ without using preformed apertures.
[0054] The bone attachment material 11 is typically between about 0.25 mm to about 20 mm thick, and is more typically between about 0.5 mm to about 5 mm thick. In some embodiments, the mesh comprises a DACRON mesh of about 0.7 mm thick available as Fablok Mills Mesh #9464 from Fablok Mills, Inc., located in Murray Hill, N.J. The mesh may comprise cryogel material to increase rigidity.
[0055] FIG. 1 illustrates that the implant 10 is secured using a plurality of suture anchors 20 , some above and some below the implant 10 . Although shown as four suture anchors 20 , additional or lesser numbers of the suture anchors 20 may be used. Further, although the suture anchors 20 are shown as being substantially aligned (side to side and vertically) in proximate vertebral bone and in the bone attachment material 11 , the suture anchors 20 may be arranged asymmetrically. In addition, bone screws or other devices may be used with one or more of the suture anchors 20 (not shown). The implant 10 can be attached to bone 25 using the cooperating suture anchors 20 in a manner that allows substantially normal, or at least not unduly restrictive, spinal movement.
[0056] FIG. 2A illustrates that the bone attachment material 11 can be configured with discrete tabs lit spaced apart laterally; each tab lit can engage at least one suture set 22 s . FIG. 2A also illustrates that the bone anchor 20 b can reside under (behind) the bone attachment material 11 , rather than above or below as shown in FIG. 1 . FIG. 2B illustrates that the upper bone attachment material 11 may be configured differently from the lower bone attachment material. FIG. 2B also illustrates that the bone anchor 20 b ( FIG. 4A ) may reside above the bone attachment material 11 while the lower bone anchors 20 b ( FIG. 4A ) may reside substantially behind the bone attachment material 11 . The mounting configuration can also be reversed with the lower bone screws 20 b below the material 11 and the upper bone anchor 20 b behind the material 11 .
[0057] FIG. 3 illustrates a vertebral bone 25 with a mortise or keel recess 26 formed therein. The mortise or recess 26 can be formed into the vertebral bone 25 to accept fins or keels of implants (shown for example as feature 50 in FIG. 12 ). FIG. 3 illustrates exemplary bore locations 120 a , 120 b that can be used and/or formed by bone anchors 20 b relative to the mortise 26 . An implant 10 may employ bone anchors 20 b at one or more of the bore locations. The bore locations 120 a typically reside behind the bone attachment material 11 (shown in broken line) while the bore locations 120 b typically reside above (or below) the material 11 .
[0058] FIG. 4A illustrates a threaded bone anchor 20 b with an attached suture set 22 s in position in a vertebral body 25 . As shown, a suture 22 is held by a head portion 20 h of the bone anchor 20 b . The head 20 h can be recessed into or be substantially flush with the natural boundary of the vertebral bone 25 . For recessed configurations, bone chips or other void filling (bone growth) material 325 ( FIG. 9 ) may be inserted in the cavity between the material 11 and the bone anchor head 20 h . The material 325 can be provided as part of a medical kit 500 ( FIG. 9 ). Typically, the head 20 h includes an aperture 21 and a length of suture 22 is threaded through the aperture 21 to form a suture set 22 s with a pair of legs 22 L. The opposing end portions of the suture legs 22 L (the end portion away from the head 21 ) can include/merge into a needle 23 ( FIG. 6 ). In use, after inserting the needle 23 through the bone attachment material 11 , the corresponding suture leg 22 L can be pulled through the material 11 and the suture set 22 s can be tied or stitched together proximate an outside surface of the material 11 .
[0059] FIG. 4B illustrates that the bone anchor 20 b can be inserted through the cortical layer such that at least a tip portion thereof resides in cancellous bone. It is contemplated that the bone anchor 20 b may have improved pullout strength if the threads of the bone anchor 20 b bear on cortical bone. As shown, the bone anchor 20 b can angularly reside in the bone 25 (rather than be substantially horizontal as shown in FIG. 4A ). Combinations of these and other orientations may also be used.
[0060] FIG. 5 illustrates that the bone anchor 20 b may be configured to hold a plurality of suture sets 22 1 , 22 2 , 22 3 . Although shown as holding three, one or more of the bone anchors 20 b may hold lesser or greater numbers of suture sets 22 s . Each suture set 22 1 , 22 2 , 22 3 may be formed so that the respective sutures legs 22 L have a different color or pattern for matching to allow easier alignment and/or attachment in situ. A template 300 ( FIG. 9 ) may also be provided to help a clinician mark locations on vertebral bodies for the bone anchor 20 b to help provide proper seating and alignment. The bone attachment material 11 may also include needle insertion indicia 122 ( FIG. 9 ) to provide visual references that a clinician can use to attach the suture 22 to the implant 10 . The indicia 122 may also be color coded to the suture for that location.
[0061] Also, although not shown, the bone anchor 20 b may include a single suture leg rather than a suture set 22 s . A first end portion can be integrally attached to the head of the bone anchor 20 h with the other end portion including the needle 23 . To attach to the bone attachment material 11 , the single suture leg can be tied to another single leg or suture set or a discrete anchor member can be attached after the needle 23 is pulled through the material 11 , or the single leg can be adhesively attached, stapled and/or clipped to the outer surface of the bone attachment material 11 (not shown).
[0062] The bone anchor 20 b can be self-tapping and/or self-drilling. The bone anchor 20 b may be implanted into a prior formed bore. The threads of the bone anchor 20 b can be adapted to the porosity of the vertebral cancellous bone (which may be less dense than in other regions). The bone anchor 20 b may have a largest diameter of between about 3-10 mm, typically between about 5-8 mm. The bone anchor 20 b may have a length between about 8-30 mm, typically between about 10-20 mm.
[0063] FIG. 9 illustrates an alternate configuration of a bone anchor 20 b . In this embodiment, the suture attachment region (aperture) 21 is recessed into the head 20 h so that the threads extend substantially the entire length of the bone anchor body 20 b . The threads can bear on the cortical layer of the vertebral body while still being substantially flush or slightly recessed with the outer layer of the vertebral body. This configuration may increase pull-out strength.
[0064] FIG. 6 illustrates that a first suture set 22 1 may be provided in a different length than a second suture set 22 2 . Also, although shown as being attached to different corner portions of the bone material, the two suture sets 22 1 , 22 2 may be attached adjacent each other in a common corner (side by side or one above the other) or one can be attached at a corner and the other at a medial portion. Other configurations may also be used.
[0065] The suture 22 and/or the bone anchor 20 b may comprise a resorbable or non-resorbable biocompatible material.
[0066] As shown in FIG. 6 , the needle 23 may be swaged, threaded or otherwise attached to the suture 22 . The needle 23 may be straight or curved. As shown, the needle 23 is curved and may also include a substantially blunt tip 23 b . Where a mesh is used to form the material 11 , the blunt tip 23 b may inhibit damage to mesh or other sensitive or susceptible fibers when suturing mesh material 11 to the bone. The suture legs 22 L can have lengths between about 5-20 cm with the needles 23 on one end and the aperture or loop 21 of the head 20 h at the other. The needle 23 is typically removed from the suture leg 22 L after pulling the suture leg through the bone attachment material 11 , and the suture leg 22 L can be tied or otherwise secured to the material 11 and the surplus lengths thereof can be removed (cut).
[0067] FIGS. 7A-7E illustrate a sequence of steps that can be used to attach a spinal implant to cooperating suture anchors 20 in situ. As shown in FIG. 7A , the primary implant body 10 b can be positioned in an intervertebral space. The bone attachment material 11 can be pulled, pushed or folded back as shown in FIG. 7B . Then, as shown in FIG. 7C , the bone anchor 20 b can be introduced into the target vertebral bone 25 proximate the implant 10 . The bone can be “pre-drilled”, then the bone anchor inserted, or the bone anchor can be inserted without requiring pre-drilling. In other embodiments, the bone anchor(s) 20 b can be introduced before the implant 10 and/or material 11 . In still other embodiments, the bone attachment material 11 can be attached to the implant after the implant is in the body and/or after the bone anchor(s) is in position. As shown in FIG. 7D , in an exploded view for clarity, a suture set 22 s can be pulled through the material 11 . That is, the needles 23 can be inserted from one side of the material (i.e., flexible skirt) from the posterior (inner) to the anterior (outer) side. The suture set 22 s can be pulled substantially taut and tied together to form a knot 22 t against the outer surface of the material 11 while the bone anchor 20 b remains in the vertebral bone 25 to tighten the material 11 against the vertebral body 25 . The incision can then be closed with the knot 22 t inside the incision (not pulled through the skin).
[0068] FIG. 8 illustrates three different exemplary mounting configurations for a suture anchor 20 that may be used to attach to spinal implants 10 . As shown, two TDR implants 10 are in position in respective intevertebral spaces. The upper implant 10 1 includes a single level multi-attachment point suture anchor 20 sm . The lower portion of the upper implant 10 1 and the upper portion of the lower implant 10 2 illustrate a double level multi-attachment point suture anchor 10 dm . That is, sutures 22 from respective bone anchors 20 b extend to different levels (above and below the bone anchors 20 b ). The lower level of the second implant 10 2 illustrates a single level, single attachment point suture anchor 20 ss.
[0069] FIG. 9 illustrates a medical kit 500 that can provide the suture anchors 20 . The kit 500 can include at least one implant 10 and a plurality of suture anchors 20 . The kit 500 can also include the void filler 325 and at least one surgical template 300 . The template 300 can include indicia for the bone anchor entry location 301 and may optionally include needle indicia 322 that can align with indicia on an interior surface of the bone attachment material 11 proximate the indicia 122 that can be placed on the outside surface of the material 11 (for indicating a target needle exit location). The template 300 may be configured so that each target bone anchor 20 b location 301 is color-coded to bone anchors 20 b and/or suture sets 22 s and a location on material 11 . A similar or different template 300 can be provided for attachment to a lower location or an upper location, or a combination template can be provided with both sets of alignment/target location indicia (not shown).
[0070] FIG. 10A illustrates that the bone anchor 20 b can reside in a cavity 25 c . FIGS. 10A, 11A and 11 B illustrate that the attachment material 11 can include at least one plug 111 that is sized and shaped to enter the cavity 25 c and reside between the bone anchor 20 b and the outer perimeter of the bone and/or outer surface of material 11 . The plug 111 can be attached to the attachment material 11 or be a separate component. FIG. 10B illustrates one exemplary shape of the plug 111 . The plug 111 can comprise a metal, polymer or other suitable material. In some embodiments, the plug 111 is a mesh plug. The mesh plug 111 may comprise polyester fibers, such as DACRON and/or a polyvinylalcohol (PVA) cryogel. As shown in FIGS. 10A, 10B and 11 A, the plug 111 can include macropores 111 p . The plug 111 is typically a single one plug that has through holes 111 p for bone to grow into. The bone growing in those through holes 111 p can provide a solid long-term fixation of the plug 111 to the bone. The plug 111 can be integrally attached to the material 111 and/or the implant body 10 . In some embodiments, the plug 111 is integrally attached to the skirt or tab material 11 and each may comprise a mesh fabric that is molded to the implant body 10 b . FIG. 11A illustrates that the plug 111 faces into the bone and FIG. 11B illustrates the plug 111 can extend inward from a rear primary surface of the external attachment member (e.g., skirt or tab and the like). FIG. 10A illustrates that the bone anchor resides furthermost in the bone cavity with the plug(s) 111 residing between the external bone attachment member and the bone anchor 20 b.
[0071] Referring to FIG. 12 , in some embodiments, the shape of the implant 10 can be described as a three-dimensional structure that provides a desired anatomical shape, shock absorbency and mechanical support. In some embodiments, the anatomical shape can have an irregular solid volume to fill a target intervertebral disc space. The coordinates of the body can be described using the anatomic directions of superior (toward the head), inferior (toward the feet), lateral (away from the midline), medial (toward the midline), posterior (toward the back), and anterior (toward the front). From a superior view, the implanted device has a kidney shape with the hilum toward the posterior direction. The margins of the device in sagittal section are generally contained within the vertebral column dimensions. The term “primary surface” refers to one of the superior or inferior surfaces.
[0072] FIG. 12 illustrates one embodiment of spinal disc implant 10 . The implant 10 can include at least one keel 50 on at least one primary surface. As shown, the implant 10 includes at least one flexible keel 50 . In this embodiment, the flexible keel 15 is an anterior/posterior keel. In the embodiment shown in FIG. 12 , the implant 10 includes both upper and lower keels 50 on respective superior and inferior primary surfaces. In other embodiments, the keel 50 can be oriented to extend substantially laterally. The keel 50 can be defined by a fold in a unitary layer of flexible material.
[0073] The size of the prosthetic spinal disc 10 can vary for different individuals. A typical size of an adult lumbar disc is 3-5 cm in the minor axis, 5 cm in the major axis, and 1.5 cm in thickness, but each of these dimensions can vary. It is contemplated that the implant 10 can be provided in a range of predetermined sizes to allow a clinician to choose an appropriate size for the patient. That is, the implant 10 can be provided in at least two different sizes with substantially the same shape. In some embodiments, the implant 10 can be provided in small, medium and large sizes. Further, the sizes can be configured according to the implant position—i.e., an L3-L4 implant may have a different size from an L4-L5 implant. In some embodiments, an implant 10 can be customized (sized) for each respective patient.
[0074] The implant 10 can be configured as a flexible elastomeric MRI and CT compatible implant of a shape generally similar to that of a spinal intervertebral disc. The implant 10 can have a solid elastomeric body with mechanical compressive and/or tensile elasticity that is typically less than about 100 MPa (and typically greater than 1 MPa), with an ultimate strength in tension generally greater than about 100 kPa, that can exhibit the flexibility to allow at least 2 degrees of rotation between the top and bottom faces with torsions greater than 0.01 N-m without failing. The implant 10 can be configured to withstand a compressive load greater than about 1 MPa.
[0075] The implant 10 can be made from any suitable elastomer capable of providing the desired shape, elasticity, biocompatibility, and strength parameters. The implant 10 can be configured with a single, uniform average durometer material and/or may have non-linear elasticity (i.e., it is not constant). The implant 10 may optionally be configured with a plurality of durometers, such as a dual durometer implant. The implant 10 can be configured to be stiffer in the middle, or stiffer on the outside perimeter. In some embodiments, the implant 10 can be configured to have a continuous stiffness change, instead of two distinct durometers. A lower durometer corresponds to a lower stiffness than the higher durometer area. For example, one region may have a compressive modulus that is between about 11-100 MPa, while the other region may have a compressive modulus that is between 1-10 MPa.
[0076] The implant 10 can have a tangent modulus of elasticity that is about 1-10 MPa, typically about 3-5 MPa, and a water content of between about 30-60%, typically about 50%.
[0077] Some embodiments of the implantable spinal disc 10 can comprise polyurethane, silicone, hydrogels, collagens, hyalurons, proteins and other synthetic polymers that are configured to have a desired range of elastomeric mechanical properties, such as a suitable compressive elastic stiffness and/or elastic modulus. Polymers such as silicone and polyurethane are generally known to have (compressive strength) elastic modulus values of less than 100 MPa. Hydrogels and collagens can also be made with compressive elasticity values less than 20 MPa and greater than 1.0 MPa. Silicone, polyurethane and some cryogels typically have an ultimate tensile strength greater than about 100 or 200 kiloPascals. Materials of this type can typically withstand torsions greater than 0.01 N-m without failing.
[0078] As shown in FIG. 12 , the spinal disc body 10 may have a circumferential surface 11 , a superior surface 12 , and an inferior surface 13 . The superior and inferior surfaces 11 , 12 may be substantially convex to mate with concave vertebral bones. One or more of the surfaces may also be substantially planar or concave. The circumferential surface 11 of spinal disc body 10 corresponds to the annulus fibrosis (“annulus”) of the natural disc and can be described as the annulus surface 11 . The superior surface 12 and the inferior surface 13 of spinal disc body 10 correspond to vertebral end plates (“end plates”) in the natural disc. The medial interior of spinal disc body 10 corresponds to the nucleus pulposus (“nucleus”) of the natural disc.
[0079] The implant 10 can include a porous covering, typically a mesh material layer, 12 c , 13 c on each of the superior and inferior primary surfaces 12 , 13 , respectively. As shown, the implant 10 can also include a porous, typically mesh, material layer 14 c on the annulus surface 14 . The annulus cover layer 14 c can be formed as a continuous or seamed ring to inhibit lateral expansion. In other embodiments, the annulus cover layer 14 c can be discontinuous. As also shown, the three coverings 12 c , 13 c , 14 c can meet at respective edges thereof to encase the implant body 10 . In other embodiments, the coverings 12 c , 13 c , 14 c may not meet or may cover only a portion of their respective surfaces 12 , 13 , 14 .
[0080] FIG. 12 illustrates that the annulus cover 14 c , the superior cover 12 c , and or the inferior cover 13 c can be oversized to extend beyond the bounds of the implant body 10 b above or below an anterior portion of the implant body 10 b to define the attachment material 11 that can cooperate with bone anchors 20 b and sutures 22 . The material 11 can extend above or below the body 10 b with a height between about 2-35 mm, typically 5-15 mm.
[0081] The implant 10 may be configured to allow vertical passive expansion or growth of between about 1-40% in situ as the implant 10 absorbs or intakes liquid due to the presence of body fluids. The passive growth can be measured outside the body by placing an implant in saline at room temperature and pressure for 5-7 days, while held in a simulated spinal column in an intervertebrate space between two simulated vertebrates. It is noted that the passive expansion can vary depending, for example, on the type of covering or mesh employed and the implant material. For example, in some embodiments, the mesh coverings 14 c , 12 c , 13 c along with a weight percentage of (PVA) used to form the implant body are configured to have between about 1-5% expansion in situ.
[0082] In addition, in some embodiments, the mesh may comprise a biocompatible coating or additional material on an outer and/or inner surface that can increase the stiffness. The stiffening coating or material can include PVA cryogel. The annulus cover 14 C (also described as a “skirt”) can be a continuous skirt that defines the bone attachment material 11 and may include stiffening or reinforcement means.
[0083] Some embodiments of the spinal disc implant 10 are configured so that they can mechanically function as a substantially normal (natural) spinal disc and can attach to endplates of the adjacent vertebral bodies. As shown in FIG. 12 , the spinal disc body 10 b is generally of kidney shape when observed from the superior, or top, view, having an extended oval surface and an indented portion. The anterior portion of spinal disc 10 can have greater height than the posterior portion 10 p of spinal disc 10 in the sagittal plane. The implant 10 can be configured with a mechanical compressive modulus of elasticity of about 1.0 MPa, ultimate stretch of greater than 15%, and ultimate strength of about 5 MPa. The device can support over 1200 N of force. Further description of an exemplary flexible implant is described in co-pending U.S. Patent Application Publication No. 20050055099, the contents of which are hereby incorporated by reference as if recited in full herein.
[0084] Elastomers useful in the practice of the invention include silicone rubber, polyurethane, polyvinyl alcohol (PVA) hydrogels, polyvinyl pyrrolidone, poly HEMA, HYPAN™ and Salubria® biomaterial. Methods for preparation of these polymers and copolymers are well known to the art. Examples of known processes for fabricating elastomeric cryogel material is described in U.S. Pat. Nos. 5,981,826 and 6,231,605, the contents of which are hereby incorporated by reference. See also, Peppas, Poly(vinyl alcohol)hydrogels prepared by freezing-thawing cyclic processing. Polymer, v. 33, pp. 3932-3936 (1992); Shauna R. Stauffer and Nikolaos A. Peppas.
[0085] In some embodiments, the implant body 10 is a substantially solid PVA hydrogel having a unitary body shaped to correspond to a natural spinal disc. An exemplary hydrogel suitable for forming a spinal implant is (highly) hydrolyzed crystalline poly(vinyl alcohol) (PVA). PVA cryogels may be prepared from commercially available PVA material, typically comprising powder, crystals or pellets, by any suitable methods known to those of skill in the art. Other materials may also be used, depending, for example, on the application and desired functionality. Additional reinforcing materials or coverings, radiopaque markers, calcium salt or other materials or components can be molded on and/or into the molded body. Alternatively, the implant can consist essentially of only the molded PVA body.
[0086] In some embodiments, the attachment material 11 is integrally attached to a moldable implant material via a molding process. The moldable primary implant material can be placed in a mold. The moldable material comprises an irrigant and/or solvent and about 20 to 70% (by weight) PVA powder crystals. The PVA powder crystals can have a MW of between about 124,000 to about 165,000, with about a 99.3-100% hydrolysis. The irrigant or solvent can be a solution of about 0.9% sodium chloride. The PVA crystals can be placed in the mold before the irrigant (no pre-mixing is required). The mold has the desired 3-D implant body shape. A lid can be used to close the mold. The closed mold can be evacuated or otherwise processed to remove air bubbles from the interior cavity. For example, the irrigant can be overfilled such that, when the lid is placed on (clamped or secured to) the mold, the excess liquid is forced out thereby removing air bubbles. In other embodiments, a vacuum can be in fluid communication with the mold cavity to lower the pressure in the chamber and remove the air bubbles. The PVA crystals and irrigant can be mixed once in the mold before and/or after the lid is closed. Alternatively, the mixing can occur naturally without active mechanical action during the heating process.
[0087] Typically, the mold with the moldable material is heated to a temperature of between about 80° C. to about 200° C. for a time sufficient to form a solid molded body. The temperature of the mold can be measured on an external surface. The mold can be heated to at least about 80-200° C. for at least about 5 minutes and less than about 8 hours, typically between about 10 minutes to about 4 hours. The (average or max and min) temperature can be measured in several external mold locations. The mold can also be placed in an oven and held in the oven for a desired time at a temperature sufficient to bring the mold and the moldable material to suitable temperatures. In some embodiments, the mold(s) can be held in an oven at about 100-200° C. for about 2-6 hours; the higher range may be used when several molds are placed therein, but different times and temperatures may be used depending on the heat source, such as the oven, the oven temperature, the configuration of the mold, and the number of items being heated.
[0088] The liners 14 c , 12 c , 13 c can be placed in the mold to integrally attach to the molded implant body during the molding process. In some embodiments, osteoconductive material, such as, for example, calcium salt can be placed on the inner or outer surfaces of the covering layers 14 c , 12 c , 13 c , and/or the inner mold surfaces (wall, ceiling, floor) to coat and/or impregnate the mesh material to provide osteoconductive, tissue-growth promoting coatings.
[0089] After heating, the implant body can be cooled passively or actively and/or frozen and thawed a plurality of times until a solid crystalline implant is formed with the desired mechanical properties. The molded implant body can be removed from the mold prior to the freezing and thawing or the freezing and thawing can be carried out with the implant in the mold. Alternatively, some of the freeze and thaw steps (such as, but not limited to, between about 0-10 cycles) can be carried out while the implant is in the mold, then others (such as, but not limited to, between about 5-20 cycles) can be carried out with the implant out of the mold.
[0090] Before, during and/or after freezing and thawing (but typically after demolding), the molded implant can be placed in water or saline (or both or, in some embodiments, neither). The device can be partially or completely dehydrated for implantation. The resulting prosthesis can have an elastic modulus of at least about 2 MPa and a mechanical ultimate strength in tension and compression of at least 1 MPa, preferably about 10 MPa, and under about 100 MPa. The prosthesis may allow for between about 1-10 degrees of rotation between the top and bottom faces with torsions of at least about 1 N-m without failing. The implant can be a single solid elastomeric material that is biocompatible by cytotoxicity and sensitivity testing specified by ISO (ISO 10993-5 1999: Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity and ISO 10993-10 2002: Biological Evaluation of medical devices—Part 10: Tests for irritation and delayed-type hypersensitivity).
[0091] The testing parameters used to evaluate the compressive tangential modulus of a material specimen can include:
[0092] Test type: unconfined compression
[0093] Fixtures: flat platens, at least 30 mm diameter
[0094] Rate: 25.4 mm/sec to 40% strain
[0095] Temperature: room temp (˜22° C.)
[0096] Bath: samples stored in saline or water until immediately before test
[0097] Samples: cylinders, 9.8±0.1 mm height, 9.05±0.03 mm diameter
[0098] Compressive Tangential Modulus calculated at 15, 20, and 35% strain
[0099] Embodiments of the instant invention employ anchors 20 to attach any suitable prosthesis and the present invention is not limited to spinal implants. In some embodiments, the suture anchors can be used to attach or affix implants comprising PVA cryogel material. The PVA cryogel implants can be manufactured to be mechanically strong, or to possess various levels of strength among other physical properties with a high water content, which provides desirable properties in numerous applications. For example, the cryogel tissue replacement construct is especially useful in surgical and other medical applications as an artificial material for replacing and reconstructing soft tissues or as orthopedic implants in humans and other mammals.
[0100] FIGS. 13A and 13B illustrate that suture anchors 20 can be used to secure other implants in the body. As shown in FIG. 13A , a spinous process sleeve or cuff implant 210 is in position on the spinous process 35 in the body. The suture anchor 20 is attached to the implant 210 . That is, the bone anchor 20 b resides in the spinous process 35 while the suture set 22 s is tied 22 t to the implant 210 . FIG. 13B illustrates that attachment extensions 211 (such as tabs or a skirt) can be used to secure the sutures 22 . The extensions 211 can include the needle indicia 122 . FIG. 13A illustrates that the sutures 22 may be attached directly to the cuff body. The cuff body may include reinforced regions (i.e., PVA cryogel with polymeric mesh fabric, laminated layers of mesh fabric and the like) with increased rigidity or strength that inhibits tearing that define the attachment zones.
[0101] FIG. 14 illustrates a synthetic wide range facet implant 310 secured in position in the spine using a cooperating suture anchor 20 . The implant 310 is configured as a “spinal facet joint” or joint surface. This term refers to the location at which vertebral bodies meet at a rear portion of the spine. The shape of facet joints change along the length of the spine. The facet joint includes bone, cartilage, synovial tissue, and menisci. The implant 310 can be an elastic body that is configured to substantially conformably reside on an outer surface of the bone in a manner that allows a relatively wide range of motion between the bones forming the joint. Also, as shown in FIG. 14 , the suture knots can be recessed within the implant 310 device (such as in a small cylindrical recess or well for example) so that the knots are inhibited from rubbing against the opposite articulating surface of the facet joint.
[0102] The implants 310 and 210 can be substantially “conformal” so as to have sufficient flexibility to substantially conform to a target structure's shape. The facet implant or prosthesis can be applied to one surface (one side) of the facet joint (the bone is resurfaced by the implant) or to both surfaces of the joint, and/or may reside therebetween as a spacer to compress in response to loads introduced by the cooperating bones at the facet joint and still allow motion therebetween. The implant may be an elastic body that is configured to conformably reside on an outer surface of the bone in a manner that allows a relatively wide range of motion between the bones forming the joint. A facet implant or prosthesis can be applied to one surface (one side) of the facet joint (the bone is resurfaced by the implant) or to both surfaces of the joint, and/or may reside therebetween as a spacer to compress in response to loads introduced by the cooperating bones at the facet joint and still allow motion therebetween.
[0103] The spinal facet joint implant 310 can be configured to provide “wide range motion”; this phrase refers to the substantially natural motion of the bones in the facet joint which typically include all ranges of motion (torsion, lateral and vertical). The term “wide range motion” refers to substantially natural motion of the bones in the facet joint, which typically include the three motions associated with a functional spine unit, flexion/extension, lateral bending, and axial rotation. The motions translate differently in the disc compared to the facets but these motions are a good reference as far as range of motion. A facet joint sees sliding motions (along the joint surface) as well as compression and tension (in which case the facets are not in contact and the load is taken by the ligament only (capsular ligament)). The term “compact” means that the device is small with a low profile and suitable for surgical introduction into the spine. The term “thin” means that the device has a thickness that is less than about 6 mm, typically between about 0.001-3 mm, and may be between about 0.01 mm to about 0.5 mm. The term “conformal” means that the implant material or member is sufficiently flexible to conform to a target structure's shape. The target structure's shape can be either the upper portion of the lower bone or the lower portion of the upper bone (one of the two vertebral bones) that meet at the rear of the spine or both.
[0104] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. The invention is defined by the following claims, with equivalents of the claims to be included therein. | Spinal implants have cooperating suture anchors. The devices include: (a) a spinal implant; and (b) at least one suture anchor comprising a threaded bone anchor holding at least one suture extending outwardly therefrom. In position, the at least one suture extends outward from the threaded bone anchor and attaches to the spinal implant while the threaded anchor is anchored in a vertebral body. | 0 |
TECHNICAL FIELD
[0001] The present invention relates to a chair and the structure for stretching a mesh over the backrest, a seat, a headrest etc. of the chair.
BACKGROUND OF THE INVENTION
[0002] U.S. Pat. No. 6,386,634B1 discloses the backrest structure of a chair and the stretching structure of a mesh in the backrest in which edge material is mounted by molding around the mesh to which tension is already applied, the edge material engaging in grooves in a front surface of a back frame to apply mesh over the front surface of the back frame.
[0003] JP2004-49685A discloses that an engagement piece mounted to the periphery of a mesh engages on a peripheral groove on the rear surface of a back frame, said engagement piece being pressed into the groove by the binding frame mounted to the rear surface of the back frame to apply tension to the mesh over the upper surface of the back frame.
[0004] A hanger for having clothes of a sitting person is mounted to the backrest of a chair in JP6-45553U, JP2004-159745A, JP9-10189U, JP11-155690A and JP5-7179U.
Problems to be Solved by the Invention
[0005] However, U.S. Pat. No. 6,386,634B1 discloses that it is necessary to take the width of the back frame to prevent flexure of the back frame by force applied to the mesh when the user sits down, a groove which engages with the edge material around the mesh being formed on the front surface of the back frame so that the periphery of the back frame is exposed from the mesh. The back frame greatly occupying the appearance of the chair causes bad appearance in design.
[0006] In JP2004-49685A, when a user sits down on the chair, flexing of the back frame against the force applied to the mesh is prevented by both the back frame and binding frame. Thus, the back frame covered with the mesh and binding frame not covered with the mesh are overlapped and exposed to the outside, which does not produce good appearance in design as well as heavy weight, a lot of the parts, a lot of time for assembling and high cost.
[0007] In JP6-45553U and JP2004-159745A, the support rod for supporting the hanger body is directly mounted in the middle of the rear surface of the backrest. It cannot be applied to a chair in which mesh is applied to the back frame. And a special device is required so that the mounting parts do not project from the front surface of the backrest when the support rod is directly attached to the middle of the rear surface of the backrest.
[0008] In JP9-10189U, JP11-155690A and JP5-7179U, the support rod is mounted to the transverse rod at the lower part of the rear of the backrest or support post standing from the lower part thereby increasing the length of the support rod. When the chair is pulled with the hunger body, the hanger is likely to be broken.
[0009] In view of the above disadvantages in the prior art, it is objects of the present invention to solve the problems below:
[0010] (A) To provide a chair with the backrest structure in which the ratio of the back frame is small with respect to the appearance of the chair, having good design, light weight, reduction in the number of parts and improvement in assembling.
[0011] (B) To provide a chair with a hanger in which the hanger is easily mounted to the backrest to allow parts for mounting the hanger not to project from the front surface of the backrest, preventing the hanger from being damaged and providing good appearance.
[0012] (C) To provide the structure for a mesh over the backrest of a chair in which the ratio of a frame to appearance of the chair is small to provide good appearance, light weight, reduction in the number of parts and improvement in assembling.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a front elevational view of the first embodiment of a chair according to the present invention;
[0014] FIG. 2 is a side elevational view thereof;
[0015] FIG. 3 is a rear perspective view thereof;
[0016] FIG. 4 is a front perspective view of the backrest;
[0017] FIG. 5 is a sectional view taken along the line V-V in FIG. 4 ;
[0018] FIG. 6 is a sectional view taken along the line VI-VI in FIG. 4 ;
[0019] FIG. 7 is an enlarged perspective view of the part VII in FIG. 4 ;
[0020] FIG. 8 is a side view of the second embodiment of a chair with a hanger according to the present invention;
[0021] FIG. 9 is an enlarged rear perspective view of main part of the chair in FIG. 8 ;
[0022] FIG. 10 is a rear enlarged exploded perspective view of the chair in FIG. 8 ;
[0023] FIG. 11 is a front enlarged exploded perspective view thereof;
[0024] FIG. 12 is an enlarged sectional view taken along the line XII-XII in FIG. 9 ; and
[0025] FIG. 13 is an enlarged sectional view taken along the line XIII-XIII in FIG. 9 .
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0026] FIGS. 1-7 show the first embodiment of the present invention.
[0027] The present application is applied to the structure of the backrest of the chair and the structure of mesh in the backrest.
[0028] As shown in FIGS. 1 and 2 , a reclining chair 1 comprises a leg 4 comprising five leg rods 3 each of which has a caster 2 at the end. At the center of the leg 4 , a telescopic leg post 6 which comprises a gas spring 5 stands. At the upper end of the leg post 6 , a rear part of a support base 7 is fixed.
[0029] The support base 7 comprises a hollow rhombus-like box which opens at an upper front part, and arms 8 , 8 are integrally formed from each side of the front part of the support base 7 .
[0030] A hexagonal pivot 9 passes through the support base 7 in the middle. At each end of the pivot 9 extending from the support base 7 , a tubular portion 11 a fits. The tubular portions 11 a are provided at the lower front ends of a pair of backrest support rods 11 , 11 that support a backrest 10 . The backrest 10 , the backrest support rods 11 , 11 and the backrest 10 are rotated around the pivot 9 with respect to the support base 7 .
[0031] Inside the support base 7 , there are provided a rubber torsion unit for promoting the pivot 8 in an anticlockwise direction and a promoting-force adjusting device (not shown). In the middle of the front lower surface of the support base 7 , there is a gas spring unit 13 for assisting promoting force of the rubber torsion unit in connection with the rubber torsion unit to form a force-promoting unit to stand the backrest 10 .
[0032] Short arms 12 , 12 project from the backrest support rods 11 , 11 at the back of the pivot 9 . At the upper ends of the arms 12 , 12 , a pair of seat-supporting frames 15 , 15 which support each side of a seat 14 are connected at the rear ends with a shaft 16 .
[0033] The backrest 10 will be described with respect to FIGS. 3-7 .
[0034] In FIG. 3 , a back frame 17 of the backrest 10 comprises a rectangular synthetic-resin front face frame 18 . The front face frame 18 comprises an upper frame rod 18 a , a lower frame rod 18 b , a left-side frame rod 18 c and a right-side frame rod 18 d . The rods 18 b , 18 d are wider than the rods 18 a , 18 b . A mesh is held on the rods 18 a , 18 b , 18 c , 18 d.
[0035] In FIGS. 4 and 5 , a pair of grooves 19 , 20 is formed longitudinally on the outer side surfaces of the right and left side frame rods 18 c , 18 d.
[0036] In FIG. 6 , a groove 21 is horizontally formed along the lower edge of the front surface of the upper frame rod 18 a , and a groove 22 is horizontally formed along the upper edge of the front surface of the lower frame rod 18 b.
[0037] A surface 21 a between the lower edge of the front surface of the upper frame rod 18 a and the groove 21 and a surface 22 a between the upper edge of the front surface of the lower frame rod 18 b and the groove 22 are grooved by thickness of an outward portion 25 b of an edge piece 25 . When the edge piece 25 engages with a corner between the lower surface and the front surface of the upper frame rod 18 a and the front surface and with a corner between the upper surface and the front surface of the lower frame rod 18 b , the end face of each of the edge piece 25 is coplanar with the front surfaces of the upper frame rod 18 a and the lower frame rod 18 b.
[0038] A mesh 23 may be preferably net-like or mesh-like material knitted or woven from high-tension plastic or other elastic fibers, or may be woven fabric, synthetic resin sheet or porous sheet. Synthetic resin edge pieces 24 , 24 which engage in a pair of grooves 19 , 20 are fixed in the left and right side edges of the mesh 23 by molding. The synthetic-resin edge pieces 25 , 25 which has a hook-like portions 25 d , 25 d and engage in the grooves 21 , 22 are fixed in the upper and lower edges by molding.
[0039] The edge piece 25 comprises a base 25 a , the outward portion 25 b , and a turning portion 25 c which turns in parallel with the base 25 a from the end of the outward portion 25 b . The base 25 a and the outward portion 25 b constitute the hook-like portion 25 d.
[0040] The size of the mesh 23 mounted to the edge pieces 24 , 24 , 25 , 25 is formerly determined to apply a suitable tension to the mesh 23 when the edge pieces 24 , 24 , 25 , 25 engage in the grooves 19 , 20 or the grooves 21 , 22 .
[0041] In FIGS. 4-7 , the right and left edge pieces 24 , 24 of the mesh 23 engage in the grooves 19 , 20 of the right and left side frame rods 18 c , 18 d . The upper and lower ends of the mesh 23 are wound from the front surface to the rear surface around the upper and lower surfaces of the upper and lower frame rods 18 a , 18 b . The hook-like portions 25 d , 25 d of the upper and lower edge pieces 25 , 25 engage on the corner between the lower surface and the front surface, and the corner between the upper surface and the front surface. The turning portions 25 c , 25 c of the upper and lower edge pieces 25 , 25 engage in the upper and lower grooves 21 , 22 , so that the mesh 23 is stretched over the entire front surface of the front face frame 18 tensionally.
[0042] Thus, the front surface of the front face frame 18 or the front surface of the back frame 17 is entirely covered with the mesh 23 . So the back frame 17 is not so occupied in the appearance of the chair, so that good impression is given in design.
[0043] In FIGS. 3 and 6 , to each side end of the upper frame rod 18 a of the front face frame 18 , an arcuate upper reinforcement rod 26 is joined so that the middle of the rod 26 is spaced apart from the upper frame rod 18 a . The upper reinforcement rod 26 and the upper frame rod 18 a is like crescent.
[0044] The upper reinforcement rod 26 keeps strength of the upper part of the back frame 17 together with the back frame 17 . When a user is reclined on the backrest 10 , it is allowed for the upper frame rod 18 a to be slightly flexed elastically.
[0045] The upper reinforcement rod 26 is spaced apart from the upper frame rod 18 a . Thus, without hindering attachment of the mesh 23 , a headrest 27 as shown by dotted lines in FIG. 4 and an optional member such as a hanger for clothes in FIG. 8 and so on are detachably mounted.
[0046] The upper reinforcement rod 26 is also used with a hand when the chair is moved.
[0047] In FIGS. 3 , 6 and 7 , to the lower ends of the right and left side frame rods 18 c , 18 d of the front face frame 18 , both ends of the lower reinforcement rod 28 are coupled. The middle of the lower frame rod 18 b is spaced forward of the lower reinforcement rod 28 , but each end thereof is fastened to each end of the lower reinforcement rod 28 with a screw 29 .
[0048] The lower end of the mesh 23 is wound around the lower frame rod 18 b after the lower frame rod 18 b is fastened to the front surface of the lower reinforcement rod 28 . A folding portion 25 c of the lower edge piece 25 is engaged in the groove 22 of the lower frame rod 18 b , so that the mesh 23 is mounted to the lower frame rod 18 b.
[0049] When the chair is scrapped, a tool such as a screwdriver (not shown) is stuck through the mesh 23 and engaged with a head of the screw 29 which is loosened, so that the lower frame rod 18 b is removed from the lower reinforcement rod 28 . Thereafter, the upper edge of the mesh 23 and the right and left side edges are removed from the upper frame rod 18 a and the right and left side frame rods 18 c , 18 d with the edge members 25 , 24 , 24 . The mesh 23 is separately removed from the back frame 17 and replaced with a new one.
[0050] When the chair is moved and hit with another chair, the lower frame rod 18 b is protected by the lower reinforcement rod 28 , so that the lower ends of the lower frame rod 18 b and the mesh 23 are prevented from being damaged.
[0051] FIGS. 8-13 show the second embodiment in which a hanger is mounted to the chair in the first embodiment of the present invention. The basic structure of the chair is similar to the first embodiment, and the same numerals are allotted to the same members. Description thereof is omitted.
[0052] A chair 30 with a hanger in the second embodiment of the invention comprises a hanger 31 that moves up and down behind the backrest 10 .
[0053] The hanger 31 comprises a hanger body 32 on which a suit can be hung; and a pair of support rods 33 , 34 which support the body 32 . The support rods 33 , 34 are mounted on the backrest 10 with a mounting member 35 and a screw seat piece 36 by a screws 37 .
[0054] The backrest 10 comprises the back frame 17 in which the mesh 23 in FIGS. 1-7 is stretched over the front face frame 18 . The middle of the hanger 31 is spaced apart from the upper frame rod 18 a of the front face frame 18 , and each end of the hanger 31 is mounted to the middle of the upper reinforcement rod 26 connected to the upper frame rod 18 a.
[0055] A pair of support rods 33 , 34 comprises parallel vertical rod portions 33 a , 34 a ; extending rod portions 33 b , 34 b inclined upward of the vertical rod portions 33 a , 34 a ; and connecting portions 33 c , 34 c curved downward of the vertical rod portions 33 a , 34 a . The support rods 33 , 34 are connected at inner ends of the connecting portions 33 c , 34 c.
[0056] The upper ends of the extending rod portions 33 b , 34 b are plain. The extending rod portions 33 b , 34 b are mounted to the right and left ends of the hanger body 32 with screws (not shown), so that the support rods 33 , 34 are fixed to the hanger body 32 .
[0057] The extending rod portions 33 b , 34 b of the support rods 33 , 34 are curved forward. So the hanger body 32 is positioned in front of the rear end of the upper reinforcement rod 26 .
[0058] FIGS. 12 and 13 are enlarged sectional views taken along the line XII-XII and XIII-XIII in FIG. 9 .
[0059] In FIGS. 9-12 , plain portions 40 , 41 are formed on opposite surfaces 38 , 39 of the vertical rod portions 33 a , 34 a of the right and left support rods 33 , 34 .
[0060] A mounting member 35 comprises a thick rectangular plate. The right and left ends 42 , 42 are formed in size such that the mounting member 35 can engage in the plain portions 40 , 41 of the vertical rod portions 33 a , 34 a of the right and left support rods 33 , 34 .
[0061] On the inner side edges of the plain portions 40 , 41 , vertical projections 43 , 44 are provided in parallel with each other.
[0062] The projections 43 , 44 engage in engagement grooves 45 , 45 on the front surface of the mounting member 35 so that the support rods 33 , 34 slidably move with respect to the mounting member 35 .
[0063] In FIGS. 11 and 12 , vertical forward projections 46 , 46 are provided on the front surface of the vertical rod portions 33 a , 34 a of the right and left support rods 33 , 34 . On the rear surface of the upper reinforcement rod 26 of the backrest 10 , vertical engagement grooves 47 , 47 are provided to engage with the forward projections 46 , 46 .
[0064] Through holes 48 , 48 are formed in the mounting member 35 , and through holes 49 , 49 are formed in the upper reinforcement rod 26 . Blind bores 50 , 50 are formed in the rear surface of a screw seat piece 36 at a position corresponding to the through holes 48 , 48 .
[0065] The hanger 31 will be mounted to the upper reinforcement rod 26 below.
[0066] The right and left support rods 33 , 34 having the hanger body 32 at the upper end contacts the upper reinforcement rod 26 to allow the forward projections 46 , 46 of the vertical rods 33 a , 34 a of the support rods 33 , 34 to engage in the engagement grooves 47 , 47 on the rear surface of the screw seat piece 26 , thereby positioning the support rods 33 , 34 .
[0067] Then, the right and left ends of the mounting member 35 engage in the plain portions 40 , 41 of the vertical rod portions 33 a , 34 a of the right and left support rods 33 , 34 . In the engagement grooves 45 , 45 on the front surface of the mounting member 35 , the projections 43 , 44 of the plain portions 40 , 41 of the vertical rod portions 33 a , 34 a engage, and the mounting member 35 is positioned between the right and left vertical rod portions 33 a and 34 a.
[0068] Then, the screw seat piece 36 contacts the front surface of the upper reinforcement rod 26 . While the support rods 33 , 34 are put between the upper reinforcement rod 26 and the mounting member 35 , the upper reinforcement rod 26 is held between the mounting member 35 and the screw seat piece 36 . The screws 37 , 37 pass into the blind bores 50 of the screw seat piece 36 through the through holes 48 , 49 , so that the hanger 31 is mounted to move up and down with suitable resistance behind the backrest.
[0069] An engagement bore 52 for mounting a cover member 51 is formed in the middle of the mounting member 35 . An inward projection 53 is provided on a rear edge of the engagement bore 52 . The cover member 51 comprises a thin elongate plate and has in the middle an engagement claw 54 which is engagable with the inward projection 53 of the engagement bore 52 .
[0070] On the rear surface of the mounting member 35 , there is formed a recess 55 which engages with the cover member 51 . The engagement claw 54 of the cover member 51 is put in the engagement bore 52 of the mounting member 35 to allow the claw 54 to engage on the inward projection 53 . The entire cover member 51 engages in the recess 55 , so that the cover member 51 is mounted to the mounting member 35 .
[0071] The cover member 51 is also used as nameplate.
[0072] The hanger 31 is slidable up and down. When a suit is hung at an upper limit where the hanger slides, the hanger 31 moves down owing to the weight of the suit and the lower end of the suit contacts a floor, so that the suit is likely to become dirty.
[0073] For prevention, in FIGS. 10 and 12 , a plurality of small rearward projections 56 a , 56 b are provided on the vertical rod portions 33 a , 34 a . and an engagement groove 57 which is elastically engagable with the small projections 56 a , 56 b are provided in FIGS. 11 and 12 . Thus, at a plurality of vertical positions where the small projections 56 a , 56 b elastically engage in the engagement groove 57 , the hanger can be held against a certain load.
[0074] By tightening the screw 37 , the support rods 33 , 34 may be held between the upper reinforcement rod 26 and the mounting member 35 . To change a height of the hanger 31 , the screw 37 is loosened to allow the support rods 33 , 34 to move up and down. Thereafter, the screw 37 is tightened again to allow the hanger 31 to be held at a desired height.
[0075] Various modifications of the present invention may be possible without departing from the scope of claims.
[0076] For example, in the foregoing embodiment, the upper reinforcement rod 26 and the lower reinforcement rod 28 are mounted on the rear surface of the upper and lower frame rods 18 a , 18 b . But the upper reinforcement rod 26 or the lower reinforcement rod 28 may be omitted.
[0077] In the foregoing embodiments, the present invention is applied to the stretching structure of the mesh 23 of the backrest 10 of the chair, but may be applied to a seat of a chair or a headrest.
[0078] The edge member 25 is made like a letter L and may engage to a corner between the lower surface and front surface of the upper frame rod 18 a or lower frame rod 18 b. | A stretching structure of a stretching material in a chair in which the ratio of the rear frame of a backrest to the outline of the chair is small, design is smart, weight is reduced, the number of parts is reduced, and assemblability is improved and the backrest of the chair. In the chair having the backrest formed by stretching the stretching material on the front surface of the rear frame, the rear frame comprises a front frame to which the peripheral edge part of the stretching material is fixed and an upper reinforcement frame rod. The laterally facing upper reinforcement frame rod is connected at its both ends to both ends of the laterally facing upper frame rod at the top of the front frame with the center part of the upper reinforcement frame rod separated backward from the upper frame rod. | 0 |
This application is th U.S. national phase of Intenational Application No. PCT/EP2001/051876, filed 9 Feb. 2011, which disgnated the U.S. and claims priority to Italian application RM2010A000053, filed 11 Feb. 2010; the entire contents of each of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of Nebivolol. Nebivolol is a racemic mixture of the two enantiomers [2S[2R[R[R]]]]α,α-[imino-bis(methylene)]bis[6-fluoro-chroman-2-methanol] and [2R[2S[S[S]]]]α,α-[imino-bis(methylene)]bis[6-fluoro-chroman-2-methanol] (Scheme 2).
In particular, it is reported the kinetic resolution of the two diastereoisomeric pairs of RS/SR and SS/RR epoxides (scheme 1, mixture 1) by treatment with an amine in a suitable solvent.
STATE OF THE ART
Nebivolol is known as an adrenergic beta-receptor antagonist, an antihypertensive agent, a platelet aggregation inhibitor and a vasodilating agent.
Nebivolol has basic properties and may be converted into an acceptable pharmaceutical salt form by treatment with an acid. The hydrochloride salt is the marketed form.
Nebivolol contains four asymmetric centres, and therefore 16 stereoisomers are theoretically possible. However, because of the particular structure of the molecule (the presence of an axis of symmetry), only 10 stereoisomers can actually be formed (Scheme 3).
Scheme 3
Possible stereoisomers for nebivolol
B =
A =
SSSS
SSSR I-nebivolol
SSRR
SSRS
RSSS (= SSSR)
RSSR
RSRR
RSRS
RRSS
RRSR
RRRR
RRRS d-nebivolol
SRSS
SRSR
SRRR (= RRRS)
SRRS
In fact, because of the symmetry of the molecule, RSSS═SSSR, RRSS═SSRR, SRSS═SSRS, RRSR═RSRR, SRSR═RSRS and RRRS═SRRR.
U.S. Pat. No. 4,654,362 (EP 0145067, Janssen) describes the preparation of Nebivolol with use of epoxide isomers (Scheme 1, mixture 1: RS, SR, RR and SS) as key intermediates in the synthesis. These are separated, with a chromatography column, into the two epoxide racemates (RS/SR) and (RR/SS).
EP 334429 (Janssen) describes the same process reported in EP 0145067, but with more experimental details. EP 0334449 describes a stereoselective synthesis of the isomer [2R,αS,2′S,α′S]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].
WO 2006/016373 (Hetero Drugs Limited) describes fractional crystallization methods applied at the level of the diastereoisomeric mixture of benzyl nebivolol in the form of hydrochloride salt, but is silent on epoxide opening or separation methods (compound 1).
Also WO 2006/025070 (Torrent Pharmaceutical) remains within the classical synthesis described by U.S. Pat. No. 4,654,362 and merely introduces a method of separation of the diastereoisomeric pairs at the level of benzyl nebivolol in the form of hydrochloride salt. In the subsequent WO 2007/083318 it is claimed the use of diisopropyl ether for the crystallization of benzyl Nebivolol intermediate as free base. WO 2007/041805 (Egis Gyógyszergyár) describes a process for the preparation of [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its individual pure [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]] enantiomers starting from very different compounds.
In WO 2008/010022 (Cimex Pharma) and WO 2008/064826 (Zach System) other synthetic methods are advanced, in which however more or less complex procedures for isomer separation have to be provided for.
WO 2008/064827 describes the separate and enantioselective synthesis of d- and 1-Nebivolol.
On the basis of literature evidence available to date, Nebivolol synthesis still entails numerous synthetic problems. The original Janssen synthesis going through the epoxides (Scheme 1, mixture 1) is surely the shorter one, but requires a separation by preparative HPLC of the two diastereoisomeric epoxide pairs. The other methods generally envisage many more synthetic steps.
Therefore, the need to develop a novel synthetic process, suitable for industrial use and possibly avoiding the use of preparative HPLC though maintaining a limited number of synthetic steps, is markedly felt.
SUMMARY OF THE INVENTION
It has now surprisingly been found a more effective process for the synthesis of Nebivolol, which is summarized in Scheme 1. This process allows to eliminate the drawbacks highlighted hereto for the synthesis routes previously known, i.e., it:
a) avoids separation by preparative HPLC of the pairs (4RR/SS RS/SR) of epoxides enantiomers). b) does not envisage the separate and parallel synthesis of the various enantiomers. The reaction of the mixture 1 with an amine in primary alcohols such as methanol, ethanol, propanol, etc., proceeds quickly and cleanly, but almost without any diastereoselectivity, i.e. the two pairs of epoxides contained in 1, (SR+RS) and (RR+SS) exhibit very similar reaction velocities. From studies reported in the literature [Can. J. Chem. (1967), 45, 1597-1600] it seems that the role of alcohol in the opening of epoxides by an amine is not merely that of a solvent, but also of providing acid catalysis.
By conformational analysis studies, we were able to prove that the two epoxides have different conformational preferences. Consequently, a specific interaction with an alcohol can be influenced by the steric hindrance of the alcohol itself. Surprisingly, we demonstrated that by using sterically hindered alcohols the kinetics of the reaction of opening epoxides 1 by amines is modified so as to make the reaction selective toward one of the two epoxides.
This type of kinetic resolution is obtainable also with other nitrogen nucleophiles, such as ammonia, the azide ion (N 3 − ), hydroxylamines.
The remaining epoxide and the product of the opening exhibit very different chemico-physical characteristics, allowing an easy separation thereof extractively, chromatographically or by crystallization.
Hence, object of the present invention is a process for the preparation of Nebivolol, the process comprising:
a. reacting the epoxide mixture 1 (RS, SR, RR and SS) of formula
with an amine R—NH 2 , wherein:
R is a protective group selected from methyl, allyl, t-butyl, benzyl, diphenylmethyl, triphenylmethyl, fluorenyl, 9,10-dihydroanthracen-9-yl, dibenzyl, wherein the aromatic rings present in the groups can be possibly mono- or disubstituted with a group selected from: halogen, nitro, a C1-C4 alkyl chain, CF 3 , CHF 2 , an OR 2 group, where R 2 is a hydrogen, a C1-C4 alkyl; and preferably a benzyl group,
in a suitable solvent represented by a sterically hindered alcohol, alone or in mixture with an apolar solvent, to obtain a mixture of the four compounds 2, 3, 4 and 5, from which the pair 2/3 is separated from the pair 4/5;
b. reacting the amines 2 and 3, in mixture, with the pair of epoxides 4 and 5, in mixture, to obtain a mixture of 4 compounds (6, 7, 8 and 9);
c. separating 6 and 8 (RSSS+SRRR) in mixture from 7 and 9 by fractional crystallization, by a first solvent selected from ethanol, propanol, isopropanol, tert-butanol, 2-methyl-2-butanol (preferably 2-methyl-2-butanol) and subsequently by a mixture between a polar aprotic solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, and an apolar solvent selected from pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, toluene (preferably an ethyl acetate/cyclohexane mixture).
d. removing the protecting group R, with concomitant or subsequent forming of the hydrochloride salt.
As an alternative, the reaction described at point a. can be carried out by:
e. reacting the epoxide mixture 1 with ammonia or the azide ion, followed, in the case of azide, by reduction (Scheme 7);
f. separating the primary amine from the epoxides 4/5 by extraction in a suitable solvent or by chromatography;
g. carrying out a reductive amination of the amines 10/11 with an aldehyde R 1 CHO, wherein R 1 is H, vinyl, phenyl, phenyl mono- or disubstituted with a group selected from: halogen, nitro, C1-C4 alkyl chain, CF 3 , CHF 2 , OR 2 , where R 2 is a hydrogen, a C1-C4 alkyl; preferably phenyl, to obtain the mixture of amines 2/3;
Or, as an alternative to the reaction described at point e.:
h. reacting the epoxide mixture 1 with hydroxylamines, followed by N—O bond hydrogenation to produce amines 10/11.
A specific solution of the present invention is a process analogous to that described above, in which, as a partial alternative to point a., after reacting the amine RNH 2 with the epoxide mixture 1, the pair of compounds 2/3 is not separated from compounds 4/5, but:
k. excess of unreacted amine RNH 2 is removed i. an alcoholic solvent selected from methanol or ethanol is added, and the compounds are left to react as envisaged at point b.
Another specific solution of the present invention is a process analogous to the above-described one in which, always as an alternative to point a.:
m. the reaction is had with a secondary amine of RR 3 NH type, wherein R has the meaning seen in the foregoing, and R 3 is a benzyl group, possibly mono- or disubstituted with a group selected from: halogen, nitro, a C1-C4 alkyl chain, CF 3 , CHF 2 , an OR 2 group, where R 2 is a hydrogen, a C1-C4 alkyl, and preferably a benzyl group, to obtain a mixture of the four compounds 12, 13, 4 and 5, from which the pair 12/13 is separated from the pair 4/5;
n. deprotecting from group R 3 , to obtain a mixture of the compounds 2/3.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention the nebivolol compound is obtained with the method described in Scheme 1 starting from the mixture of the four isomers SR, RS, RR and SS of the epoxide of formula (1)
The epoxide mixture 1 is dissolved in a sterically hindered alcohol selected from iPrOH (isopropanol), sec-BuOH, tert-BuOH, isoamyl, 2-methyl-2-butanol, 2-methyl-2-pentanol, preferably an alcohol selected from: 2-methyl-2-butanol, tert-BuOH, and 2-methyl-2-pentanol, used alone or containing a variable amount of an apolar solvent selected from the group: petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, toluene, preferentially cyclohexane, in the ratio alcohol:apolar solvent of 1:1 to 10:1.
The solution is maintained at a temperature comprised between −20° and 60° C., preferably between 0° C. and 40° C., and even more preferably at 25° C. and additioned with an amine R—NH 2 , where:
R is a protecting group selected from methyl, allyl, t-butyl, benzyl, diphenylmethyl, triphenylmethyl, fluorenyl, 9,10-dihydroanthracen-9-yl, dibenzyl, wherein the aromatic rings can be possibly mono- or disubstituted with a group selected from: halogen, nitro, a C1-C4 alkyl chain, CF 3 , CHF 2 , a group OR 2 , where R 2 is a hydrogen, a C1-C4 alkyl; and preferably a benzyl group, in an amount of 1 to 10 equivalents, preferably 2 to 3 equivalents calculated with respect to the RS/SR epoxide mixture of formula 1. The mixture thus obtained is stirred for 10-40 hours and preferentially for 12 hours. The precipitate formed (a mixture of compounds 2 and 3) is filtered off. The remaining solution is diluted with an apolar solvent selected from the group: petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, toluene, preferentially cyclohexane, in an amount that may range from 1 to 40 volumes, and washed with an aqueous acid solution (preferably NaHSO 4 or NaH 2 PO 4 ). The organic phase, containing epoxides 4 and 5, is concentrated.
Amounts of the mixtures of compounds 2/3 and 4/5 are reacted in a ratio ranging from 0.7:1 to 1:0.7, and preferentially in an equimolar amount, in an inert organic solvent, like an aromatic hydrocarbon, a low molecular weight alcohol such as methanol, ethanol, isopropanol, butanol, a ketone, an ether or a polar aprotic solvent, preferentially ethanol (as reported in U.S. Pat. No. 4,654,362). The mixture, maintained at a temperature comprised between 40° C. and 120° C., preferentially between 50° C. and 90° C., is mixed to completion of the reaction; then, the solvent is evaporated.
The residue thus obtained is crystallized from an alcohol selected from ethanol, propanol, isopropanol, tert-butanol, 2-methyl-2-butanol, preferably 2-methyl-2-butanol, and subsequently from a mixture between a polar aprotic solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, and an apolar solvent selected from pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, toluene; preferably a ethyl acetate/cyclohexane mixture, until reaching a >99% purity in the pair 6/8.
The compounds of formula 6/8 thus obtained, in case R is a benzyl group, are converted into nebivolol free base by hydrogenolysis with methods known to a person skilled in the art, and with a catalyst selected from Pd/C, Pd(OH) 2 /C. Among those, the use of Pd(OH) 2 is preferable, as it offers advantages related to final product purity and reaction velocity. In case R is one of the other groups envisaged, deprotections are carried out by methods known in the state of the art; e.g., in case R=methyl, deprotection can be carried out photochemically, as described in Tetrahedron Letters (1989) 3977, for R=allyl, a catalytic hydrogenation can be done with a Pd-based catalyst, for R=t.butyl a treatment with methanol and hydrochloric acid is carried out, as described in J. Org. Chem. (2002), 8928-8937.
The nebivolol free base is converted into its hydrochloride salt after dissolution in ethanol according to methods known to a person skilled in the art (WO 95/22325). In an alternative embodiment of the present invention, intermediates 2 and 3 are produced through steps (e) and (g). The SR, RS, RR and SS epoxide mixture 1 is reacted in an alcohol sterically hindered as seen in the foregoing, with ammonia or an azide, preferably sodium azide, at a temperature comprised between −20° and 60° C., preferably between 0° C. and 40° C. and even more preferably at 25° C. In case the azide is used, the reaction is followed by an intermediate reaction according to methods known in the state of the art, preferably by catalytic hydrogenation with a Pd/C or Pd(OH) 2 /C type catalyst, with obtainment of the corresponding primary amine according to the following scheme (7):
Then, primary amine is separated from epoxides 4/5 by extraction in a suitable solvent or by chromatography. Finally, a reductive amination of amines 10/11 is performed with an aldehyde R 1 CHO, wherein R 1 is selected from the group: H, vinyl, phenyl, phenyl mono- or disubstituted with a group selected from: halogen, nitro, C1-C4 alkyl chain, CF 3 , CHF 2 , OR 2 , where R 2 is a hydrogen, a C1-C4 alkyl, according to methods known in the art, typically with a borohydride. Thus, the mixture of amines 2/3 is obtained.
In another alternative embodiment of the invention, the SR, RS, RR and SS epoxide mixture 1 is reacted with hydroxylamine followed by N—O bond hydrogenation according to methods known in the art, typically by catalytic hydrogenation with a Pd-based catalyst, with obtainment of amines 10 and 11, which are then subjected to reductive amination, as described above, with an aldehyde R 1 CHO and a borohydride, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, triacetoxysodium borohydride.
In another different embodiment, the pair of compounds 2 and 3 is not separated from compounds 4 and 5, but, after removal of the unreacted excess of amine RNH 2 and addition of a suitable solvent, the compounds 2 and 3 are left to react with the compounds 4 and 5 as already described above, directly obtaining the mixture of compounds 6, 7, 8 and 9. The suitable solvent added to the mixture is an alcoholic solvent, selected e.g. from methanol and ethanol.
The process of the invention can also be carried out according to a further variant, according to which the SR, RS, RR and SS mixture of the epoxide 1 is reacted, always in a sterically hindered alcohol analogously to what described in synthetic step a., with a secondary amine of RR 3 NH type, wherein R has the meaning seen in the foregoing, and R 3 is a benzyl group, possibly mono- or disubstituted with a group selected from halogen, nitro, a C1-C4 alkyl chain, CF 3 , CHF 2 , an OR 2 group, where R 2 is a hydrogen, a C1-C4 alkyl, to obtain a mixture of the four compounds 12, 13, 4 and 5, from which the pair 12/13 is separated from the pair 4/5.
Finally, a deprotonation from group R 3 is performed, with obtainment of the mixture of the compounds 2/3. Deprotonation from group R 3 may be performed with known procedures, e.g. through catalytic hydrogenation with a known catalyst such as Pd/C or Pd(OH) 2 /C.
EXAMPLES
The invention is hereinafter described in detail by the following examples, purely by way of illustration and not for limitative purposes, and with reference to scheme 9 herebelow:
Example 1
Opening of Epoxides 1 with Benzylamine in 2-methyl-2-butanol
The diastereometric mixture of (RR/SS)- and (RS/SR)-6-fluoro-2-(oxiran-2-yl) chroman (mixture 1) (50 g, 88%, 226.8 mmol, epoxides ratio≈1:1) is placed in the reaction vessel and dissolved in 2-methyl-2-butanol (420 mL). Benzylamine (42.5 mL, 352.9 mmol) is added in one time to the solution under stirring. The solution is kept under stirring for 12 hours. At the end of the reaction, the amine 2a/3a formed is filtered under vacuum and dried (purity 96.2% 18.2 g, 57.9 mmol). The filtered solution is washed with 1M NaHSO 4 and H 2 O (200 mL×3) to pH=5-6 and then concentrated under reduced pressure to ¼ of the volume (110 mL). To the mixture thus obtained, cyclohexane (420 mL, equal to the initial volume of the reaction) is added under brisk stirring. The solution is then filtered, dried (Na 2 SO 4 ) and concentrated to obtain 18.4 g (purity 80%, 74.2 mmol, 65%) of mixture 4/5.
The amines deriving from the opening of epoxides 4/5 with benzylamine are formed in very low percentages and eliminated with the acid washing of the organic solution.
The identity and purity of the compounds obtained is evaluated by comparison with reference standards by HPLC, using a Merck Symmetry C-8 chiral column, 5 δm, 250×4.6 mm, and a suitable binary gradient.
Mixture 2a/3a:
1H-NMR (400 MHz, DMSO-d 6 , δ): 7.31 (5H, m); 6.88 (2H, m); 6.68 (1H, m); 4.99 (brs, 1H), 3.88 (1H, m); 3.73 (2H, m); 3.66 (1H, m); 2.73 (2H, m); 2.73 (1H, m); 2.58 (1H, m); 2.10 (1H, br); 2.03 (1H, m); 1.68 (1H, m). MS: calcd for C 18 H 20 FNO 2 301.1, found: 302.1
Mixture 4/5:
1H-NMR (400 MHz, DMSO-d 6 , δ): 1.80 (1H, m), 2.00 (1H, m), 2.65-2.85 (4H, m), 3.15 (1H), 3.75 (2H, m), 6.80 (1H, m), 6.90 (2H, m MS (m/z): calcd. for C 11 H 11 FO 2 194.1; found 236.5 [M+H + +MeCN] + ; 194.5 [M] + .
Example 2
Opening of Epoxides 1 with Benzylamine in 2-methyl-2-butanol/cyclohexane Mixture
The mixture of epoxides 1 (10 g, purity 89.5%, 46.1 mmol) is dissolved in a 4:1 mixture of cyclohexane and 2-methyl-2-butanol (50 mL), benzylamine (8.5 mL, 7.65 mmol) is added and the mixture is mixed at room temperature. After about 10 hours a white precipitate is formed. After 38 hours a control by HPLC shows that the RS/SR epoxides pair has been completely consumed. The precipitate is filtered, obtaining 4.80 g of amine 2a/3a (purity: 99%, yield: 70%), while the filtrate is additioned with cyclohexane (40 mL).
This organic solution is washed with 1M NaHSO 4 (3×100 mL). During the first washing a yellow oil is separated from the solution (this oil contains possible dialkylation products and the amine of epoxides 4/5) and is eliminated. Then, it is washed with water (2×100 mL) to neutral pH, dried on Na 2 SO 4 , filtered and the solvent is removed under reduced pressure to obtain 3.70 g of mixture 4/5 (purity: 76%, yield: 83%).
The identity and purity of the compounds obtained is evaluated by comparison with reference standards by HPLC, using a Merck Symmetry C-8 chiral column, 5 μm, 250×4.6 mm, and a suitable binary gradient.
Comparison Example 3
Synthesis of Amines Deriving from the Pair of Epoxides 4/5
A sample of mixture 4/5 (0.5 g, 2.57 mmol), obtained by chromatographic purification of mixture 1, is dissolved in ethanol (5 mL) and additioned with benzylamine (0.84 mL, 7.72 mmol).
The mixture is heated to reflux until complete disappearance of the starting epoxides. The product is isolated by precipitation from the reaction mixture placed at 4° C.
1 H-NMR (DMSO-6d): 7.31 (5H, m); 6.88 (2H, m); 6.68 (1H, m); 4.85 (brs, 1H), 3.95 (1H, m); 3.73 (2H, s); 3.66 (1H, m); 2.75-2.60 (4H, m); 2.10 (1H, br); 1.90 (1H, m; 1.72 (1H, m).
Example 4
Reaction of Amines 2/3 with Epoxides 4/5
The compounds (±)-(RS/SR)-2-(Benzylamino)-1-(6-fluorochroman-2-yl)ethanol 2a/3a (18.26 g) and (±)-(RR/SS)-6-fluoro-2-(oxiran-2-yl) chroman 4/5 (18.4 g) are dissolved in absolute ethanol (60 mL) and maintained at reflux until disappearance of the starting reagents. At the end of the reaction the mixture is left to reach room temperature and the solvent is removed under reduced pressure. The residue is taken up in 2-methyl-2-butanol (150 mL, 4 vol) heated to dissolution (80° C.) and left at room temperature for 24 h under gentle stirring. The obtained solid is filtered, taking it up with 2-methyl-2-butanol (20 mL) and dried on a filter. The solid thus obtained (10.5 g) is suspended in cyclohexane/ethyl acetate 9/1 (100 mL, 10 vol) and heated to reflux until dissolution. It is then left to reach room temperature and the obtained solid is filtered, taking it up with cyclohexane (20 mL). It is dried on a filter, obtaining 9.80 g of mixture 6a/8a with purity higher than 99%. The compounds 7a/9a remained in the crystallization waters.
The identity and purity of the compounds is evaluated by comparison with reference standards by HPLC, using a Merck Symmetry C-8 chiral column, 5 μm, 250×4.6 mm, and a suitable binary gradient.
1 H-NMR (DMSO-6d): 7.33-7.19 (m, 5H), 6.90-6.72 (4H, m), 6.68-6.51 (m, 2H), 4.82 (d, 1H, J=3.0 Hz), 4.74 (1H, d, J=5.0 Hz), 4.00-3.90 (m, 1H), 3.87-3.70 (m, 4H), 3.53 (d, 1H, J=16.0 Hz), 2.83-2.40 (m, 8H), 1.90-1.70 (m, 2H), 1.68-1.50 (m, 2H). MS (m/z): calcd. for C 29 H 31 F 2 NO 4 495.2; found 496.7 [M+H] +
Example 5
Removal of Protective Group
The mixture 6a/8a (4.00 g) is dissolved in EtOAc/absolute ethanol 1/4 (450 mL), and 20% Pd(OH) 2 /C (50% wet, 200 mg) is added to the solution, under inert atmosphere (N 2 ). The mixture is maintained under hydrogen atmosphere. Upon disappearance of the initial compound, the mixture is filtered on celite or on material suitable for the purpose, washing it with the reaction mixture (50 mL). The solvents are removed under reduced pressure, obtaining a white solid residue (3.30 g) utilized as such in the subsequent step.
The identity and purity of the compounds is evaluated by comparison with reference standards by HPLC, using a Merck Symmetry C-8 chiral column, 5 μm, 250×4.6 mm, and a suitable binary gradient.
1 H-NMR (DMSO-6d): 6.92-6.82 (4H, m), 6.75-6.65 (m, 2H), 5.00 (d, 1H), 4.85 (1H, d), 3.98-3.82 (m, 2H), 3.70-3.60 (m, 2H), 2.85-2.60 (m, 8H), 2.10-2.00 (m, 1H), 1.98-1.82 (m, 1H), 1.80-1.60 (m, 2H).
MS (m/z): calcd. for C 22 H 25 F 2 NO 4 405.2; found 406.6 [M+H] + .
Example 6
Salification of Nebivolol
Nebivolol free base (3.30 g, 8.70 mmol) is suspended in absolute ethanol (100 mL) and heated to fall until complete dissolution. To this solution, 1.25 M ethanolic HCl (7.5 mL) is added. The obtained solution is concentrated under reduced pressure, until obtaining a 15% concentration of the product. During solvent evaporation, progressive formation of a white precipitate is observed. The solid is filtered by washing with cold absolute ethanol, to obtain 3.10 g of nebivolol hydrochloride salt. The chiral purity of the product and the ratio between the two enantiomers is evaluated by comparison with reference standards, by HPLC with an AKZO NOBEL column, Kromasil 5-AmyCoat, 5 μm, 250 mm×4.6 and a suitable binary gradient.
1 H-NMR (DMSO-6d): 8.66 (brs, 2H), 6.96-6.85 (m, 4H), 6.80-6.70 (2H, m), 5.96 (d, 1H, J=5.0 Hz), 5.77 (d, 1H, J=5.0 Hz), 4.12-4.06 (1H, m), 4.05-3.93 (m, 2H), 3.92-3.86 (m, 1H), 3.40-3.28 (m, 1H), 3.27-3.10 (m, 2H), 3.00 (t, 1H, J=6.0 Hz), 2.90-2.68 (m, 4H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.60 (m, 2H). MS (m/z): calcd. for C 22 H 25 F 2 NO 4 405.2; found 406.6 [M+H] + .
Example 7
Opening of Epoxides 1 with Sodium Azide
A mixture of epoxides 1 (200 mg, 1.03 mmol) and sodium azide (100 mg, 1.5 mmol) in teramyl alcohol (2 mL) is additioned of DMF dropwise until complete solubilization. the solution thus obtained is mixed at room temperature until complete disappearance of the pair of RS/SR epoxides. Then, the mixture is washed with water (5×) and dried on sodium sulphate; it is filtered, the solvents are evaporated under reduced pressure and the residue is purified by flash chromatography, obtaining 90 mg (73%) of the pair of azides deriving from RS/SR epoxides (Scheme 7, X═N 3 ) and 80 mg of the pair 4/5. MS (m/z): calcd. for C 11 H 12 FN 3 O 2 237.0; found 238.1 [M+H] + .
Example 8
Azide Reduction and Reductive Amination
A solution of the azides deriving form the opening of the RS/SR epoxides (90 mg, 0.38 mmol) is subjected to catalytic hydrogenation in EtOH and in the presence of 5% Pd/C. The solution thus obtained is filtered and additioned with benzaldehyde (40 mg, 0.38 mmol) and triacetoxysodium borhydride (90 mg, 0.41 mmol). At the end of the reaction the solvents are distilled at reduced pressure and the residue is taken up with dichloromethane and washed with 5% Na 2 CO 3 , followed by anhydrification on sodium sulphate. A chromatographic purification of the residue thus obtained yields 68 mg (60%) of the mixture of amines 2a/3a.
Example 9
Opening of Epoxides 1 with Benzylhydroxylamine
A mixture of epoxides 1 (200 mg, 1.03 mmol) and O— benzylhydroxylamine (184 mg, 1.5 mmol, from commercial hydrochloride salt) in teramyl alcohol (3 mL) is additioned with DMF dropwise until complete solubilization. The solution thus obtained is mixed at room temperature until disappearance of the RS/SR epoxides. Then, the mixture is washed with water (5×) and thereafter dried on sodium sulphate. It is filtered, solvents are evaporated under reduced pressure and the residue is purified by flash chromatography, obtaining 103 mg (65%) of the pair of hydroxylamines deriving from the RS/SR epoxides and 75 mg of the pair 4/5.
MS (m/z): calcd. for C 18 H 20 F 2 NO 3 317.1; found 318.2 [M+H] + .
By treatment analogously to what reported in Example 8, the pair of hydroxylamines thus obtained is converted into the amines 2a/3a.
Example 10
Opening of RS/SR Epoxides with t-butylamine and Reaction In Situ with Epoxides 4/5)
To a mixture of epoxides 1 (500 mg, 85%, 2.2 mmol) in teramyl alcohol (5 mL) terbutylamine (0.34 mL, 3.28 mmol) is added and the mixture is mixed until disappearance of the mixture of RS/SR epoxides. The solution is washed with 0.01 N NaHSO 4 (4×) to remove excess terbutylamine, additioned with ethanol (2 mL) and heated to reflux until disappearance of the pair of epoxides 3/4. The solvents are distilled under reduced pressure, and the residue purified by flash chromatography to obtain the mixture of compounds 6-9, wherein R=tert-butyl (363 mg, 72%).
MS (m/z): calcd. for C 27 H 35 F 2 NO 3 459.3; found 460.4 [M+H] + .
Example 11
Opening of the Epoxydes with Dibenzylamine and Selective Deprotection of a Benzyl
A solution of the epoxydes 1 (100 mg, 0.51 mmol), dibenzylamine (150 μL, 0.70 mmol) in teramyl alcohol (1 mL) is mixed at room temperature, until disappearance of the RS/SR epoxides. Then, the crude product of the reaction is purified by flash chromatography, obtaining 63 mg (63%) of the amine mixture deriving from the opening of the RS/SR epoxydes with dibenzylamine and 51 mg (65%) of the pair of epoxides 4/5.
The dibenzylamine mixture is dissolved in ethanol (5 mL) and hydrogenated with 5% Pd/C to obtain the benzylamines 2a/3a as main products (29 mg, 74%). | The present invention relates to a novel process for the synthesis of Nebivolol product represented in Scheme (1), comprised of a reduced number of high-yield steps, and characterized by the kinetic resolution of the two epoxide pairs diastereoisomeric therebetween (mixture 1), allowing to avoid complex chromatographic separations. | 2 |
RELATED APPLICATION
The present patent document claims the benefit of the filing date under 35 U.S.C. §119(e) of Provisional U.S. Patent Application Ser. No. 60/875,231, filed Dec. 15, 2006, which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates generally to a medical device. More particularly, the invention relates to a device for extracting an elongated structure, such as a cardiac electrical lead, that has previously been implanted in biological tissue of a human or veterinary patient.
2. Background Information
A variety of medical treatments and surgical methods entail implanting an elongated structure into the body of a human or veterinary patient. Examples of such elongated structures include catheters, sheaths and cardiac electrical leads (such as pacemaker leads and defibrillator leads), as well as a variety of other devices. Over time, it may become necessary or desirable to remove such an elongated structure from the body of the patient. However, difficulty is often encountered when attempting removal of such implanted structures, particularly after they have been implanted in biological tissue for a significant period of time.
For example, a heart pacemaker is typically implanted in a subcutaneous tissue pocket in the chest wall of a patient. A pacemaker lead is introduced into the vascular system of the patient, and positioned such that it extends from the pacemaker through a vein into a chamber of the patient's heart. The pacemaker lead commonly includes a coiled structure, such as an electrical wire coil, for conducting electrical signals (such as stimulating and/or sensing signals) between the pacemaker and the heart. Defibrillator leads are typically structured in a similar manner and, like pacemaker leads, are located about the heart. However, defibrillator leads may be affixed both internally and externally of the heart. A typical lead includes one or more coaxial or lateral helical wire coils having a hollow inner passageway that extends the entire length of the wire coil or coils. The wire coils are surrounded by an electrically insulating material such as a flexible tube, sheath or coating. The insulating material may be silicone or polyurethane, and serves simultaneously to protect the wire coils from body fluids and to insulate the wire coils from one another.
While cardiac electrical leads typically have a useful life of many years, over time such leads may become encapsulated by fibrotic tissue against the heart itself, or against the wall of the vein or other surrounding tissue. Encapsulation is especially prone to be encountered in areas where the velocity of the flow of blood is low. Since the encapsulating fibrotic tissue may be very tough, it is difficult to remove the lead from the area of the heart without causing bleeding or other trauma. Thus, for example, when small diameter veins through which a pacemaker lead passes become occluded with fibrotic tissue, separation of the lead from the vein can cause severe damage to the vein, or even destruction of the vein in some cases. Furthermore, separation of the lead from a vein is generally not possible without restricting or containing movement of the lead, that is, fixing the lead in position with respect to the patient, in particular, with respect to the patient's vein.
To avoid this and other possible complications, some inoperative pacemaker or other leads are simply left in the patient when the pacemaker or defibrillator is removed or replaced. However, such a practice can incur the risk of an undetected lead thrombosis, which can result in stroke, heart attack, or pulmonary embolism. Such a practice can also impair heart function, as plural leads can restrict the heart valves through which they pass.
There are additional reasons why removal of an inoperative lead is desirable. For example, if there are too many leads positioned in a vein, the vein can be obliterated. In addition, multiple leads may be incompatible with one another, thereby interfering with their pacemaking or defibrillating function. Of course, an inoperative lead can migrate during introduction of an adjacent second lead, and mechanically induce ventricular arrhythmia. Other potentially life-threatening complications can require the removal of the lead as well. For example, removal of an infected pacemaker lead is desirable, so as to avoid septicemia or endocarditis. Surgical removal of a heart lead in such circumstances often involves open heart surgery, with its accompanying risks, complications and significant costs.
A variety of successful methods and apparatus have been devised as alternatives to open heart surgery for heart lead removal. For example, U.S. Pat. No. 5,697,936 (Shipko et al.) discloses a device for removing from a patient a previously implanted elongated structure such as a catheter, a sheath, a defibrillator lead, a pacemaker lead or the like. The device disclosed in the patent includes a snare having one or more proximal or distal loops which can encircle and reversibly grasp either the proximal end or the distal end of the elongated structure to be removed. The device also includes a sheath member for delivering the snare loop or loops to the particular end of the elongated structure which is to be grasped. In some disclosed embodiments for grasping the distal end of the elongated structure, the sheath member is advanced along the elongated structure and separates the structure from any tissue which has encapsulated the structure after its implantation. The snare can be either positioned over or contained within a second sheath located in the sheath member.
Numerous other devices for snaring fragments or foreign bodies have been disclosed. For example, U.S. Pat. No. 5,171,233 (Amplatz, et al.) is directed to a snare-type probe in which kinking of a snare loop is obviated by the use of a shape memory material for the snare. More particularly, the snare is composed of nitinol (nickel-titanium alloy system) wire in a superelastic state, having a transition temperature below the operating temperature of the snare, for example, below body or room temperature. This allows the snare to be manipulated in a relatively severe manner during introduction into a patient, but to recover its desired shape after such manipulation, without kinking or other deformation. The loop of the snare of the device is oriented at an angle with respect to an elongate proximal member on which it is carried.
U.S. Pat. No. 5,562,678 (Booker) discloses a reversible snare for grasping and retrieving an article such as a cardiac lead, which includes a retractable closed loop carried by a sheath member adapted for introduction into a patient. The closed loop of the snare is composed of nitinol or another shape memory material, and defines a hook adapted to partly encircle the cardiac lead. The snare also includes a threader also carried by the sheath member. The threader is reversibly extendable through the closed loop, in the manner of a thread through a needle's eye, such that the hook and threader together fully encircle the lead. Retraction of the closed loop causes the hook and threader to close around the lead and permit its withdrawal into the sheath member.
U.S. Pat. No. 5,318,527 (Hyde et al.) is directed to a system for removing an in-place intravascular device (such as a catheter or guidewire) from a patient's body lumen, such as from a coronary artery, in which a catheter or other similar device is advanced through the vascular system alongside the in-place device until its distal end is located at a desired location within the vascular system. The disclosed removal system includes an exchange catheter having a flexible strand which forms a loop at the distal end of the catheter, the loop being adapted to be disposed about the catheter or guidewire that is in-place within the patient. The exchange catheter includes a lumen through which the strand passes and from which the loop extends. The exchange catheter does not appear to be dimensioned or otherwise adapted for receiving the in-place catheter or guidewire within the exchange catheter as the exchange catheter is advanced. To the contrary, it is an express purpose of the disclosed device to maintain access to a region of the body lumen about the distal end of the in-place catheter or guidewire during use of the exchange catheter, and receipt of the in-place device in the exchange catheter would interfere with the desired access to that region.
U.S. Pat. Publ. No. 2004/0153096 A1 (Goode et al.) discloses a snare-type device for removing an elongated structure that includes a sheath having a first lumen formed therein. The lumen is dimensioned to receive the elongated structure therein, and is adapted to allow advancement of the sheath along the elongated structure. The sheath also has second and third parallel lumens formed therein, such that all of the first, second and third lumens may be unitarily formed in the sheath. The device also includes a snare contained in the second and third lumens. The snare has a snare loop extending out of the second and third lumens, at and generally extending around the distal end of the first lumen. The snare loop is configured to be closeable around the elongated structure when the elongated structure is received in the first lumen of the sheath.
Each of the above-referenced devices is subject to its own advantages and disadvantages during use. For example, although the devices of Shipko et al. and Booker are generally effective for their intended purposes, these devices are somewhat more complex in structure than may sometimes be preferred, since it is often desirable to employ removal devices having a minimal cross-sectional area. The device of Amplatz et al. may require a disadvantageously high degree of axial and/or rotational manipulation before the loop can be slipped over the distal end of the device to be removed. The device of Hyde et al. purportedly avoids this particular problem by having its loop slipped over the proximal end of the in-place device and tightened about it before the exchange catheter is advanced, but not tightened about the in-place device so much that the exchange catheter cannot be readily advanced over the in-place device, or that the in-place device cannot be readily withdrawn. The device and procedure of Hyde et al. would not be useful for retrieving an elongated structure which has been left in a patient for any extended time, since encapsulation of the structure would prevent any such advancement of the exchange catheter along the structure. Moreover, kinks or surface defects or irregularities in the in-place device could make it difficult or impossible to achieve a desirably precise degree of tightening of the loop about the in-place device. Such surface defects or irregularities could result from minor amounts of encapsulating tissue which remain on the in-place device after severing of the in-place device from the bulk of the encapsulating tissue, or from defects or breakage of the in-place device itself. Finally, although the device of Goode et al. is generally effective for retrieving and removing an implanted lead, the device is not structured to have an aggressive leading end for use in cutting tissue or otherwise extracting an implanted lead from encapsulating tissue.
It would be advantageous to provide a device that is structured for extracting an implanted structure from surrounding biological tissue, and that overcomes the disadvantages existing in the art.
BRIEF SUMMARY
The problems of the prior art are addressed by the features of the present invention. In one form thereof, the invention comprises a device for extracting an implanted elongated structure from biological tissue. The device comprises a sheath having a proximal portion and a distal portion, wherein the distal portion extends to a distal end of the sheath. The sheath includes first, second and third lumens, each of the lumens opening to the sheath distal end. The first and second lumens are disposed in a wall surface of the sheath and extend generally adjacent one another along the wall surface. The third lumen is dimensioned to receive the elongated structure therein. The sheath includes a bending zone along a length thereof. The sheath wall surface having the first and second lumens disposed therein is alternately compressible and expandable responsive to a bend along the bending zone. The sheath further includes a first wire segment and a second wire segment. The first wire segment is positioned in the first lumen such that the proximal end of the first wire segment is affixed proximal to the bending zone to one of the sheath and the second wire segment. The second wire segment is positioned in the second lumen such that the proximal end of the second wire segment is affixed proximal to the bending zone to one of the sheath and the first wire segment. A remainder of the first wire segment extends distally in the first lumen, and a remainder of the second wire segment extends distally in the second lumen. The first wire segment has a length such that the segment extends distally a first distance relative to the wall surface when the bend compresses the wall surface generally adjacent the first and second lumens, and extends distally a second distance relative to the wall surface when the bend expands the wall surface generally adjacent the first and second lumens, wherein the first distance is greater than the second distance, and the distal end of the first wire segment extends distally beyond the sheath distal end at least the first distance.
In another form thereof, the invention comprises a method for extracting an implanted elongated structure from biological tissue encapsulating at least a portion of said structure in a vessel. A lead extraction device is provided. The lead extraction device comprises a sheath having a proximal portion and a distal portion, wherein the distal portion extends to a distal end of the sheath. The sheath has first, second and third lumens defined therein, each lumen opening to the sheath distal end. The first and second lumens are disposed in a wall surface of the sheath, and extend generally adjacent one another along the wall surface. The third lumen is dimensioned to receive the elongated structure therein. The sheath includes a bending zone along a length thereof. The sheath wall surface having the first and second lumens disposed therein is alternately compressible and expandable responsive to a bend along the bending zone. The sheath includes a first wire segment and a second wire segment. The first wire segment is positioned in the first lumen such that the proximal end of the first wire segment is affixed proximal to the bending zone to the sheath or the second wire segment. The second wire segment is positioned in the second lumen such that the proximal end of the second wire segment is affixed proximal to the bending zone to the sheath or the first wire segment. A remainder of the first wire segment extends distally in the first lumen, and a remainder of the second wire segment extends distally in the second lumen. The first and second wire segments each have a length such that the segments extend distally a first distance relative to the wall surface when the bend compresses the wall surface generally adjacent the first and second lumens, and extend distally a second distance relative to the wall surface when the bend expands the wall surface generally adjacent the first and second lumens, the first distance being greater than the second distance. The distal ends of the first and second wire segments extend distally beyond the sheath distal end at least the first distance. The sheath distal end is inserted into said vessel, and the sheath is advanced along one or more bends in the vessel by rotating the sheath along the bends such that the segments extend the first distance. The encapsulating tissue is cut by engaging the tissue with the segments when the segments are at the first distance.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of a device for extracting an elongated structure that has been implanted in biological tissue, according to one embodiment of the present invention;
FIG. 2 is a sectional view of the sheath of the device of FIG. 1 , taken along line 2 - 2 of FIG. 1 ;
FIG. 3 is an enlarged top view of the distal end of the device of FIG. 1 ;
FIG. 4 is an enlarged end view of the distal end of the device of FIG. 1 ;
FIG. 5 illustrates one typical configuration of the sheath upon passage of the device through a branched blood vessel;
FIG. 6 illustrates a configuration of the sheath when it is flexed upon passage through a blood vessel in an opposite direction compared to the bend in FIG. 5 ;
FIG. 7 is an enlarged top view of the distal end of the device of FIG. 1 illustrating a modified tip;
FIG. 8 is an enlarged top view of the distal end of the device of FIG. 1 , illustrating yet another embodiment of a modified tip;
FIG. 9 is a side view of the modified tip in the embodiment of FIG. 8 ;
FIG. 10 is an enlarged top view of the distal end of the device of FIG. 1 , illustrating an embodiment wherein a wire wrap covers the distal end of the tip;
FIG. 11 is an enlarged sectional view of the distal end of an alternative embodiment of the inventive device;
FIG. 12 is an enlarged sectional view of the distal end of yet another embodiment of the inventive device;
FIG. 13 illustrates another alternative embodiment of an extracting device; and
FIG. 14 is an end view from the distal end of the device of FIG. 13 .
DESCRIPTION OF PREFERRED EMBODIMENTS
For purposes of promoting an understanding of the present invention, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated device, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
In the following discussion, the terms “proximal” and “distal” will be used to describe the opposing axial ends of the inventive device, as well as the axial ends of various component features. The term “proximal” is used in its conventional sense to refer to the end of the device (or component thereof) that is closest to the operator during use of the device. The term “distal” is used in its conventional sense to refer to the end of the device (or component thereof) that is initially inserted into the patient, or that is closest to the patient during use.
The present invention comprises a device for extracting an implanted elongated structure from a body vessel, such as a blood vessel, when the elongated structure is at least partially encapsulated in biological tissue. The implanted elongated structure targeted for removal may comprise a cardiac lead. As the term is used herein, a cardiac lead refers to a lead that is used in connection with a heart-related device. Non-limiting examples of cardiac leads that may be extracted from biological tissue by the inventive device include pacemaker leads, defibrillator leads, coronary sinus leads, and left ventricular pacing leads. In addition to cardiac leads, the invention may also be used in the extraction of other devices or leads, such as neurological pacing and stimulation leads. When used to extract a cardiac lead, the distal end of the cardiac lead will normally be located within the vascular system of the patient, and in particular, within a chamber of the patient's heart (such as in an atrium or ventricle of the heart). When the implanted elongated structure is a defibrillator lead, the distal end of the structure may be located either in or about the heart of the patient. The distal ends of other types of implanted elongated structures targeted for extraction may not be, and need not be, near the heart.
For convenience, the following discussion will refer to the extraction of a cardiac lead, such as a pacemaker lead. However it should be understood that this is no way intended to be a limitation on the scope of the invention, and that at least the other elongated structures referred to above may also be extracted by the inventive device. Typically, a cardiac lead comprises an inner core, comprising a cable or a coil, surrounded by a layer of insulating material. Some cardiac leads have a lumen extending therethrough, while others (i.e., “lumenless” leads) do not. The inventive device is useful for extracting implanted leads having a lumen, as well as lumenless leads.
When the inventive device is used for extraction of a cardiac lead, those skilled in the art will appreciate that the lead should initially be severed from the control device, such as a pacemaker, prior to any attempts to extract or remove the lead. The control device will normally have a much larger diameter than the remainder of the lead, and thus only an unreasonably large sheath could fit over the control device.
The invention may be better understood with reference to the drawings. FIG. 1 illustrates a side view of an extraction device 10 according to one embodiment of the present invention. Among other possible uses, device 10 may be used for extracting an elongated structure, such as a cardiac lead, from biological tissue that has at least partially encapsulated the cardiac lead in a blood vessel. In the embodiment shown, device 10 includes an elongated sheath 12 having a proximal portion 13 and a distal portion 14 . Distal portion 14 terminates in distal end 15 . Sheath proximal portion 13 may be mechanically supported by an optional handle 19 . Handle 19 facilitates gripping and manipulation of device 10 in well known fashion. A wire tip 20 projects in a longitudinal direction from distal end 15 .
In the embodiment of FIGS. 2-4 , sheath 12 is a tri-lumen sheath having a larger diameter main lumen 16 , and smaller diameter lumens 17 , 18 . Larger diameter lumen 16 is dimensioned for receiving the elongated structure therein as extraction device 10 is advanced into the vessel. Generally, smaller diameter lumens 17 , 18 are positioned adjacent each other along a wall surface 29 of sheath 12 . Preferably, sheath wail surface 29 comprises a thickened area along one side of sheath 12 . Sheaths used for extracting elongated structures, such as cardiac leads, are well known in the art. Those skilled in the art will appreciate that virtually any conventional sheath composition, modified as described herein, may be utilized in the inventive extraction device 10 . Although sheath 12 is illustrated and described herein as a tri-lumen sheath, those skilled in the art will appreciate that with minor modification, sheaths having more, or fewer, lumens may be substituted for the tri-lumen sheath illustrated and described herein.
As stated, tip 20 extends in a generally longitudinal direction from sheath distal end 15 . In the embodiment shown, tip 20 comprises a wire loop. Preferably, wire loop 20 is formed by threading a first end of a wire at the proximal end of sheath 12 through one of lumens 17 , 18 until the wire exits the lumen, and therefore the sheath, at distal end 15 . This end of the wire is then looped back through the other one of lumens 17 , 18 until it exits the other lumen, and therefore the sheath, at proximal portion 13 . The two wire ends, both extending through a separate one of lumens 17 , 18 at sheath proximal portion 13 , may then be twisted or otherwise joined at the proximal end to form wire end 21 . Wire end 21 may be folded, adhered, or otherwise anchored to the sheath proximal end, in a manner such that longitudinal translation of wire end 21 relative to sheath proximal portion 13 is substantially prevented.
Although the embodiment of FIG. 1 illustrates an arrangement wherein the respective ends of the wire are joined at sheath proximal portion 13 to form wire end 21 , such joinder of the wire ends is not required. Rather, each individual wire end may be separately folded, adhered or otherwise anchored to a discrete portion of sheath proximal portion 13 in a manner such that longitudinal translation of each of the wire ends is substantially prevented.
In FIG. 1 , device 10 is shown wherein sheath 12 is in an elongated configuration. When sheath 12 is elongated in this manner, device 10 is structured such that wire tip 20 projects from the distal end a discrete distance, designated in the figures as distance a. Distance a is referred to herein as the nominal projection distance. Upon insertion of device 10 into a blood vessel in which an elongated structure, such as a cardiac lead, has previously been implanted, device 10 is often subjected to a tortuous vessel path. Frequently, the vessels that the device must traverse bend at moderate to extreme angles. Device 10 is structured such that upon bending or flexing of the device, tip 20 extends or retracts in a manner to be described.
FIG. 5 illustrates one typical configuration of sheath 12 as the inventive device is passed through a branched or otherwise curved blood vessel. When passing through such a vessel, the sheath 12 flexes in conformance with the bend of the vessel. In this instance, smaller diameter lumens 17 , 18 are at the inside of the bend. When the sheath is flexed in this manner, the sheath material 12 ′ at the inside of the bend is compressed to a shorter length, when compared to the neutral axis of the sheath. The sheath material 12 ″ at the outside of the bend is concomitantly stretched to a longer length when compared to the neutral axis. The wires, however, are neither stretched nor compressed. The proximal ends of the wires are joined to each other, or otherwise anchored to the sheath, at a position in the device proximal to the bending zone of the sheath.
As used herein, the term “bending zone” refers to the portion of the length of the sheath that is distal to the point of joinder or anchoring of the proximal ends of the wires to each other or to the sheath. This is the portion, or zone, of the sheath that is subject to bending or flexure as the sheath is advanced in the vessel, thereby causing the stretching or compressing of the sheath material as described, and the resulting retraction or extension of the wire tip from the distal end of the sheath. As shown in FIG. 5 , compression of the inner sheath material 12 ′ causes the tip 20 to project outwardly in a longitudinal direction to a distance b, which distance exceeds the nominal projection distance a shown in FIG. 1 .
FIG. 6 illustrates a configuration of sheath 12 as the inventive device is passed through a branched or otherwise curved blood vessel, wherein the curve is present in an opposite direction when compared to the curve in FIG. 5 . In this case, sheath 12 is flexed in a manner such that the smaller diameter lumens 17 , 18 are at the outside of the bend. When the sheath is flexed in this manner, the sheath material 12 ″ at the inside of the bend is compressed to a shorter length, when compared to the neutral axis. The sheath material 12 ′ at the outside of the bend is concomitantly stretched to a longer length when compared to the neutral axis. As shown in FIG. 6 , stretching of the outer sheath material 12 ′ causes the tip 20 to retract inwardly in a longitudinal direction to a minimal projection distance c, which distance is less than the nominal projection distance a of FIG. 1 .
In use, device 10 is typically rotated as it is threaded through a vessel. As the device is rotated while confined to a bend in the vessel, such as the vessel resulting in the bend to the sheath shown in FIG. 5 , sheath material 12 ′ (adjacent smaller diameter lumens 17 , 18 ) and sheath material 12 ″ are therefore alternately at the inside of the bend during various stages of the rotation. Since the wire ends are anchored to the sheath proximal to the bend in sheath 12 , the tip 20 alternately extends and retracts between respective distances b and c upon rotation of the sheath. In particular, the tip is extended to position b when the tip is oriented at the inside of the curve, and retracted to position c when it is oriented at the outside of the curve. At position b, the tip is configured to cause maximal disruption to the encapsulating tissue. At position c, the tip is configured to cause minimal disruption to the tissue. This latter arrangement minimizes the possibility of inadvertent perforation of the blood vessel.
The tip in the embodiment of FIGS. 1-6 comprises a wire in which the tip is generally U-shaped. This is best shown in FIG. 3 . On some occasions, it may be preferred to provide the tip with a more aggressive leading end. In this event, U-shaped tip 20 can be geometrically modified, such as by machining or forging the tip material to provide a more aggressive configuration. One example of a modified tip is shown in FIG. 7 . In this embodiment, a notch 30 is cut into the loop of wire tip 20 ′. Another example is shown in FIGS. 8 and 9 . In this embodiment, the far distal portion of tip 20 ″ is modified by sharpening the tip to form a point 32 . Those skilled in the art will appreciate that an almost infinite number of alterations of the tip can be made to make it more aggressive for a particular purpose, with the embodiments shown and described hereinabove merely representing possible examples of such alterations.
Another variation of a tip is shown in FIG. 10 . In this embodiment, a wire 34 is wrapped around tip 20 . The wrapped wire may be attached to tip 20 by any conventional mechanism, such as by soldering or welding. The presence of the irregular leading end comprising the wrap provides a more aggressive end than when only the smooth loop of tip 20 is provided.
Another variation of the present invention comprises device 60 , as shown in FIG. 11 . Device 60 may comprise a tri-lumen sheath 62 having a distal end 65 as before. A length of wire 64 , 66 extends through each of smaller diameter lumens 68 , 70 , respectively. Attached to, and interconnecting the distal end of each of wires 64 , 66 is a tip 76 . In the preferred embodiment shown, tip 76 comprises a resistance or heater element. The wire ends may be attached to the resistance or heater element by any conventional attachment mechanism, such as crimps 72 , 74 . In this embodiment, tip 76 may be heated, e.g., by applying an electrical voltage to the proximal end of the wires. In this instance, the disruption of the tissue enveloping a cardiac lead can be enhanced if desired by simultaneous application of mechanical force and heat. Those skilled in the art will appreciate that respective wires 64 , 66 and tip 76 may be formed of any compositions suitable for providing the electrically conductive properties noted. In a preferred embodiment, wires 64 , 66 can be copper and tip 76 can be nichrome wire. As a further alternative, tip 76 also may be provided with an aggressive leading end, as described hereinabove.
Another variation of the present invention comprises device 80 , as shown in FIG. 12 . Once again, device 80 may comprise a tri-lumen sheath 82 having a distal end 85 . A length of wire 84 , 86 extends through each of smaller diameter lumens 88 , 90 , respectively. In this embodiment, device 80 includes electrodes 92 , 94 , each connected to a separate one of wires 84 , 86 , and extending in the distal direction therefrom. In the embodiment shown, electrode 92 is connected to the distal end of wire 84 by crimp 96 . Similarly, electrode 94 is connected to the distal end of wire 86 by crimp 98 . Wires 84 , 86 and electrodes 92 , 94 are formed of any composition that is capable of conducting energy through the wires and electrodes in the distal direction, such as radio frequency energy. Preferably, wires 84 , 86 are formed of copper, and electrodes 92 , 94 are formed of tungsten, although those skilled in the art will appreciate that other compositions capable of attaining the desired function may also be used. With the greater protrusion of the electrodes while on the inside of a curved blood vessel (see, e.g., the bend in the sheath of FIG. 5 ) greater energy can be delivered to attack the enveloping tissue.
During use of an extracting device as described hereinabove, as the tip of the device progresses beyond a curve in the blood vessel, continued rotation of the sheath causes sequential extension and retraction of the tip from the distal end of the sheath, even though the tip is no longer on a curve. In some cases, however, a continued extension of the tip may not be desirable; as such rotation may increase a risk of perforating the vessel. FIG. 13 illustrates an alternative embodiment wherein the extension and retraction of the wire tip can be minimized, or even eliminated, when such action is not necessary or helpful to extracting the lead.
In this embodiment, extracting device 100 comprises a sheath, such as tri-lumen sheath 102 having a distal end 105 . When a tri-lumen sheath is utilized, sheath 102 may include larger diameter lumen 106 , and smaller diameter lumens 108 , 110 . Wire loop tip 114 extends between lumens 108 , 110 . In this embodiment, lumens 108 , 110 wind along sheath 102 in the proximal direction from distal end 105 , such as in a generally spiral fashion shown in the figure. With this configuration, extension and retraction of tip 114 only occurs while the tip is confined to a curve.
While these features have been disclosed in connection with the illustrated preferred embodiments, other embodiments of the invention will be apparent to those skilled in the art that come within the spirit of the invention as defined in the following claims. | A device for extracting an implanted elongated structure from biological tissue comprises a sheath having a plurality of lumens therein opening to the sheath distal end. First and second lumens are disposed along a wall of the sheath, and a third lumen is dimensioned to receive the elongated structure. The sheath wall having the first and second lumens disposed therein is alternately compressible and expandable responsive to a bend along a bending zone of the sheath. A first wire segment is positioned in the first lumen, and a second wire segment is positioned in the second lumen, wherein the respective proximal ends of the segments are affixed proximal to the bending zone. The respective wire segments extend distally in the respective first or second lumen a first distance beyond the distal end of the sheath when the bend compresses the wall surface generally adjacent the first and second lumens, and extend distally a second distance, less than the first distance, when the bend expands the wall surface. | 0 |
STATEMENT OF RELATED APPLICATION
This application is a continuation of co-pending application Ser. No. 07/839,411, filed Feb. 20, 1992 U.S. Pat. No. 5,261,922.
BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates generally to ultrasonic surgical instruments and, more particularly, to an improved ultrasonic knife.
Description of Related Art
The use of ultrasonic surgical instruments for cutting various types of tissues and/or removal of cement within the body is well known. An ultrasonic surgical instrument commonly comprises a knife blade connected to an ultrasonic oscillation source. The edge of the knife blade is brought into direct contact with the tissue being operated on and vibrated at ultrasonic frequencies. Conventional ultrasonic surgical instruments are used to cut or shatter a variety of living tissues such as the soft tissue found in cataracts, the cartilaginous tissue found around bones, and the osseous tissue of the bone itself. Surgeons are also finding ultrasonics to be an excellent tool for the removal of cements, such as, for example, Polymethylmethacrylate (PMMA), which is frequently used to affix a prosthetic hip joint to the existing femur.
The mechanical oscillation at the end of an ultrasonically vibrated knife blade reduces the amount of pressure required to initiate and propagate a cut or incision which allows the surgeon to concentrate more on the direction of cut. Advantageously, the surrounding tissue experiences minimal stretching and tearing as compared to procedures utilizing conventional stationary blades.
Problems which can be associated with ultrasonic surgery include excessive heat generation, tearing of tissue, or inadvertent cutting of nearby structures. Other problems have been associated with the ergonomics of ultrasonic surgical instruments. Moreover, different surgeons desire different tactile feedback and operating performance. The prior art generally has demonstrated a lack of understanding of the tactile feedback necessary to carefully re-sect different types of living tissues with one particular knife.
Some examples of prior art have attempted to reduce the "thermal footprint" of the ultrasonic cutting tool. For example, in U.S. Pat. No. 5,026,387 issued to Thomas, an ultrasonic surgical cutting tool is disclosed which automatically shuts off upon removal from the tissue. The automatic shut-off switch reduces the time that the surgical cutting knife is vibrating and thus decreases its heat build-up. U.S. Pat. No. 4,188,952 issued to Loschilov et al., discloses an ultrasonic surgical instrument which relies on a pentagonal cross section to reduce the thermal damage to the side surfaces of the tissue being cut because of a smaller area of surface contact. The thermal footprint of an ultrasonic surgical knife is defined by its surface area in contact with the tissue, both frontally and on the sides. In general, the inventions of the prior art had been fairly simple in their approach to reducing thermal footprint of ultrasonic blades and have failed to provide any real sophistication for the design of these tools which is sorely needed.
A need exists for an improved ultrasonic surgical blade which gives better feedback when cutting through various types of tissue and provides enhanced ergonomics to surgeons.
SUMMARY OF THE INVENTION
There is provided in accordance with one aspect of the present invention, a method of cavitation-assisted surgery utilizing an ultrasonic knife. An ultrasonic knife is provided, of the type having a source of ultrasonic vibrations, a knife blade coupled to the source, and a control for selectively causing the source to produce ultrasonic vibrations in the knife blade.
The source is activated to induce reciprocal movement of the knife blade throughout a predetermined axial stroke amplitude, and the blade is contacted with the tissue to be cut. The formation of cavitation bubbles is induced in the fluid media surrounding the knife blade, and the cavitation bubbles are thereafter permitted to implode, thereby producing shockwaves for breaking the tissue bond adjacent the cutting edge of the knife blade.
Preferably, the inducing formation of cavitation bubbles step is accomplished by providing the knife blade with a surface texture for creating cavitation bubbles. In one embodiment, the surface texture comprises a plurality of rounded spherical or hemispherical irregularities, having a width within the range of from about 20 microns to about 100 microns. The surface irregularities may be either pitted recesses such as by acid etching or other techniques known in the art, or beads adhered to the surface of the blade.
The inducing formation of cavitation bubbles may alone or in addition to the blade texturing be enhanced by providing a plurality of surfaces on the cutting edge of the knife, which extend generally perpendicular to the longitudinal axis of ultrasonic energy propagation through the knife. In a further aspect of the present method, inducing formation of cavitation bubbles may also be enhanced by modulating the energy driving the knife to include at least a first low frequency component for increasing cavitation, and a high frequency component for minimizing the depth of penetration of heat generated by the blade into the adjacent tissue.
In accordance with a further aspect of the present invention, there is provided an ultrasonic knife for conducting wet, cavitation-assisted surgery, or dry, cauterizing surgical procedures. The knife comprises a source of ultrasonic vibrations, a knife blade coupled to the source, and a control for selectively causing the source to produce ultrasonic vibrations, thereby inducing reciprocal movement of the knife blade through a predetermined stroke.
The blade comprises at least two teeth defining a recess therebetween, wherein the distance between the two teeth is no more than about the predetermined stroke. Preferably, the distance between the two teeth is no more than about 80% of the predetermined stroke. The predetermined stroke is preferably within the range of from about 0.001 to about 0.002 inches, and, most preferably, the predetermined stroke is approximately 0.0015 inches.
The width of each of the teeth is within the range of from about 30% to about 60% of the stroke, and preferably the width of each of the teeth is about 50% of the stroke. Preferably, a plurality of teeth are provided on the blade, extending throughout the cutting surface thereof.
The recess formed between each two adjacent teeth comprises a bottom portion and two sidewall portions, each sidewall portion terminating in a tooth edge at the most lateral extent, and the distance between the bottom of the recess and the tooth edge is within the range of from about 20% to about 100% of the stroke. Preferably, the distance between the bottom of the recess and the tooth edge is about 80% of the stroke.
Preferably, the bottom of the recess and sidewalls of the recess merge to form a generally parabolic shape. Alternatively, the two sidewalls are generally parallel to each other, and generally perpendicular to the bottom of the recess. In general, the two sidewalls and the bottom of the recess define a continuous boundary of the recess, and at least a portion of the boundary extends perpendicular to the longitudinal axis of ultrasonic energy propagation through the knife, and at least a second portion extends generally parallel to the longitudinal axis of ultrasonic propagation energy through the knife.
In a preferred embodiment, in which the thermal footprint of the knife is minimized, the blade comprises a generally planar body portion having a proximal connection end and at least one cutting edge thereon, and a width in a central region thereof which is less than the width at at least one point between the central region thereof and the cutting edge.
In accordance with a further aspect of the present invention, there is provided a blade for ultrasonic surgery. The blade comprises a generally planar body having at least one cutting edge thereon, and, preferably, two cutting edges thereon having different surface texture or draft configurations. A coupler is provided for coupling the body onto a source of ultrasonic vibration, and a plurality of teeth are provided on each cutting edge, each adjacent pair of teeth forming sidewalls for a recess therebetween. The width of the recess is optimally no more than about 0.0015 inches. Preferably, at least one shallow recess is provided on the side of the planar body for reducing the thermal footprint of the blade.
Further advantages and features of the present invention will become apparent to one of skill in the art from the detailed description of preferred embodiment which follows, when taken together with the claims and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic of the ultrasonic surgical tool system of the present invention;
FIG. 2 is a side view of the preferred cutting blade of the present invention;
FIG. 3 is a top view of the blade of FIG. 2;
FIG. 4 is a cross section of an edge of the blade of FIG. 2 along line 4--4;
FIG. 5 is an enlargement of the teeth of the blade of FIG. 2 illustrating the preferred depth and pitch;
FIG. 6 is a top view of the ultrasonic surgical tool of FIG. 1;
FIG. 7 is an exploded view of the ultrasonic surgical tool of FIG. 1;
FIG. 8 is a cross section of the ultrasonic surgical tool along lines 8--8 of FIG. 6;
FIG. 9 is a top view of an ultrasonic medical tool of the present invention showing a handpiece, an extender and a preferred blade.
FIG. 10 is a partial cross-sectional view of the ultrasonic medical tool of FIG. 9 taken along line 10--10 illustrating two junctions of the present invention;
FIG. 11 is an exploded partial cross-sectional view of the junctions of FIG. 10;
FIG. 12 is an exploded perspective view of one of the junctions of FIG. 10, illustrating the generally cylindrical male component on the proximal end of a surgical tool having a pair of splines interrupted by a pair of flats;
FIG. 12a is a cross-sectional view of the junction of FIG. 12 taken along line 12a-12a;
FIG. 13 is an assembly perspective view of the junction of FIG. 12 with a male component inserted into a female component;
FIG. 14 is an assembly perspective view of the junction of FIG. 13 with the components rotated to engage corresponding splines of each component;
FIG. 15 is a cross-sectional view of the junction of FIG. 13 taken along lines 15--15;
FIG. 16 is a cross-sectional view of the junction of FIG. 14 taken along lines 16--16;
FIG. 17 is a top view of an ultrasonic medical tool of the present invention showing a handpiece, an extender and an alternative flat blade held in a split chuck;
FIG. 18 is a side view of the split chuck and collet of FIG. 17 along lines 18--18;
FIG. 19 illustrates a knife blade carrier in accordance with the present invention; and
FIG. 20 is an end elevational view of the blade carrier of FIG. 19.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, the improved ultrasonic surgical tool provides enhanced tactile feedback to the surgeon and may be adjusted to customize the feedback, depending on the preference of the surgeon. Additionally, the ultrasonic tool of the present invention can be configured to cut a wide variety of tissues by altering the blade structure alone, or in combination with the operating mode. The improved cutting tool is disclosed in the following specification with reference to the above-mentioned drawings.
As schematically shown in FIG. 1, an ultrasonic surgical system 24 ultimately vibrates a surgical blade 26. The blade 26 couples to an ultrasonic transducer (not shown) mounted in a handpiece 28 which is driven by a control system 30. A surgeon grasps the handpiece 28 and manipulates the blade 26 within a patient. A cable 32 transmits the ultrasonic driving signals from the control system 30 to the transducer within the handpiece 28.
Referring to FIG. 2, a preferred embodiment of surgical blade 26 is shown. The blade 26 includes a cutting section 34 at its distal end. As seen best in FIG. 4, the cross section of the cutting section 34 reveals a central channel or relief 36 machined into each side. The blade 26 is symmetric about a vertical plane through the center. The relief portion 36 allows the knife blade 26 to cut through various types of tissue with a minimum thermal footprint. The thermal footprint of a blade includes all the surfaces in contact with the tissue. At ultrasonic vibrations, the blade 26 can produce a substantial amount of heat from the frictional and ultrasonic contact with the tissue. The size of the relief 36, or percentage of area of the blade 26 out of contact with the tissue, directly affects the thermal footprint.
Adjacent the relief 36, tissue contact surfaces 38 extend for a distance generally parallel to the plane of the blade 26 towards the edge of the blade 26. In general, the width of each contact surface 38 in this plane is within the range of from about 0.0 to about 0.050 inches, and preferably within the range of from about 0.015 to about 0.025 inches .
These contact surfaces 38 represent the widest portion of the blade 26 along an axis transverse to the plane of the blade and produce a substantial amount of thermal friction with the tissue. Typically, the thickness of the blade through contact surface 38 is within the range of from about 0.010 to about 0.050 inches, and preferably within the range of from about 0.015 to about 0.025 inches. The size of the contact surfaces 38 also directly affects the thermal footprint. Smaller contact surfaces 38 reduce the thermal footprint of the blade 26.
The sharpened edge 27 of the blade 26 comprises a first taper 40 which is separated from the contact surface 38 by a second taper 42. Both the first and second tapers widen in the medial direction. The first taper 40 preferably ranges between about 10° and about 30°, and more preferably the first taper 40 is about 15°. The second taper 42 ranges between about 3° and about 45°, and more preferably the taper is about 8°. The angles of the tapered portions directly affect the character of cut and associated drag, or feel, experienced by the surgeon. A short taper, such as 45 degrees, would provide a duller blade generating more cavitation and drag. A longer, sharper taper would have substantially less tissue differentiation. The blade may have a continuous, sharp cutting edge as with conventional scalpels, or may have serrations or teeth as described below.
Referring now to FIG. 5, a preferred shape of serrations is shown enlarged. The serrations comprise parabolic-shaped recesses 44 separated by outwardly protruding teeth 46. The teeth 46 are spaced a certain distance apart to result in optimal cutting. Advantageously, the teeth 46 are separated by a distance 46c of less than one longitudinal stroke of the blade 26 to ensure that the tips of at least two teeth 46 cross any one point in a single stroke. The spacing 46c of the teeth 46 is most preferably eight-tenths of the blade stroke so that every tissue bond is contacted by two teeth 46 during each stroke, while internal material stresses are minimized.
The advantageous shape of the teeth 46 of the blade 26, shown in FIG. 5, provides an enhanced feel of cut at all times. A straight-edged ultrasonic knife blade will slip through tissue with a substantially constant resistance due to the blade edge being everywhere parallel to the tissue. Ultimately, the surgeon might apply more pressure than necessary, without realizing the depth of cut, and sever tissue not intended to be cut.
The contour of the recesses 44 on the ultrasonic blade 26 of the present invention changes the angle of the portion of the blade edge which strikes the tissue. During light cuts, the surgeon notices little resistance as bond severing occurs primarily at the tip edges of the teeth 46 parallel to the plane of uncut tissue ahead of the cutting edge. To provide ample light cutting surfaces, the width 46b of the tips of the teeth 46 are preferably 30-60% of the stroke amplitude, and most desirably the width 46b is 50% of the stroke.
Slightly more pressure results in cutting at the sidewalls 45 of the recesses 44, at least a portion of which is perpendicular to the plane of uncut tissue. The sidewalls 45 extend from the tip 46 of the teeth to the bottom 44 of the recess a sufficient distance to expose the perpendicular surfaces to the tissue. To ensure this exposure while retaining some strength for the extending teeth 46, the depth 46a of the sidewalls 45 is 20-100% of the blade stroke amplitude, and preferably the depth 46a is 80% of the stroke.
An increase in the downward force causes more of the sidewalls 45 perpendicular to the tissue, between the teeth 46 to contact the tissue, resulting in a change of resistance due to the increased surface area contact at a high vector angle. Thus, the surgeon experiences a greater resistance as the blade 26 is pressed harder into the tissue, and may adjust accordingly to prevent inadvertent injury to the patient.
The surface texture of the blade 26 directly affects the amount of frictional and ultrasonic heat generation, in addition to the level of cavitation. Highly polished surfaces tend to slide through the tissue with minimal friction and associated heat generation and sound transfer. The tapered surfaces 40, 42 and the recessed region 36 are preferably polished to minimize thermal damage to the tissue. Concurrently, if dry cutting is preferred, the contact surfaces 38 may be finished slightly rougher to ensure heat will build up mostly at this region and increased hemostasis will occur. Alternatively, the surfaces of the blade 26 may be roughened all over, a saline solution introduced at the operative site, and the blade oscillated at preferred rates to minimize thermal damage yet increase the amount of cavitation. Such a situation is seen in brain surgery where a constant stream of water, or other coolant fluid, is applied to the incision area, and the majority of the cut is cavitation-assisted.
Referring again to FIGS. 2 and 3, a transition section 48 alters the cross section of the blade 26 from the flat cutting section 34 to a generally cylindrical portion 50 comprising opposing wrench flats 52. The transition section 48 amplifies the gain of the ultrasonic oscillations. A coupling member 54 adjacent to the cylindrical portion 50 mates with an opposite sex coupling member on the distal end of the handpiece 28 or an extender. Due to the minimum time-constraints imposed by surgery, the coupling members are preferably rapid connect/disconnect types described below, with reference to FIGS. 9-16, showing an alternative embodiment with an extender 55.
FIGS. 9-11 illustrate two junctions on either end of the extender 55. FIG. 10 shows a partial cross section of the coupling between the handpiece 28 and the extender 55, and the extender 55 and the blade 26. Of course, it is understood that the coupling between the extender 55 and the preferred surgical blade 26 applies equally as well to a direct coupling between the blade 26 and the handpiece 28.
Each junction comprises a generally cylindrical male component 56 and a tubular female component 58 comprising a generally cylindrical recess 60 adapted to receive the male component 56. These components quickly connect by inserting the male component 56 into the female component 58 and rotating one component with respect to the other component, preferably through a relatively short rotational arc, and optimally about 90°, plus or minus 10°.
Only one junction will be referred to, as the junctions are identical. When joined, the junction produces a relatively high axial compression force, which is preferably uniformly distributed symmetrically about the contact surfaces between the two components to optimize the transfer of ultrasonic energy across the junction. Non-uniform distribution of the axial compression force about the longitudinal axis of the junction tends to decrease the efficiency of the transfer of energy across the junction, and can cause unwanted transverse motion (whipping) and may lead to premature mechanical failure.
Although FIGS. 9 through 14 illustrate the male component 56 extending in a distal direction, it is understood that the relationship of the male and female components can be reversed.
Referring to FIGS. 9-12, the male component 56 comprises at least two axially extending splines 62 spaced apart by at least two axially extending flats 64. Preferably, the male component 56 comprises two diametrically opposed splines 62 and two diametrically opposed flats 64, alternatively positioned around the circumference of the component, as seen in FIG. 12.
Each spline 62 comprises a plurality of external threads 66 preferably configured in accordance with the American National Standard for Unified Threads ("UN"). It will be understood that other thread configurations, such as the American National Standard Acme Screw Threads ("Acme"), can be used as well. It has been found preferable, however, to employ the UN thread design instead of others, such as the Acme thread design, primarily for manufacturing ease.
Advantageously, the thread pitch and the pitch diameter of the threads 66 and the length of the splines 62 are selected to produce high axial compression between the components without structural failure. It is also preferable to select a generally standard thread for manufacturing convenience. Additionally, the threads 66 must engage to produce high axial compression with little rotation. Preferably, circumferentially, 75% of the threads 66 engage with rotation of no more than about 90° plus or minus 10°. For example, in one preferred embodiment the splines 62 comprise a series of 4-56 UNS-2A threads 66 along a length of 0.215 inches, and in another embodiment, the splines 62 comprises a series of 5-48 UNF-3A threads 66 along a length of 0.250 inches In general, the spline 62 preferably comprises about twelve interrupted threads 66.
In general, the junction has a minimum of 45° of total engagement between the spline threads 66 to produce the high axial compression without mechanical failure. Preferably, the junction has an engagement between about 90° to about 179°, and most preferably about 173° (48% of 360°=172.8°). Thus, in a most preferred embodiment, the sum of the lengths of the threads 66 on the male component 56 measured in a circumferential direction preferably range from 90° to 179°, and more preferably equal 173°.
The circumferential length of each spline thread 66 (i.e., the circumferential width of each spline) depends upon the number of splines 62 employed. For example, in a most preferred embodiment having two splines 62, the length of the thread 66 in a single spline along the circumferential direction ranges between 45° and 89.5°, and preferably equals 86.5°.
The female component 58 likewise comprises at least two axially extending splines 68 and at least two axially extending flats 70, disposed on the recess 60 circumference in a corresponding relationship with the flats 64 and splines 62 on the male component 56, as best seen in FIGS. 9, 15 and 16. Preferably, the female component 58 comprises two diametrically opposed splines 68 and two diametrically opposed flats 70 alternatively positioned around the circumference of the recess 60, as best seen in FIG. 15. Each spline 68 comprises a plurality of internal threads 72 configured to match and engage with the threads 66 on the male component 56.
As discussed above, the sum of the length of the threads 72 around the circumference of the recess 60 is preferably not less than about 90° and not greater than about 179°, and most preferably equal 173°. Each spline thread length depends upon the number of splines 68 employed. For example, in a most preferred embodiment having two splines 68, the threads 72 of each spline extend around the circumference of the recess 60 for at least approximately 45°, but less than approximately 89.5°, and preferably equal 86.5°.
The two splines 68 and two flats 70 alternately disposed on the interior circumference of the female component 58 recess 60 provide an axial key-way 74 for receiving the two opposing splines 62 on the male component 56, as shown in FIG. 15. The male component 56 is inserted into the recess 60 of the female component 58 and rotated to interlock the corresponding splines 62, 68 on the male and female components, as shown in FIG. 16. It is desired that minimum rotation of one component with resect to the other component will produce a junction which achieves a relatively high efficiency of energy transmission therethrough.
In general, it has been found that a high compression across the junction symmetrically distributed about its longitudinal axis optimizes energy propagation. Preferably, the thread design of the junction produces greater than about 100 pounds of axial compression force between the components with rotation of about 90°±10%. More preferably, a compression in excess of about 200 pounds will be achieved. As a result of higher compression, the ultrasonic pressure wave propagates across the junction with minimal energy loss.
It is preferred that the points of contact between the two joined surgical components be symmetric about the longitudinal axis of the male component 56 to uniformly distribute the compression force about the junction in the radial direction. As a result, the ultrasonic oscillation maintains its propagation along the longitudinal axis of the joined surgical components without deflection from that axis. If deflection occurs, the tool will tend to whip resulting in undesired heat build-up and loss of energy at the tool tip.
In this regard, the female component 58 preferably additionally comprises an annular engagement surface 76 on the proximal end thereof which contacts a corresponding annular engagement surface 78 of the male component 56. Preferably, the engagement surface 76 of the female component 58 extends radially outwardly along a plane substantially perpendicular the axis of the internal recess 60, and the engagement surface 78 of the male component 56 extends radially outward along a plane substantially perpendicular to the axis of the male component 56. Referring to FIG. 10, as the splines 62, 68, interlock, the two components draw together to force the engagement surfaces 76, 78, against each other, resulting in an axial compression force across the junction.
Preferably, the engagement surfaces 76, 78, are smoothly polished to produce a substantially liquid-tight seal between the components as the surfaces abut. In addition to optimizing energy propagation, a liquid-tight seal reduces cavitation erosion of the components at the junction and thereby extends the life of each component.
In a preferred embodiment, the female component 58 additionally comprises an axially extending, generally cylindrical counterbore 80 at the distal end of the recess 60 for receiving a generally cylindrical shank barrel 82 on the proximal end of the male component 56. The counterbore 80 and the shank barrel 82 are preferably centered with respect to the longitudinal axis of the male component 56. Preferably, the shank barrel 82 smoothly fits into the counterbore 80 to center the female component 58 with respect to the male component 56.
Advantageously, the male component 56 further comprises an undercut region 84 positioned between the engagement surface 78 and the spline so that the spline threads 66 are fully formed (i.e., no run-out region). As a result, the splines 62, 68 can be reduced in overall length, as will be understood in the art.
Referring to FIG. 11, the female component 58 preferably additionally includes a generally cylindrical pilot recess 86 for receiving a corresponding generally cylindrical tip barrel 88 at the proximal end of the male component 56. Preferably, the diameters of the pilot recess 86 and the tip barrel 88 substantially coincide with the minor diameter of the threads 72. Advantageously, the pilot recess 86 and the tip barrel 88 are centered about the longitudinal axis of the male component 56 for optimizing the concentricity of the engagement surfaces, between the components to optimize the longitudinal transfer of ultrasonic energy through the junction.
To facilitate rapid interconnection between the components, the female component 58 preferably additionally comprises an annular internal chamfer 90 and the male component 56 additionally comprises an annular tip chamfer 92. When the male component 56 is inserted into the female component 58, the chamfers 90, 92 ease the insertion by funneling the components together. Additionally, the edges of the leading spline threads 66 of the male component 56 preferably include a chamfer 94 to ease the engagement between the splines 62, 68 of the male component 56 and female component 58.
Referring to FIGS. 13-16, it is preferred that the surgical components include alignment arrows 96 etched on the exterior surface of the components to aid in the connection process. By aligning the arrows 96, the splines 62 of the male component 56 align with the key-way 74 of the female component 58, as seen in FIGS. 13 and 15. By rotating the components as shown in FIG. 14, the splines 62, 68 of the two components interlock, as shown in FIG. 16. Flat opposing surfaces 98 are provided on the exterior of all parts to receive a wrench to facilitate tightening and untightening of the junctions.
Those skilled in the art can manufacture the disclosed junction by processes known in the art. For example, the generally cylindrical male component 56 and the shank barrel 82 thereto can be cut into an end of the shank of a surgical component, such as the extender or the tool bit. The threads 66 can either be cold rolled onto the cylinder or preferably machine cut into the cylinder. The flats 64 can then be milled onto the component thereby interrupting the threads 66. Finally, the tip barrel 88 can be cut onto the distal end of the male component 56 such as by lathing operations well known in the art and the chamfers 92, 94, similarly added thereto.
The recess 60 of the female component 58 can be made by drilling the pilot hole recess 86 into the end of a surgical component. The counterbore 80 then can be milled and a portion of the pilot hole 86 tapped with the appropriate internal threads 72 by processes known in the art. The flats 70 can be milled and broached into the recess 60 thereby interrupting the threads 72 on the recess wall. Finally, the internal annular chamfer 90 can be drilled or milled to form a smooth transition from the counterbore 80 to the threaded recess 60.
Referring again to the improved ultrasonic surgical knife system 24 of FIG. 1, the control system 30 comprises an ultrasonic signal generator 100 which supplies an electric impulse to the handpiece 28, the voltage of which can be varied at different frequencies and with different waveshapes. The signal may, for example, be a pure sinusoidal wave or may be modulated with one or more other frequencies. Alternatively, the signal may be a stepped or spiked pulse. In a preferred embodiment, the ultrasonic generator 100 transmits a signal of between 20-80 kHz. More preferably, the signal is at about 60 kHz. The signal generator 100 includes a liquid crystal or other display device 102 for convenient display of selected power or frequency mode. The signal generator 100 may, for example, transmit a constant amplitude signal at a constant frequency, or alternate one or both of these parameters. The cutting power level is normally selected as a percentage of maximum cutting power. Although not illustrated in FIG. 1, an audio output indicative of mode changes and present mode is preferably included which is responsive to the ultrasonic signal generator output 100.
The signal transmits through a multi-conductor shielded cable 32, for safety and durability, to the handpiece 28 which imparts ultrasonic, generally longitudinal, movement to the surgical blade 26. As will be described more fully later, high-efficiency piezo-ceramic washers 164 which generate the ultrasonic vibrations within the handpiece (FIG. 7), allow a thin high-flex cable 32 to be used. The electronic signals are a lower than usual voltage not requiring a thick cable, which gives the surgeon added freedom to maneuver the handpiece 28. A high quality autoclavable connector 106 couples the cable 32 to the signal generator 100.
Referring to FIGS. 6 and 7, the outer protective cover of the handpiece 28 generally comprises a nose cone 108, a cylindrical casing 110 and an end cap 112 of durable stainless steel or other corrosion resistant material. Advantageously, the protective cover is stainless steel and the sections are sealed hermetically, to protect the internal components from the corrosive fluids of surgery and temperatures in a steam autoclave. The handpiece 28 is preferably about 6 inches long and 1/2 inch in diameter.
The distal end of the handpiece 28 is the end proximate the blade 26, and the proximal end is the end proximate the cable 32. An acoustic horn 114 transmits standing pressure waves from the piezo-ceramic washers 164 to the blade 26. A central bolt 116 extends substantially the length of the handpiece 28 and provides a central coupling member rigidly joining the internal elements, as seen in cross section in FIG. 8. A heel slug 118 includes internal threads 120 for engagement with external threads 122 of the central bolt 116. The horn 114 also includes internal threads 124 which couple with external threads 126 on the central bolt 116. The piezo-ceramic washers 164 include a central bore 128 sized to fit over the external threads 122 of the central bolt 116. The horn 114 and heel slug 118 compress the washers 164 therebetween via longitudinal movement along the central bolt threads 122, 126. The piezo-ceramic washers 164, in combination with portions of both the horn 114 and heel slug 118, comprise an electromechanical transducer, converting electrical energy to mechanical pressure waves.
A rear annular bulkhead 130 is silver soldered to the rear of the central bolt 116 and supports the outer casing 110 at the proximal end of the handpiece 28. The interface between the outer circumference of the bulkhead 130 and cylindrical casing 110 provides a hermetic seal and a solid ground connection. Additionally, an O-ring 132 disposed between a front flange of the horn 114 and the nose cone 108 provides a fluid-tight interface. The piezo-ceramic washers 164, and all other internal components shown in FIG. 8 between the seals 130, 132, are thus enclosed within the cylindrical casing in a fluid-tight manner allowing the handpiece 28 to be immersed in a steam autoclave without harm.
The horn 114 comprises generally three sections, a cross-sectionally enlarged section 134, a transition section 136 and a narrow section 138 (see FIG. 7). The narrow section 138 at the distal portion of the horn 114 includes a female junction component 140 adapted to receive a male junction component (not shown) of a surgical blade 26, or other surgical component. The mechanical energy which is produced by the piezo-ceramic washers 164 propagates along the horn 114 and amplifies at the transition section 136.
As is well known in the art, decreasing the cross section of a structure transmitting longitudinal pressure waves increases the stroke, i.e., produces a positive gain in longitudinal oscillation. A stepped horn produces a gain which is approximately equivalent to the ratio of the larger area to the smaller area of the horn 114, while a more gradual change in diameter produces a gain equivalent only to the ratio of the diameters. Moreover, the location of the cross-sectional changes along the structure affects the degree of gain produced, as described below.
Thus, by adjusting the change in cross section of the horn 114, the shape of the dimensional transition, and the location of the dimensional transition, a specific gain may be obtained to tailor the stroke of the blade 26 for optimum performance. Preferably the gain achieved by the transition section 136 works in conjunction with a transition section of the blade 26 to produce an optimum longitudinal amplitude at the blade tip. The longitudinal amplitude of the blade 26 is preferably between 0.00025 and 0.004 inches peak-to-peak, and more preferably 0.0015 inches peak-to-peak, reducing the chance of material failure and controlling the energy for a fixed thermal footprint.
The piezo-ceramic washers 164 remain in a stationary, compressed state between the horn 114 and the heel slug 118 and thus occupies a node of a standing wave created along the heel slug-washer-horn combination. At the nodes of vibration there is no motion but maximum stress. Nodes are spaced exactly one half wavelength apart and thus from the piezo-ceramic washers 164, nodes occur every half wavelength down the horn 114 (e.g. front transition 136).
Anti-nodes are points of absolute maximum amplitude, experience the largest longitudinal movement and the least stress, and are located 1/4 wavelength from each node. The closer the location of the cross-sectional change 136 to a node of vibration, the greater the gain realized, because the ultrasonic energy is stored as internal potential at these points, as opposed to kinetic energy at the anti-nodes.
The elongated, cylindrical horn 114 preferably includes one step concentrator to tailor the gain to cause a preferred blade 26 to function optimally; i.e., to preferably stroke from 0.00025 to 0.004 inches, peak-to-peak, and more preferably at 0.0015 inches, peak-to-peak. The small stroke advantageously reduces internal stresses in the horn 114 and blade 26 and thus reduces the chance of material failure.
The proximal end of the horn 114 defines an aperture leading to a central cylindrical cavity 142 sized to receive the distal end of the central bolt 116. The cavity 142 includes internal threads 124 which mate with external threads 126 on the central bolt 116. The cavity 142 extends axially in the distal direction, past the internal threads 124, and ends at a chamfered portion 144. The central bolt 116 includes opposing axial flats 119 for a wrench-assisted insertion into the cavity 142. A second set of flats 117 allows a wrench-assisted connection of the heel slug 118 over the bolt 116.
The majority of the enlarged section 134 comprises a solid cylinder to optimize ultrasonic energy propagation. The horn 114 is thus preferably constructed of a high strength material which efficiently propagates ultrasonic energy. More preferably, the horn 114 is constructed of titanium.
The distal portion of the horn 114 includes a female coupling portion 140, as described above. The distal portion of the horn 114 additionally comprises a central lumen 146 extending proximally from the female coupling 140 preferably throughout the length of the narrow section 138. The lumen 146 extends slightly past the transition section 136. The lumen 146 assists in amplifying the ultrasonic energy propagated down the horn 114. As described previously, pressure waves crossing a reduction in the cross-sectional area of a structure experience a gain. The lumen 146 defines a tubular section at the distal portion of the horn 114, further reducing the cross-sectional area of the material of the narrow section 138.
The overall length of the horn 114 is preferably less than about 2.5 inches, and more preferably the length of the horn 114 is 2.40 inches. The horn 114 is sized so that the front coupling junction 140 experiences a minimum of stress from being positioned close to an anti-node of vibration. The transition section 136 is desirably less than 0.75 of an inches from the farthest front portion of the horn 114, and more desirably the transition section is 0.600 inches from the front of the horn 114. The enlarged section 134 has a diameter of no more than 1/2 inch to fit comfortably in the hand of a surgeon, and more preferably the diameter of the enlarged section is 0.425 inch. Advantageously, the inside diameter of lumen 146 in the narrow section 138 of the horn 114 is less than about 0.1 inches to provide a sufficient wall thickness of the frontal section to minimize stress failure. More preferably, the diameter of the lumen 146 is about 0.07 inches. The outer diameter of the narrow section 138 of the horn 114 is preferably no more than about 0.25 inches, and more preferably the outer diameter of the narrow section is 0.125 inches. Advantageously, an exterior annular flange 150 at a position proximal to the transition section 136 provides a shoulder against which the O-ring 132 abuts. The nose cone 108 of the outer cover compresses the O-ring 132 rearward against the flange 150 in a semi-rigid manner, and in a fluid tight manner between the inside diameter of the tubing 110 and the outside diameter of the horn 114.
Referring to the cross-sectional view of FIG. 8, the length of the central bolt 116 is shown. The central bolt 116 comprises a solid, generally cylindrical metallic rod with a chamfer 152 at the distal end of a distal cylindrical portion 154. The distal cylinder 154 fits in the distal cavity 142 of the horn 114, as previously described. The distal chamfer 152 bottoms out at the internal chamfer 144, providing a flush stop for the central bolt-horn interface, thus more efficiently transmitting ultrasonic energy.
The distal thread region 126 separates the cylindrical portion 154 from a middle cylindrical region 156. The threads 126 are preferably 0.2 inches from the front of the central bolt 116, and the proximal section of threads 122 is located 1.4 inches further rearward. Preferably, the threads 126 are 10-56 UNS-2A type threads, and configure to meet with similar internal threads 124 of the horn 114.
The middle cylindrical portion 156 extends through the central bore 128 of the piezo-ceramic washers 164. The washers 164 slide along the middle portion 156 to abut the horn 114 adjacent the distal threads 126 of the central bolt 116. The distal axial face of the washers 164 and proximal axial face of the horn 114 lie flush against a thin annular spacer 170 therebetween to optimize transmission of ultrasonic vibrational energy.
The proximal thread region 122 separates the middle region 156 from a cylindrical heel slug receiving portion 158. The bolt 116 terminates in a reduced diameter isolation region 160 and a rear bulk head support shaft 162. The rear thread 122 region is adapted to receive the heel slug 118. As stated previously, the heel slug 118 threads onto the central bolt 116, compressing the piezo-ceramic washers 164 against the horn 114. The rear-most portion of the heel slug 118 terminates at the transition of the central bolt 116 to the isolation region 160. The large change in diameter between the heel slug 118 and the isolation region 160 causes the isolation region to tend to vibrate at its own frequency, interfering with sound propagation at the fundamental frequency in this direction. In this manner, little ultrasonic energy is propagated rearward. The additional 1/4 wave length 162 of the central bolt 116 forces the bulkhead to be an artificial node (a node and an anti-node separated by less than λ/4). This reinforces the stability of the bulkhead 130 location and minimizes any loading of the handpiece when the bulk head 130 is silver soldered to the central bolt 116 and the inside diameter of the tube 110.
The material of the thin annular washers 164 is a piezo-ceramic compound of lead-titanate or lead-zirconate. Advantageously, two to eight washers 164 may be utilized, depending on the strength of vibration desired, and preferably there are two washers 164. These washers 164 include central bores 128 to fit over the middle cylindrical region 156 of the central bolt 116. The central bore 128 passes over the rear threads 122, and thus polymide tape 168 is wrapped around the central region 156 to fill the annular void formed and hold the washers centered on the bolt 116.
Two very thin annular spacers 170 separate the piezo-ceramic washers 164 from the horn 114 and heel slug 118, and distribute the compressive forces evenly. A layer of electrically insulating material 166 covers the washers 164 and isolates them from the outer casing 110 of the handpiece 28. An air gap 172 between the insulating layer 166 and the casing 110 effectively isolates the ultrasonic vibrations from the outer casing. Preferably, the air gap 172 is approximately 0.17 inches, which has been found to reduce the 35 radiation of internal heat to the outer casing 110. A "hot" electrode 174a and a ground electrode 174b connect to the appropriate piezo-ceramic washer 164 to effectuate mechanical vibrations. The electrodes 174 extend proximally from the piezo-ceramic washers 164 within the air gap 172. The "hot" electrode 174a passes through a small passage 176 in the bulkhead 130 and from there to the rear end cap 112 and a "hot" circuit of the connector 106 of the cable 32. The ground electrode 174b connects directly to the bulkhead 130 which is in electrical contact with the ground circuit of the connector 106.
As is well known in the art, piezo-ceramic materials produce mechanical vibrations upon excitation by an applied voltage. This mechanical vibration is caused by changes in the internal structure when under the influence of the external voltage. The layers of piezo-ceramic washers 164 are held under compression between the horn 114 and the heel slug 118. Preferably, the compression of the piezo-ceramic washers 164 is between 500 and 5000 psi, and most preferably about 1500 psi.
Aligning the washers so that the positive side of one abuts the positive side of another causes the washers to oppose each other's motion, and in effect double their amplitude vibrations. Such piezo-ceramic washers 164 held in compression are restricted from thickening; their internal stresses are transmitted to the surrounding compressive members in the form of pressure waves. The preferred piezo-ceramic configuration is a "Langewin sandwich" design.
As the waves propagate along the horn 114 and heel slug 118, the potential strain energy converts to kinetic energy and back, due to the wave-like nature of the signal. The heel slug 118 and adjacent isolation region of the central bolt 116 tend to quell the vibratory motion while the excellent energy transmittal properties of the titanium horn 114 propagates the vibrations directly to the blade 26 with minimal losses. The washers are thus aligned and compressed between the heel slug 118 and the horn 114. The compression of the piezo-ceramic washers 164 results in standing pressure waves propagated down the horn 114.
As stated previously, the piezo-ceramic washers 164 preferably occupy a node of vibration and other nodes appear exactly one half wavelength later and every half wavelength subsequently. Anti-nodes are located between the nodes and experience the largest longitudinal movement and the least stress. At 60 kilohertz, each 1/2 wavelength equals approximately 1.6 inches in the preferred titanium horn 114. The horn 114 is machined so that the transition region 136 desirably occupies a node. In addition, the coupling region 140 at the front portion of the horn 114 is preferably placed close to an anti-node to reduce the stress of the coupling. Thus, locations of the transition region 136 and the front coupling region 140 are multiples or fractions of the preferred 1/2 wavelength of 1.6 inches.
The heel slug 118 is preferably fabricated from tool steel or stainless steel. A central bore 178 extends through the heel slug 118 and includes internal threads 120 at the rear (proximal) end. The heel slug 118 also comprises two opposing wrench flats 180 at the rear end.
The parameters of the blade 26 may be altered, or the ultrasonic signal may be varied, to customize the type and character of incision desired. As stated previously, higher frequency surgical knives tend to propagate energy shorter distances into surrounding tissue and thus inflict less thermal damage. At times though, some thermal effect on the tissue is desirable, especially when dry cutting. Modulating a high frequency signal with a substantially lower carrier frequency allows the surgeon to nominally retain the advantageous features provided at high frequencies (hemostatis) while periodically applying a lower frequency to effectuate some increased degree of cavitation. At lower frequencies there is more drag, and thus more feel and tissue differentiation. Adjusting the modulating frequency to decrease the periods of high frequency results in more feel, and thus the surgeon may selectably alter the response of the surgical blade 26 to different types of tissue. In a preferred embodiment, the surgical blade 26 of the present invention is vibrated at 60 kHz with a modulating frequency of between 10 and 10,000 Hz, and a preferred frequency of 600 Hz.
Referring now to FIGS. 17 and 18, a split chuck 182 connects with an extender which couples with the handpiece 28 in an alternate form of the present invention. The split chuck 182 is shown in greater detail in FIG. 18. The split chuck 182 includes a forward slot 184 which receives a flat surgical cutting blade 186. The blade 186 is placed within the slot 184 and a collet 188 threads over the chuck 182 to tighten the blade within the chuck. Chuck 182 is provided with opposing wrench flats 190 to tighten the chuck in the handpiece 28, or an extender, with a wrench.
Advantageously, the extenders allow the handpiece of the present invention to be remain external to the body while the blade extends within a catheter for endoscopically-assisted surgery. The extenders possess excellent sonic transmission properties with minimal losses at the interfaces. Additionally, the rapid connect/disconnect coupling feature allows rapid changing of extenders, blades and chucks. Preferably, the present invention may be used endoscopically with a 4 millimeter catheter opening. Preferably, extenders allow surgery at a depth of as much as 24 inches from the handpiece 28.
Referring to FIG. 19, there is disclosed a blade carrier 195 in accordance with a further aspect of the present invention. Blade carrier 195 facilitates handling of the ultrasonic surgical blade in a sterile environment prior to installation on an ultrasonic handpiece. In addition, the use of the blade carrier 195 minimizes the risk of inadvertent blade sticks during handling and installation of the blade.
Blade carrier 195 generally comprises a blade housing having a blade connector end 196, and a blade tip end 198. The overall length of the blade carrier 195 is preferably about 2.5 inches. Blade cavity 200 is disposed therebetween, for receiving the sharp end of the blade. The connection end of the blade, which may be threaded or provided with other quick connection/disconnection means previously disclosed, projects from the blade cavity 200 axially through the open channel 204 and out the open end 210. The open channel 204 is provided with a pair of opposing surfaces 206 and 208 for frictionally engaging the wrench flats on the connector end of a blade, as has been previously described. Referring to FIG. 20, opposing surfaces 206 and 208 can be more clearly seen. In a preferred embodiment, projections 209 and 211 are additionally provided for retaining the connection end of the blade within the open channel 204.
The blade cavity 200 is a shallow flat or rounded bottomed recess, having a length dimension 201 of about 1.5 inches and a width dimension 202 of about 0.50 sufficient to accommodate a variety of blade sizes. In general, blades contemplated to be utilized with the ultrasonic knife in accordance with the present invention have a cutting edge length within the range of from about 0.5 inches to about 1.5 inches. In addition, the width along the plane of the blade varies within the range of from about 0.030 inches to about 0.40 inches for most applications. Specialty blades, for unique applications, may vary considerably from the foregoing ranges.
The blade carrier 195 is provided at its blade tip end 198 with a knob 212. Knob 212 comprises a generally cylindrical body, preferably having a diameter of about 0.05 inches, and length of about 0.5 inches, having friction enhancing structures such as knurling on the radially exterior wall thereof. The axis of knob 212 is aligned with the axis extending through the open channel 204. In this manner, the clinician can spin the knob 212 between two fingers to threadably engage the connector on the knife with the corresponding connector on the ultrasonic handpiece or extender as discussed below.
The blade carrier 195 is preferably also provided with a pair of opposing wings 214 and 216 to provide leverage for rotating the blade carrier to tighten the connection between the blade and the ultrasonic knife handpiece. Preferably, the overall width of the carrier through the wings 214, 216 is about 1.2 inches. As has been previously discussed, the typical connection between the knife tip and the handpiece is a rotatably engagable connection. For example, with the quick connect and disconnect embodiment previously disclosed, the blade is inserted onto the handpiece or the connector by an axial advancement and then the blade is tightened by rotating the blade through an angle of approximately 90°. In an alternate embodiment, the blade is simply threaded onto the handpiece or connector by rotating through a series of complete revolutions. In either embodiment, the blade must be appropriately rotationally tightened into the handpiece or extender.
For this purpose, the opposing surfaces 206 and 208 and a hinge region 207 therebetween are preferably molded from a material having a suitable resilience that the rotation of the blade carrier 195 will rotate the blade contained therein until the blade is suitably tightened against the handpiece or extender. Further rotation of the blade carrier 195 will cause the opposing surfaces 206 and 208 to spread slightly, permitting relative rotation between the blade carrier 195 and the blade contained therein. The clinician simply rotates the blade carrier 195 until the assembly "snaps" or starts to cam over. In this manner, a predetermined predictable and repeatable amount of torque within the range of from about 0.50 to from about 0.80 inch-lbs., preferably about 3.0 inches/lbs., can be applied during installation of the blade. Wings 214 and 216 provide both a friction surface and leverage for the clinician to use to rotate the blade carrier 195 during installation. Following sufficient tightening of the blade, the blade carrier 195 is simply pulled laterally away from the tip of the blade and discarded, or saved, to be reinstalled at the end of surgery and then discarded with "sharps".
The blade carrier 195 may be constructed in any of a variety of ways which will be well known to one of skill in the art. For example, the entire blade carrier may be integrally molded such as by injection molding, thermo forming or vacuum forming of a pre-formed sheet of plastic. Alternatively, the blade carrier 195 can be fabricated from premolded component parts, such as by premolding the blade connection end 196 and the knob 212. The main body of the blade carrier 195 is preferably stamped or molded from a sheet of plastic, and may be thereafter secured to the blade connector end 196 and knob 212 using thermal bonding, solvent bonding, ultrasonic welding or other techniques known in the art.
Alternatively, some or all of the blade carrier 195 can be formed from an appropriate metal sheet, and preferably thereafter provided with an appropriate plastic coating. In general, the construction of the blade carrier 195 is of appropriate materials that will permit sterilization of the assembly of the blade carrier 195 with a blade therein. The blade carrier 195 and blade are thereafter introduced into a sealed packet or pouch for sterilization and shipment.
Problems associated with ultrasonic surgery can be generally classed in two categories. The first category would be the effect on the living tissue on either side of the cut. Excess heat generation, tearing of tissue or inadvertent cutting of nearby anatomical structures are all problematic to ultrasonic surgery. The second category of problems is a relative lack of operator comfort, flexibility and feedback.
In ultrasonic surgery, the knife blade may oscillate at any where within the range of from about 1 kHz to about 100 kHz. Typically, however, frequencies of lower than about 23 kHz are not used because they are within the audio range. In addition, frequencies in excess of about 50 or 60 Khz produce an excess amount of localized heating along the tissue contacting sides of the blades.
For relatively low frequencies, e.g. below about 20 or 30 kHz, high carbon steel or stainless steel is an appropriate construction material for the ultrasonic knife blades of the present invention. However, frequencies in excess of about 30 kHz, which are considered relatively high, are preferably used in conjunction with ultrasonic knife blades made from or coated with titanium, aluminum, or other metals or alloys which will transmit ultrasonic energy efficiently, with less internal heating.
Approximately 50% of the heat is produced from sound absorption in the surrounding tissue, 25% produced from internal frictional heating of the blade itself, and 25% produced by friction of the blade and tissue. At times, heat is preferred if a hemostatic nature of cut is desired. Hemostasis is the coagulation or formation of white gelatinous substance at the sides of the cut, and is commonly referred to as "bloodless surgery." At temperatures above 65° C. (149° F.), proteins in human tissue are denatured, producing coagulation. Although in some instances hemostasis is desirable, the increased temperatures involved in ultrasonic surgery potentially increase the likelihood of denaturing protein in tissue and can produce localized thermal damage, or necrosis, to the tissue surrounding the incision.
As mentioned above, sound absorption into the surrounding tissue comprises the majority of heat generation in ultrasonic surgery. Ultrasonic surgical instruments propagate pressure waves down the blade and into the surrounding tissue. At the interface of the blade material and the tissue, there is an impedance mismatch, causing the sound waves to dampen or "deaden" as they attempt to propagate further into the tissue. The energy absorbed by the damping characteristics of the tissue is converted to heat. Preferably, the ultrasonic energy does not propagate far into the tissue, to limit the negative effect the heat produces. It is well known that higher frequency, shorter wavelength signals dissipate faster and in shorter distances in elastic material, such as biological tissue, and therefore would appear to be favorable.
A smaller percentage of the total heat produced in an ultrasonic surgical procedure occurs from internal frictional heating of the knife blade. In general, the construction material of the surgical blade determines the level of internal friction, and potentially damaging heat. Stainless steel, for example, is a relatively inefficient conductor of acoustic energy, and a lot of internal friction results. Stainless steel, in fact, should not be used at frequencies above about 20 kHz as it gets too hot. The titanium used for the present surgical blade 26 on the other hand is an excellent conductor of acoustic energy and may be used at the highest frequency contemplated (60 kHz) with a minimum heat buildup, especially if caused to start and stop vibrating intermittantly. However, as stated previously, some heating may be necessary if bloodless surgery is desired.
Sharp surgical blades oscillating at ultrasonic frequencies can tend to fall through living tissue, much like a hot knife through butter. Conversely, a duller knife, or one which has low or no ultrasonic assistance, requires a greater amount of force, and more subsequent tearing of the tissue occurs. Such slower cutting, which may result in more scarring, may be desirable when performing surgery proximate vital organs so that the surgeon can feel the blade advancing through the tissue and more carefully continue. Ultimately, ultrasonic surgery results in the breaking of living tissue bonds which are of varying strengths. The present invention addresses this issue and provides the surgeon with multitudes of configurations of blades, depending on the type of cut desired.
The second category of problems associated with ultrasonic surgical tools are those relating to the lack of operator control of, and poor ergonomics of, the instruments. First, there has been a lack of understanding of the tactile feedback necessary to carefully resect different types of living tissues with one particular knife. As discussed above, a very sharp knife might be desirable, for instance in cosmetic surgery, but provide the surgeon with little or no feedback of the type of tissue the knife is cutting through. Conversely, a knife with lots of drag may provide feedback, but may have a substantial reduction in the quality of cut desired. Additionally, the amount of feedback desired is a subjective determination by the individual surgeon. A more experienced surgeon would tend to require less feedback than a novice. The amount of heat generated is another critical control parameter, previously addressed by simply altering the thermal footprint of the blade. Another phenomenon associated with ultrasonic surgery is the formation of cavitation bubbles in the region proximate the surgical blade. Control of the amount of cutting from mechanical shearing of the tissue bonds, as opposed to that from cavitation-assisted cutting, has not previously been addressed.
Cavitation occurs when the local pressure in a fluid decreases below the vapor pressure of that fluid. Local voids or vacuum pockets, in effect, are created which then tend to implode violently upon an increase in pressure. Objects moving rapidly through a fluid can induce such cavitation in their wakes by skin and form frictional forces, as is known in the art of fluid dynamics. Ultrasonically oscillating surgical blades have a tendency to cavitate in the bodily fluids surrounding an incision. In addition, normal saline or other fluids can be supplied to a surgical site to enhance normal cavitation. At lower frequencies, e.g., below about 20 to 30 kHz, ultrasonic knives tend to create a cavitation emulsification layer which nominally provides better lubrication for the knife blade, and tends to minimize the damage resulting from heat transfer to the surrounding tissue.
The amount of cavitation plays a major role in the characteristics of the final cut. The implosion of cavitation "bubbles" can be severely detrimental to the surgical instrument, but also can assist the cutting action by breaking tissue bonds at the same time. The physics of the formation of cavitation bubbles is such that the temperature at their surface can reach 5000° F. This intense but highly localized energy is converted to the kinetic energy of a shock wave upon implosion. The result is that the knife tends to "blow through" the tissue and the energy which would have been converted to thermal transfer to the surrounding tissue is used for cutting. In some instances cavitation primarily, in conjunction with some hemostatic action, is a preferred cutting method.
The present invention addresses the aforementioned problems associated with ultrasonic surgery in terms of varying the characteristics of the incision and providing the surgeon with proper feedback and flexibility of use. The surgeon has a wide range of blade configurations and operating modes to best perform a particular procedure to his or her preference. The tactile feedback and cutting options available with the present ultrasonic surgical blade are a major improvement over prior instruments.
The amount of heat generated and propagated into the surrounding tissue is controlled by the shape of the preferred blade 26. The area of the contact surfaces 38 can be widened to increase the heat generation from sonic and conductive energy transfer. This is desirable in regions containing numerous blood vessels to induce hemostasis. Similarly, the angle of the tapers 40,42 affects the magnitude of thermal footprint of the blade 26. A large portion of the cross-section of the blade 26 in contact with the tissue being cut is removed by the formation of the relief 36. These parameters can be cohesively managed to provide a wide range of incision characteristics. For example, cosmetic surgery requires the sharpest blade with minimal thermal damage to minimize scarring. Alternatively, a sharp blade with more heat generation may require a similar blade tip with more contact surface and less relief in the central portion. The various shapes of the current blade 26 contemplate an infinite number of functional combinations.
Another factor in heat generation is the surface texture of the blade 26 surfaces. Smoother surfaces result in less frictional resistance than rougher ones. Roughening the surface texture of the contact surfaces 38, while highly polishing the tapers 40, 42 and relief portions 36, results in some increase in heat generation, which can be customized for the type of tissue involved. Surface textures can be modified by either polishing an existing surface or roughening the existing surface of the blade. Minimal surface friction will be incurred in a blade having a highly polished surface such as an RMS of 1 or 2. RMS, or root-mean-square, is a proportionate term generally referring to the statistical average of the sizes of irregularities. Practically, however, polishes of this degree are difficult to produce on the construction material utilized for surgical blades. Relatively rough areas of the surgical blades disclosed herein are contemplated to have an RMS of about 63. This level of roughening can be accomplished by processing the knife blade with glass beading, chemical etching, or other techniques which will be known to one of skill in the art. Preferably, a random sized distribution of bumps or pockets within the range of from about 20 to about 100 micron are utilized. The bumps or pockets are preferably rounded or hemispherical in shape, to improve longevity under ultrasonic vibration conditions, and to minimize fragmentation and leaving parent material behind.
A further parameter influencing the amount of thermal generation is the frequency and mode of oscillations. The control system 30 of the present invention allows for complete flexibility for the surgeon to alter the oscillation character. As is known, a higher frequency surgical blade tends to transfer less thermal energy at a greater depth via sound propagation to the surrounding tissue but has higher internal heat of blade and at the interface of blade and tissue. The control system 30 provides a means for modulating such an advantageous frequency with lower frequencies to provide some drag, or tactile feedback, to the surgeon, and increase effective cavitation. Other combinations of frequencies and wave forms can be generated by the control system 30 to tailor the oscillations of the blade 26 to the particular surgical environment.
The present invention also identifies and presents solutions to the problems of feedback and individual surgeon needs. The advantageous shape of the serrations of the present blade 26 transfer resistance forces more efficiently to the hand of the surgeon. Providing surfaces perpendicularly vectored to the tissue means that more resistance is encountered from an increase in the pressure of cut. Reducing the stroke of the blade and spacing the teeth 46 of the blade 26 so that at least two teeth 46 encounter a specific tissue bond on each stroke reduces the internal stresses on the knife as well as the magnitude of vibrations of the handpiece, while ensuring a clean and effective cut.
Another benefit of the ultrasonic surgical system 24 of the present invention is the ability to manage the amount of cavitation generated. Cavitation minimizes thermal energy penetration into the surrounding tissue by converting the transient shock wave energy into a cutting action. The dynamic feedback associated with cavitation-assisted cutting provides enhanced tissue differentiation, as the stronger, more elastic, bonds holding such anatomical structures as blood vessels together require more energy to break than does the surrounding tissue. The feedback from cavitation cutting, in effect, increases the change in drag felt when cutting from weak to tough tissue, as opposed to the minimal change in feedback from simply mechanically shearing the same tissue layers.
Control of the various parameters of the present invention allows the surgeon to select the amount of cavitation produced. The primary factor for changing the amount of cavitation at a fixed frequency and a uniform saline solution is the surface texture of the blade 26 surfaces. Smoother surfaces result in less frictional resistance than rougher ones and thus less disturbance of the fluid boundary layer next to the blade. Roughening the surface texture of a blade results in wakes and the subsequent formation of cavitation bubbles. In general, the larger the surface irregularity, the larger and more energetic bubble that is formed. The discussion of surface roughness of the blade 26 above in terms of preferred frictional heating applies to cavitation as well. Relatively rough areas of the surgical blades disclosed herein to induce a substantial amount of cavitation are contemplated to have an RMS of about 63.
Cavitation can also be increased by increasing the angle and width of the blade cross-section which contacts the tissue. The shape and surface texture of the teeth of the present blade can be altered to increase or decrease cavitation or, in effect, manage the percentage of cutting due to cavitation.
Cavitation is highly dependent on the frequency of oscillation. Lower frequencies, in general, produce more cavitation as slower moving blades tend to form larger bubbles; there is approximately nine time more cavitation energy at 20 kHz than at 60 kHz for the same stroke (peak to peak motion). The present invention advantageously can be configured to increase the amount of cavitation at higher frequencies. In addition to altering the shape and texture of the blade, the blade 26 oscillation may be started and stopped with gated pulses to induce more cavitation. A blade operating at 60 kHz to take advantage of the reduced thermal penetration, for example, may be gated to cause a greater number of larger cavitation bubbles to form during the slow-down and start-up periods without increasing the thermal effect on the surrounding tissue. The depth of thermal penetration is desirably limited to 1 mm into the sides and bottom of an incision. Advantageously, the gated pulses would be applied directly out of phase from the original frequency to rapidly dampen out the natural vibration of the oscillating blade 26 and horn 114. The gated pulse would preferably only reduce the vibrational amplitude to 5-10% of the original and thus leave the blade and horn "singing". The start up pulse would then be applied directly in synchronous phase with the small residual vibrations, to more quickly bring the blade 26 and horn 114 back to the original amplitude.
Another primary advantage with the surgical knife of the present invention is seen in its ability to cut through a wide range of materials with a maximum of control. Coordinating the blade 26 configuration, ultrasonic signal shape and surgical technique permit an infinite number of applications. For example, in the area of tissue resection, straight cutting or dry cutting with hemostasis, or cavitation-assisted cold-cutting are all within the realm of uses for the present invention. Similarly, other more durable materials may be cut with the present blade 26. Osseous matter can be sawed easily and with minimal necrosis. Plastics and cements, such as PMMA used in affixing prosthetic devices within body cavities, are also rapidly cut through with the proper toothed blade 26 and at the proper frequency. Another possible use for the present invention is for delaminating hi-tech composites, the vibrations serving to break the chemical bonds of the laminates.
A further configuration possible with the blade 26 of the present invention is machining more than one shaped edge around the blade. This time-saving feature would provide a surgeon with essentially two or more tools in one. Normally, a surgical incision passes through many different types of tissue, requiring different techniques or a new blade altogether. The time spent switching a blade can be extremely costly to the patient. The present surgical blade 26 may have one side shaped and finished for rapid, sharp cutting through outer layers of tissue. The other edge of the blade may have a rougher wider shape to induce more cavitation and drag, for "teasing" the blade through tissue close to vital organs. Other possibilities include edges preferred for cold-cutting (more cavitation), cauterizing (localized heating) or bone cutting (minimum heating).
Finally, the variations of blade and oscillation character provide the knowledgeable surgeon with a highly advanced and flexible surgical tool. The numerous combinations of the aforementioned surgical knife parameters give the surgeon ultimate freedom in choosing the preferred embodiment.
The present invention has been described in terms of certain preferred embodiments. However, additional embodiments and variations will become apparent to one of skill in the art in view of the disclosure contained herein. Such variations are intended to be within the scope of the present invention. Accordingly, the scope of the present invention is not limited by the specific embodiments disclosed herein, but is to be defined by reference to the appended claims. | Disclosed is an improved ultrasonic knife of the type for surgical incision in various types of tissue and/or for the removal of cement within the body. The knife has a reduced thermal footprint to minimize thermally induced tissue damage. Tooth configuration on the knife cooperates with the stroke of the ultrasonic drive to produce efficient cutting, as well as tactile feedback to the surgeon with respect to the rate of cutting, and changes in tissue density. Ultrasonic knife tip extenders are also disclosed for advancing the ultrasonic knife tip through the working channel of an endoscope. Methods utilizing the foregoing apparatus are also disclosed. | 0 |
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of and priority to French Patent Application No. 1359465, filed Oct. 1, 2013. French Patent Application No. 1359465 is hereby incorporated by reference in its entirety.
BACKGROUND
The invention is related to the domain of the “medical devices” as defined by the directive 93/42/CE of Jun. 14, 1993 of the European Communities, and notably the “active implantable medical devices” as defined by the directive 90/385/CEE of Jun. 20, 1990 of the European Communities. This definition in particular includes the implants that continuously monitor the cardiac rhythm and deliver if necessary to the heart electrical pulses of stimulation, cardiac resynchronization, cardioversion and/or defibrillation in case of a rhythm disorder detected by the device. It also includes neurological devices, cochlear implants, etc., as well as devices for pH measurement or devices for intracorporeal impedance measurement (such as the measure of the transpulmonary impedance or of the intracardiac impedance).
The invention relates more particularly to those of these devices that implement autonomous implanted capsules and are free from any physical connection to a main implanted (such as the can of a stimulation pulse generator).
These autonomous capsules are called for this reason “leadless capsules” to distinguish them from the electrodes or sensors placed at the distal end of a lead, this lead being traversed throughout its length by one or more conductors connecting by galvanic liaison the electrode or the sensor to a generator connected at the opposite, proximal end, of the lead. Such leadless capsules are for example described in U.S. 2007/0088397 A1 and WO 2007/047681 A2 (Nanostim, Inc.) or in the U.S. 2006/0136004 A1 (EBR Systems, Inc.).
These leadless capsules can be epicardial capsules, fixed to the outer wall of the heart, or endocardial capsules, fixed to the inside wall of a ventricular or atrial cavity, by a protruding anchoring helical screw, axially extending the body of the capsule and designed to penetrate the heart tissue by screwing to the implantation site. The invention is nevertheless not limited to a particular type of capsule, and is equally applicable to any type of leadless capsule, regardless of its functional purpose.
A leadless capsule includes various electronic circuits, sensors, etc., and a transmitter/receiver for wireless communication for remote data exchange. The signal processing inside the capsule and its remote transmission requires a non-negligible energy compared to the energy resources this capsule can store. However, due to its autonomous nature, the capsule can only use its own resources, such as an energy harvester circuit (by the movement of the capsule), associated with an integrated small buffer battery.
The invention relates more particularly to capsules whose energy harvesting uses a mechanic-electric transducer of the piezoelectric type (hereinafter “piezoelectric component”) cyclically and alternatively stressed in bending so as to generate electric charges, which charges are then harvested by the self-supply of the capsule system. The mechanical stress of the component can in particular be caused by variations in the pressure of fluid surrounding the capsule (typically, the blood medium), which cyclically deforms or moves a flexible membrane or a mobile surface linked to a bellows (elements designated hereinafter as “actuation element”), this membrane or this surface being connected to the piezoelectric component by a suitable coupling element such as a rod, a strut, etc. (hereinafter “connection element”). EP 2639845 A1 (Sorin CRM) describes such a structure of energy harvesting. Other examples of energy harvesters implementing a piezoelectric component are disclosed by WO 2013/081560 A1, U.S. Pat. No. 3,456,134 A, US 2012/286625 A1, WO 2013/121759 A1 or WO 2013/077301 A1.
Two configurations are possible, depending on the method by which the piezoelectric component is mounted in the casing of the capsule and according to the position of the point of application of the force transmitted by the connection element which stresses the component.
In a first, not symmetrical, configuration the piezoelectric component is blade-shaped or beam-shaped (in the sense of strength of materials) secured to the body of the capsule at one of its ends (“free-clamped” configuration) and is stressed in bending by a force applied to its free opposite end. This configuration allows a maximum deformation of the blade, so a high level of charges is generated and thus provides efficient mechanic-electric conversion. However, the non-symmetrical arrangement of the various elements, in particular of the connection element relative to the body, requires a non-symmetrical displacement of the actuation element and a non-homogeneous deformation of the diaphragm or of the bellows relative to the body of the capsule, which is undesirable for mechanical reliability reasons.
In a second, symmetric, configuration the piezoelectric component is secured to the body at its two ends (“clamped-clamped” configuration) and subjected to bending stress by a force applied to its center. This configuration allows movement of the operation element parallel to itself and therefore a homogeneous deformation of the diaphragm or bellows. However, it does not allow a high amplitude of deformation of the piezoelectric component, said second configuration being more rigid than the first. Typically, for a given dimension of the component, the stiffness of a clamped-clamped configuration is eight times higher than that of a clamped-free configuration, requiring a bending displacement of the component, and thus to eight times less of harvested energy.
To increase flexibility, one must either reduce the thickness of the piezoelectric component (but the limits of this technological solution is quickly reached) or increase its length while maintaining the symmetrical configuration. This solution is proposed by the EP 2 639 845 cited above, which teaches structuring the component with a spiral or coil shape to increase the effective length and flexibility, while maintaining a centered coupling allowing symmetric deformation of the bellows or diaphragm. However, although such structures are very flexible, transduction performance remains relatively low, due to two specific phenomena:
Curved or wound structures are subject to phenomena of torsion, which consequently results in a large part of the mechanical energy applied to the transducer stored as torsion elastic energy, while only the bending energy is converted into electricity; and Mechanical deformations of an elongated and wound structure (even a simple linear structure of the clamped-clamped type) are complex, with curvature inflections. Under stress, the component has zones under tension alternating with zones under compression, creating changes of sign of the electrical potential created by the piezoelectric effect (the more elongated and complex the structure is to increase its flexibility the more changes). This phenomenon can be taken into account by providing the component with charge harvesting electrodes which are separate for each respective zone stressed in tension or compression. However, the structuring of the electrodes adds additional complexity of design and realization of the component, without completely solving the problem of the poor conversion efficiency resulting from the multiplication of sign changes of the electric potential in the piezoelectric material.
SUMMARY
An object of the invention is to overcome these constraints and limitations, by proposing a new type of energy harvester for leadless capsules incorporating a piezoelectric component with high transduction efficiency, to convert in electricity the largest part of an input mechanical energy produced by an actuating element stressed cyclically.
Another object of the invention is to ensure that the stress of the piezoelectric component, which typically results from variations of pressure of the medium such as the blood pressure changes during successive cardiac cycles, is associated with a uniform deformation of the various organs of the actuation element (bellows, membrane, etc.), thereby ensuring mechanical reliability over the long term.
Embodiments of the application include an energy harvester having:
A simple configuration of the free-clamped type, and Between the actuation element and the free end of the component, a mechanical coupling performed by an organ disposed on the free end and allowing a degree of freedom in pivoting of this free end, so as to allow the transmission of efforts without inflection of component curvature and therefore without reaction effect which would lead to a non-homogeneous deformation of the bellows or diaphragm of the capsule.
More specifically, the invention proposes an autonomous intracorporeal capsule having a body and, inside the body, an electronic circuit and an energy harvesting module for the power supply of the electronic circuits. The energy harvesting module includes an actuation element, a mechanic-electric transducer including at least one deformable piezoelectric component, a connection element coupling the actuation element and the piezoelectric component, and methods for harvesting the electrical charges produced by the piezoelectric component. The actuation element includes a mobile surface of the body of the capsule adapted to be subjected to pressure cyclic changes in the medium surrounding the capsule and to produce a cyclic mechanical stress under the effect of the pressure variations. The connection element transmits to the piezoelectric component, in an application point and according to a direction of application, this mechanical stress and thus cyclically produces bending deformations of the piezoelectric component able to generate electric charges, the piezoelectric component including a straight elongated flexible blade which extends along a main blade direction, perpendicular to the application direction of the mechanical stress.
According to aspects of the invention, the blade is configured as a clamped-free beam adapted to be forced to bend without curvature inversion, with a recessed end integral of the body of the capsule and a free end, at the opposite, connected to the connection element at the point of application of the mechanical stress. A mechanical connection for coupling the free end of the blade to the connection element are further provided, the mechanical connection having a degree of freedom in pivoting between the main direction of the blade and the direction of application of the mechanical stress.
According to various embodiments:
The mechanical connection may include an intermediate element of flexible polymeric material connecting the free end of the blade with the connection element; The mechanical connection may include a bracket connected to the connection element with two legs arranged on either side of the free end of the blade and a coupling interlayer disposed between each respective leg and the face in vis-à-vis the blade. The coupling interlayer may include, an element of flexible polymer material connecting the leg to the face vis-à-vis the blade, a needle forming a fulcrum of the leg against the face vis-à-vis the blade, or a ball bearing or a roller forming a support bearing assembly of the leg against the face vis-à-vis the screw blade; The mechanical connection may include a hinge with a ball integral with the free end of the blade, cooperating with a seat formed on the connection element, or vice versa; The capsule may include an asymmetric structure, wherein the connection element is connected at a central point of the actuation element, or a symmetrical split structure, with two components and two piezoelectric components and two respective connection elements connected to the common actuation element in diametrically opposed points of this actuation element; and The blade may have a progressively decreasing width from its recessed end towards its free end.
BRIEF DESCRIPTION OF THE FIGURES
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 of preferred embodiments of the present invention, made with reference to the drawings annexed, in which like reference characters refer to like elements and in which:
FIG. 1 schematically illustrates a set of medical devices including leadless capsules, implanted within the body of a patient.
FIG. 2 is a functional block diagram showing the various stages constituting a leadless capsule.
FIGS. 3 and 4 illustrate two possible embodiments of a leadless capsule body with means for harvesting the pressure variations of the surrounding fluid.
FIGS. 5 a , 5 b and 5 c are views, respectively in section at rest, in section during operation, and a diagrammatic perspective view, of an energy harvester unit with a piezoelectric transducer according to prior art.
FIGS. 6 and 7 are top views of piezoelectric components formed of wound coil or spiral strips, according to the prior art.
FIG. 8 is a schematic perspective view illustrating the deformations undergone by a piezoelectric component of the clamped-clamped type.
FIGS. 9 a , 9 b and 9 c are sectional views, respectively at rest, in operation with a stress in one direction and in operation with a stress in the opposite direction, of an energy harvesting system according to a first embodiment of the invention.
FIG. 10 is the counterpart of FIG. 9 b , for a variant of the first embodiment with duplication of the piezoelectric transducer.
FIGS. 11 a , 11 b and 11 c are top views of various possible shapes of a split piezoelectric component, usable in particular with the embodiment of FIG. 10 .
FIGS. 12 a , 12 b and 12 c are counterparts of FIGS. 9 a , 9 b and 9 c , for a second embodiment of the invention.
FIGS. 13 a , 13 b and 13 c are counterparts of FIGS. 9 a , 9 b and 9 c , for a third embodiment of the invention.
FIGS. 14 a , 14 b and 14 c are counterparts of FIGS. 9 a , 9 b and 9 c , for a fourth embodiment of the invention.
FIGS. 15 a , 15 b and 15 c are counterparts of FIGS. 9 a , 9 b and 9 c , for the fifth embodiment of the invention.
DETAILED DESCRIPTION
A structure of a leadless capsule, according to the prior art, will be described with reference to FIGS. 1-8 depicting exemplary embodiments of such a leadless capsule with an energy harvester including a piezoelectric component.
In FIG. 1 , a set of medical devices implanted within the body of a patient is illustrated. The patient is implanted for example with an implant 10 such as an implantable defibrillator/pacemaker/resynchronizer or a subcutaneous defibrillator or a long-term event recorder. This implantable device 10 is the master device of a network including a plurality of slave devices 12 to 18 , which may include intracardiac ( 12 ) or epicardial ( 14 ) capsules located directly on the patient's heart, other devices such as myopotential sensors or neurological stimulation devices, and optionally an external device 18 disposed on an armband and provided with electrodes in contact with the skin. The device 10 can also be used as a gateway with the external environment to communicate with an external peripheral device 20 such as a programmer or a data remote transmission device with which it communicates by telemetry.
FIG. 2 schematically illustrates the different internal circuit of the implantable autonomous capsules 12 - 16 . The capsule includes for example a pair of electrodes 22 , 24 connected to a stimulation pulse generator circuit 26 (for an active capsule incorporating this feature) and/or a detection circuit 28 for the collection of depolarization potential collected between electrodes 22 and 24 . A central circuit 30 includes all of the electronics for controlling the various functions of the capsule, for storing the collected signals, etc. It includes a microcontroller and an oscillator generating the clock signals required for the operation of the microcontroller and for the communication. It may also contain an analog/digital converter and a digital storage memory. The capsule may also be provided with a sensor 32 such as an acceleration sensor, a pressure sensor, an hemodynamic sensor, a temperature sensor, an oxygen saturation sensor, etc. The capsule includes an energy harvesting module 34 powering all the circuits via an energy power management stage 36 . Electrodes 22 and 24 are also connected to a transmission/reception circuit of pulses 38 used for wireless communication with the master device or other capsules.
The invention relates particularly to the energy harvesting module 34 . The purpose is to harvest the energy contained in the mechanical forces to which the capsule is subjected, typically the blood pressure changes. To take into account pressure variations, the capsule is formed, as shown in FIGS. 3 and 4 , with a body 40 provided with one or more deformable elements stressed at the rhythm of the pressure variations, with a rigid surface 44 on which the pressure variations are exerted, and which is connected to the body 40 by a deformable portion, such as bellows 46 . In the example of FIG. 3 , this surface/bellows set 44 / 46 is disposed on an axial end side of the capsule 40 , while in the example of FIG. 4 there are provided two surface/bellows sets 44 / 46 disposed on lateral sides of the body 40 of the capsule, the rigid surfaces 44 being parallel to each other and to the main axis of the capsule.
The capsule holds, on its face and intended to come into contact with the body wall, an anchoring device 42 (diagrammatically shown in particular in FIGS. 5 a and 5 b ), such as screws or barbs for anchoring the capsule at the location of the chosen implantation site, for example on an inner wall of a cavity of the myocardium.
FIGS. 5 a to 5 c schematically illustrate a configuration of the piezoelectric transducer according to prior art, for a harvester with bellows as illustrated in FIGS. 3 and 4 and disclosed, for example, in EP 2520333 A1 (Sorin CRM). In this embodiment, the external physical force F, resulting from changes in blood pressure on the rigid surface 44 , is transmitted via a rod 48 or a connection element analog to component 50 forming a transducer of a piezoelectric type for energy harvesting. This component 50 converts the mechanical force F into electric charges through the direct piezoelectric effect, wherein the mechanical force F transmitted by the connection element 48 generates electric charges collected by the electrodes formed on the surface of the piezoelectric component 50 . Electrical energy thus harvested is then processed by the power storage and management module 36 .
From the dimensional point of view, the structures of the piezoelectric component used are a few millimeters long, a few hundred micrometers to a few millimeters wide and tens to hundreds of micrometers thick. As regards the material, the piezoelectric layers of the component 50 may be made of a ceramic material such as PZT or single crystal such as PMN-PT, barium titanate, or lithium niobate having a high electromechanical coupling.
In general, the input mechanical energy due to the force of blood pressure is of low intensity, particularly several tens to several hundreds of mN for a displacement of the order of a few hundred microns. This means that the stiffness of the system is low, typically hundreds to thousands of mN/m. To meet this flexibility criterion (low stiffness) while remaining compatible with the requirement of miniaturization, it has been proposed, including in the aforementioned EP 2639845, to conform the component 50 with a band structure folded in a zigzag or in a spiral.
This configuration is illustrated in FIGS. 6 and 7 . The strip component 50 is secured to the body 40 of the capsule at both ends 52 , 54 , so as to obtain a thin and long structure of the type “clamped-clamped” beam, the stress being applied to the central point A. This arrangement extends the length of the piezoelectric structure without losing compactness. However, such a structure has the drawback of experiencing torsion phenomena, which is inherent to rolled or folded configurations. Thus, a significant part of the mechanical energy applied to the input is stored as torsion elastic energy which, unlike the bending energy, is not convertible into electricity, thus degrading the performance of transduction of mechanical energy into electrical energy compared to a component of the straight beam type, which is only subject to bending stresses.
Another drawback of this known configuration is that, as shown in FIG. 8 , for a “clamped-clamped” beam structure wherein the piezoelectric component 50 is rigidly secured at its two ends 52 , 54 of the capsule body, the deformation of the beam will necessarily cause the formation of a concave central region 56 with on its two sides convex regions 58 , or vice versa for a stress in the other direction. This change in curvature is electrically resulting in inversion of the polarity of the charges generated along the beam, requiring electrical isolation of the electrodes according to their concavity. Indeed, to avoid the recombination of charges, the electrodes must be separated on the different regions undergoing different curvatures. It is therefore necessary to structure the electrodes in distinct sets, each generating a different polarity. In the case of rolled or folded structures such as those of FIGS. 6 and 7 , these sign changes are multiplied, leading to many sign changes of the generated charges that lead to performance degradation of transduction yield.
We will now describe embodiments of the new invention, with reference to FIGS. 9-15 . In these figures, various embodiments configured to increase significantly the conversion efficiency of known devices such as those just described are presented. The basic idea of the invention, unlike in the “clamped-clamped” configurations proposed so far, it to use a simple “clamped-free” configuration with a blade-shaped or straight beam shaped piezoelectric component.
Used as such, this type of “clamped-free” structure has the mechanical drawback, due to the reaction effects between the piezoelectric component and the actuation element, to lead to a displacement of the actuation element not parallel to itself. This, therefore, may lead to an inhomogeneous deformation of the bellows (which would crush more at the free end than at the recessed end of the component), causing significant mechanical reliability problems of the structure in the long-term.
To avoid this, and to allow a homogeneous and symmetric deformation of the bellows, the invention proposes, as can be seen in particular in FIG. 9 a , to make a mechanical connection of the pivot type 62 between an actuator and the free end 60 of the deformable piezoelectric component. In a preferred embodiment, the actuator comprises the connection element 48 linked to the actuation element 44 receiving the efforts and transmitting the efforts in the direction D forming an axis of symmetry of the bellows 46 thereof. Thus, such a system does not affect the deformation of the bellows 46 or the displacement of the actuation element 44 , which can move parallel to itself respectively in one direction or in the other depending on the positive or negative variations of the surrounding pressure, as illustrated in FIGS. 9 b and 9 c.
The piezoelectric component 50 may bend in one direction or in the other ( FIGS. 9 b and 9 c ) on both sides of its equilibrium position ( FIG. 9 a ) corresponding to the main direction Δ along which the component extends. These movements will not transmit torsional forces to the connection element 48 , efforts which could affect, by reaction, the movement of the actuation element 44 and hence the deformation of the bellows 46 .
This is achieved by the degree of freedom in rotation (angle α in FIGS. 9 b and 9 c ), allowed by the mechanical connection of the pivot type 62 between the free end 60 of the component 50 and the connection element 48 . In FIGS. 9 a to 9 c , this connection has been illustrated in the form of a ball 64 integral with the connection element 48 and cooperating with a seat 66 integral with the free end 60 of the piezoelectric component 50 .
This configuration has several advantages: First, relative to a “clamped-clamped” (as in FIG. 8 ) configuration, the “clamped-free” configuration has a stiffness eight times lower which allows, for an inputted given force F (the value of which is imposed by the significance of changes in blood pressure and by the area of the mobile surface 44 ) to increase eight times the amplitude of displacement and thus the harvestable energy. Secondly, the “clamped-free” proposed structure has only one type of mechanical stress by piezoelectric layer, due to the lack of inversion of curvature: only voltage on one side, and only compression on the opposite side. Thus, a simple unstructured electrode is sufficient to harvest energy, which frees manufacturing of a patterning step of the electrodes. Furthermore this configuration generates a much greater amount of charges and, thus, energy. The yield of the piezoelectric transducer is therefore much higher than conventional structures of the prior art. And finally, a “clamped-clamped” configuration, in addition to having eight times higher stiffness than that of a “clamped-free” configuration, very quickly takes on a nonlinear behavior (as soon as the movement is about half the thickness of the beam), making this configuration more rigid.
FIG. 10 illustrates a configuration in which the piezoelectric component 50 occupies the maximum diametrically permitted length in the body 40 . Indeed, it may be useful to maximize the blade length of the component 50 to reduce its stiffness. In this case, to ensure a symmetrical deformation of the bellows 46 , two identical transducers 50 , 50 ′, having a upside-down configuration, symmetrical to the center of the capsule, are provided. Each transducer 50 , 50 ′ has a recessed fixed end 52 , 52 ′ and a free end 60 , 60 ′ which is connected to a respective connection element 48 , 48 ′ connected to the common actuation element 44 at two diametrically opposite points thereof. The recessed ends 52 , 52 ′ are also located at two diametrically opposite sides of the capsule body 40 , so that the forces applied on the respective free ends 60 , 60 ′ are symmetrical with respect to the central axis of the capsule. The sum of the two forces is therefore centered, resulting in a symmetrical deformation of the bellows 46 .
The configuration of FIG. 10 provides i) nearly double the length of each component 50 , 50 ′ and ii) duplication in the number of components. Therefore, in comparison with the configuration of FIG. 9 b , FIG. 10 (with the piezoelectric component 50 , 50 ′ of the same section) increases the flexibility by a factor of four. Thus, the displacement will be four times greater for a given force (and therefore a given pressure variation), which also gives four times greater energy. Finally, between the structure of the prior art such as that illustrated in FIG. 8 and the structure of the invention with dual component such as that illustrated in FIG. 10 , the power supplied is increased by a factor thirty-two.
The plan views of FIGS. 11 a , 11 b and 11 c show three possible respective variants of optimization of the shape of the beams of the configuration of FIG. 10 , with components 50 , 50 ′ of constant width ( FIG. 11 a ) or of variable, decreasing from the fixed clamped end 52 , 52 ′ to the free end 60 , 60 ′ width ( FIGS. 11 b and 11 c ).
FIGS. 12 a to 12 c are counterparts of FIGS. 9 a to 9 c for a particularly advantageous embodiment of the pivot connection 62 . In this embodiment, the connection is made from a single deformable element, such as a flexible polymer 68 interconnecting the free end 60 of the component 50 and the end of the connection element 48 . The polymer 68 may be a silicone, in particular based on PDMS (polydimethylsiloxane), PEEK (polyetheretherketone), or parylene (poly (p-xylylene)). When the actuation element 44 is lowered ( FIG. 12 b ) the polymer 68 compresses and flexes; conversely, for a movement in the opposite direction ( FIG. 12 c ) the polymer lengthens and absorbs the angular deformation of the free end 60 of the piezoelectric component 50 . During these movements, the contact surface between the polymer 68 and the free end 60 of the piezoelectric component 50 is not horizontal and forms a non-zero angle α relative to the main direction Δ of the component 50 . This angle allows the arcuate deformation of the component 50 as in the case previously described in FIGS. 9 a -9 c , with the advantage that the flexible element 68 eliminates any mechanical friction.
It is possible according to the same principle, as shown in FIGS. 13 a to 13 c , to have two such flexible polymer elements 68 on each side of the free end 60 of the component 50 , one of the elements being located on the upper surface of the component and the other in line with the first, but on the lower surface. These two polymer elements 68 are connected to the two arms 72 of a bracket 70 , itself attached to the connection element 48 . When the actuation element 44 is lowered ( FIG. 13 b ), the two polymer elements 68 are deformed. The upper surface behaves as in the case of FIG. 12 b in compression mode, while the lower one behaves in elongation mode, symmetrically, to allow pivoting of the free end 60 relative to the direction D of application of the force F. In the reverse movement ( FIG. 13 c ), the roles of the two polymer elements 68 are reversed, thereby generally have a homogeneous behavior of the material of these elements for the two directions of displacement.
FIGS. 14 a to 14 c are counterparts of FIGS. 13 a to 13 c for another embodiment of the pivot connection 62 . In this case, the coupling consists of a simple mechanical contact by a pin 74 or an analogous element provided on each of the arms 72 of the bracket 70 and bearing on the component 50 on either side of the free end 60 . This end can be, depending on the direction of movement of the connection element 48 , push ( FIG. 14 b ) or pull ( FIG. 14 c ).
FIGS. 15 a to 15 c are counterparts of FIGS. 13 a to 13 c for yet another embodiment of the pivot connection 62 . This embodiment is to implement a rolling ball or roller 76 between each face of the component and the branch 72 facing the bracket 70 . Thus, during displacement of the actuation element in one direction or in the other ( FIGS. 15 b and 15 c ), the mechanism including these rolling balls stoops or raises and moves on the surface of the component 50 along its main direction Δ, allowing the free end 60 to bow and to form an angle without curvature inflexion and thus with a homogeneous charge polarity on the same surface of the piezoelectric component 50 . | An autonomous intracorporeal capsule comprises a body containing electronic circuits and an energy harvesting module. The energy harvesting module comprises a moveable surface on the body of the capsule, subjected to pressure variations and to produce a mechanical stress under the effect of the pressure variations, and a transducer comprising a deformable piezoelectric component configured as a beam adapted to be forced to bend. The piezoelectric component has a recessed end integral with the capsule and a free end. A mechanical connection couples the free end of the piezoelectric component to the actuator. The mechanical connection may provide a degree of freedom in rotation between a main direction of the beam and the direction of application of the mechanical stress. | 0 |
BACKGROUND OF THE INVENTION
It is well known in the processing industries to treat liquid and gaseous substances by contacting them with solids such as granular agents. Such processes are often called "sorption" processes and are usually performed in beds which include a tank or vessel with a supporting grid or screen onto which a layer of granular agent is evenly distributed and through which layer the liquid or gaseous substance flows and is subjected to the sorption treatment. In this respect, the screen has a mesh size small enough to avoid entrainment of the granular agent.
Inherent disadvantages of the above-described beds are that they require renewal of the granular agent after exhaustion of its activity; and, this, in turn, requires a means to drain the granular agent and a means to refill the bed with fresh agent. Additionally, the layer of granular agent has to be of an even thickness to obtain a constant contact-time of the liquid or gaseous substance as it flows in a perpendicular direction through the whole layer-area of the granular agent.
Other known contact assemblies for sorption processes include those where a granular agent is located between two screens which are arranged such that the granular layer can be oriented in any desired angle such as vertically, for example. In this manner, with a vertically oriented layer, the direction of flow of the liquid or gaseous substance can be horizontal. An assembly of this type, however, has the disadvantage that, during its use, the granular agent tends to settle thereby leaving a space for a reduced-density portion at the upper edge of the layer. In such event, portions of the liquid or gaseous substance can flow through the assembly while having little or no contact with the granular agent. Some of the substance, therefore, remains untreated or poorly treated because of the reduced contact-time with the granular sorption agent. This disadvantage has been overcome in the past by using flexible, but tight, membranes pressed onto the upper edges of the assembly by springs or the like, but these are costly and not always desirable.
Fibrous mats have also been used to support granular agents. Such mats, however, have been impregnated with a powdered agent that is retained by means of a sticky or gluey coating applied to the fibers. This has the serious disadvantage of reducing the contact-area of the agent wherever the agent is covered by the sticky or gluey coating.
It is an object of this invention, therefore, to provide a mechanically stable mat containing at least one layer of granular sorption agent which is easily replaced; and, wherein a liquid or gaseous substance flowing across the granular agent is subjected to a uniform contact-time with the granular agent.
SUMMARY
According to principles of this invention at least one layer of granular sorption agent is located between at least two layers of fibrous mat which are mechanically interlocked by means of needling. In this manner, the liquid or gaseous substance that is flowed or trickled through the mat is brought into uniform contact with the granular sorption agent for deodorization, decolorization, or the like by the granular agent.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects, features, and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention as illustrated in the accompanying drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating principles of the invention in a clear manner.
FIG. 1 is a sectional view of a textile fiber mat with a layer of granular sorption agent therein;
FIG. 2 is a perspective view of the mat of FIG. 1 and further illustrates rows of needling for holding the mats together.
DESCRIPTION OF PREFERRED EMBODIMENTS
The mat in accordance with FIG. 1 comprises three layers of textile fibers V and sandwiched inbetween are two layers of granular agent such as activated carbon. Ionized molecules can also be removed from aqueous solutions when the granular agent is an ion exchange resin. The layers V are preferably of textile fibers, part of which are unwoven, so that some of the fibers can be transported by needling through the layers S of granular agent and be interlocked to the other layers V. That is, fibers from the upper layer V are interlocked by the penetrating needles with those of the intermediate and lower layers V at the opposite side of the mat.
FIG. 2 shows the resulting assembly after being stitched by needling. The needling operation is performed such that seams N are in parallel rows at the distance A between the rows. In this respect, the rows N are preferably between about 5 and 20 mm apart.
When the direction of the needles penetrates the mat in the direction indicated by arrow "P", the needles transport fibers from the layer V o to the layer in the middle V m and further to the bottom layer V u . This mechanical interlocking or intertwinement of the fibers from the various layers constitutes a mechanical link between all layers which results in a mechanically stable mat. The fibers linking the various layers are shown on the right cross-sectional portion of FIG. 2 and are the same along the length of each row, where the needling N has been performed.
The layers V in the illustrated examples are indicated as being non-woven fleece pads. The invention is not limited to non-woven fleece pads, however, as long as enough fiber emitting and fiber interlocking material is provided to result in the mechanically stable mat described above. Specifically it is possible to add to one or more of the layers such as V M in FIG. 2, for example, a layer of a woven fabric or "scrim", which yields a higher tear-strength than if all non-wovens are used.
Similarly, the invention is not limited to the use of fibers made of synthetic materials or natural fibers such as wool or cotton. The fibers can be made of metals. Stainless steel, for example, can be used for applications where textile fibers will not stand elevated temperature and/or the chemical activity of the liquid or gaseous substance that is passed through the mat.
It has been found that it is very easy to handle or replace the mats of the present invention. A further advantage of the present invention is that the structure performs a combination of both filtration and sorption functions. The layer V o in FIG. 2, for example, functions as a mechanical filter to solids or sticky contaminants which might be carried by the stream P of liquid or gaseous substance. Moreover, this filtration function prior to the contact with the granular agent prevents the agent's granules from becoming clogged or contaminated and from having its active surface coated with unactive material. According to this aspect of the invention, the initial layer V o can be of a selected porosity and have other selected filtration characteristics in accordance with the material it is to filter.
A further advantage of the above-described invention is that the layer V u also acts as a mechanical filter for the liquid or gaseous substance after it has passed through the layer or layers of granular agent. This filtering layer V u , therefore, prevents solids from being carried away by the gaseous substance itself. Again, this layer can be selected to obtain the desired porosity and filtration characteristics.
Still other advantages of the invention are that the thusly structured mats have been found to be easily formed into bags, sleeves, or inserts by cutting and sewing or ultrasonic welding or by using adhesives and tapes. | At least two layers of fibrous mat have a layer of granular agent therebetween and are mechanically interlocked by means of needling. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is in the field of aids for the washing of automobiles and other objects.
2. Description of the Prior Art
U.S. Pat. No. 5,029,758 shows a system for the washing of cars in a commercial environment such as a car sales lot or parking lot. The unit is very large and includes, among other things, various tanks, pumps and other features which are not in keeping with home use. For home use it amounts to a serious case of overkill. U.S. Pat. No. 6,347,847 B1 is related art but is not considered particularly relevant.
SUMMARY OF THE INVENTION
This invention is a novel tool for use in washing cars or other objects or articles. It consists of a station which includes space and provision for all things necessary for complete washing of cars in the home environment. Provision is made for water supply, a wash water container, washing brushes and other necessities, towels, and detergents and other solutions needed to wash, dry, treat surfaces, and wax the family car or other object. The station is on wheels so that it can be taken to the job, hooked up to the household water supply, provide all the things necessary for the washing job, then closed up and wheeled to wherever it is kept, whether outside or inside the house or garage.
While the invention is shown generally in the context of washing automobiles in a home environment, it could be used for washing virtually any object or article anywhere. It could be used, for example, to wash trailers, buses, recreational vehicles of all types, boats, aircraft, and buildings and other structures, and parts thereof such as windows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the preferred embodiment of the invention.
FIG. 1A is a cross section of the body of the invention showing methods of reinforcing an opening in the body.
FIG. 2 is a view of the embodiment of FIG. 1 showing the tip-brace.
FIG. 3 is a view of the embodiment of FIG. 1 showing the detachable cover.
FIG. 4 is a perspective view of a second embodiment of the invention.
FIG. 5 is a perspective view of a third embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 the portable wash station 10 of the present invention consists of a body 12 . The body 12 is generally cylindrical and upright. It may be made, for example, by injection molding of plastic. The portable wash station 10 has two wheels 14 at the rear and a handle 16 for pulling the station. On the upper rear edge of the body 12 near the handle 16 is a set of hinge halves 18 . Referring to FIG. 3 a cover 20 has mating hinge halves 18 [in phantom] at the rear which may be snapped into the hinge halves 18 on the body to allow for removing and replacing the cover 20 at will. On the rear of the body 12 is a bar 22 which may serve as a rack for hanging towels and other objects. At the lower front of the body are legs 24 on each side. These serve to hold the station level and provide access to drain 27 [in phantom].
FIG. 2 shows tip-brace 70 which may be deployed in cases when the station might tend to tip over. The tip-brace 70 consists of base 72 attached at one end to the station body 12 , tip-leg 74 attached at one end by a hinge to the base 72 , an L-shaped leg support 76 attached by a hinge to the upper part of the tip-leg 74 , support pocket 78 attached to the body 12 , and keeper 80 attached to the body 12 at a point above the base 72 . When not in use, the tip-leg 74 is stowed in the keeper 80 by a simple friction clamp. To deploy the tip-brace 70 , the tip-leg 74 is pulled from the keeper 80 and rotated about its hinge until the foot of the tip-leg is in a bracing position in contact with the ground. The leg support 76 is then rotated about its hinge and the end inserted into support pocket 80 . This will hold the tip-leg 74 rigidly in place and keep the station 10 , which may have most of its weight on the rear, from tipping over backwards. Stowing the tip-brace 70 is the opposite of deploying it.
Referring back to FIG. 1 , part of the middle of the body 12 is cut away to form a lateral opening 26 . The inside edges of the opening 26 would undoubtedly need reinforcing, which could be accomplished by rolling the edges of the opening between the front top and the front bottom of the opening 26 . This is shown in FIG. 1A which is a cross section of the body 12 through the approximate center of the opening 26 . The right side of this figure shows the edge rolled back on itself and welded by weld 25 . Alternatively the edge could be bulbed in the molding process as shown at 31 on the left side of FIG. 1A .
In the opening 26 a removable tub 13 may be positioned. This tub 13 may be held in place by its handles 28 . The tub 13 holds wash water along with any desired cleaning liquid or other substance. Upon completion of the wash job the tub 13 may be lifted from its position in opening 26 and the wash water disposed of. Alternatively the wash water may be drained from tub 13 by means of the drain 27 in its bottom. The drain 27 is accessed and discharged through an opening 29 [in phantom] in the body 12 under the tub 13 .
In the top of the body 12 is an upper lateral opening 17 in which a caddy 30 may be positioned held in place by handles 32 . The caddy 30 may be used for storing detergent, wash cloths, towels, wax or any other thing used in the task of washing and detailing cars. The caddy 30 is easily removable from the body 12 either by handles 32 or center handle 34 . The caddy may be divided into one or more compartments 36 for convenience. The cover 20 protects the contents of the caddy from the weather at all times when it is closed.
Behind the caddy 30 is a compartment 38 . This compartment is adapted to hold a spray hose 40 . In the compartment 38 is a hose fitting 41 which may be of the quick-connect type, or may be an ordinary hose fitting. The hose fitting 41 is on the end of a tube 45 which may be molded into the body 12 and which extends to a relatively low position on the body 12 . This tube bends and exits the body 12 through another hose fitting 42 . A hose [not shown] from the local water supply may be fastened in the usual fashion to the outside end of the hose fitting 42 which again may be of the quick-connect or ordinary type. Locating the hose fitting 42 low on the body 12 helps to prevent tipping of the station 10 in the event excess tension is put on the local water supply hose. Spray hose 40 is attached to the hose fitting 41 and when extended from its place in the compartment 38 serves to provide rinse water for any part of the washing operation. The spray hose 40 may be of the lightweight, collapsible type to save space and weight on the station 10 .
Mounted on the station body 12 anywhere—for example on one end of the compartment 38 —is a fixture in the form of a tube 44 . The tube 44 provides storage means for any appliance with a long handle, such as a scrub brush 36 . The storage tube 44 may be configured so that the cover 20 can be closed while a brush is in the storage tube. While only one storage tube 44 is shown in the figures it would be possible to provide two or more.
One feature of station 10 as shown in FIG. 1 is that it is relatively free of protuberances on its exterior. This makes the station 10 much more convenient for moving around in a storage area—a garage, for example—without hindrance from catching on other objects.
Another embodiment of car wash station 10 is shown in FIG. 4 . This embodiment is similar to the embodiment of FIG. 1 but instead of having a removable wash water tub 13 and caddy 30 , these features are built into the body. A wash water tub 15 is located at the same place in opening 26 in the body 12 as was the removable tub 13 in FIG. 1 . In this case however the tub 15 may have a drain 60 in its side or bottom [shown in phantom] for disposing of used wash water. As was the case with the embodiment of FIG. 1 the drain 60 is accessed by virtue of space provided under body 12 by the legs 24 . In the upper lateral opening 17 of the body 12 are located storage compartments 31 , 32 , and 34 for storing detergents, brushes, rags, sponges, etc. Three compartments are shown but any number may be provided. The compartments may be molded in, or provision may be made to adjust the arrangement of the compartments to suit the operator. When the cover 20 is closed the compartments and their contents are protected from the weather. Provision is made at the side of the body 12 for storage of long-handled appliances, such as the brush 36 . This may be effected by any means known in the art such as fixtures in the form of the clamps 61 shown in phantom.
Bracket 39 and clamps 43 are shown on the side of the body 12 . Spray hose 40 may be stored on the side of the body by means of the bracket 39 and clamps 43 . Preferably the spray hose 40 has a coupling 50 for removable attachment to the local water supply. As in the embodiment of FIG. 1 the spray hose 40 may be of the lightweight, collapsible type to save space and weight.
The advantage of the embodiment of FIG. 4 lies in manufacturing. Presumably the station could be molded in two pieces—the body 12 and the cover 20 —rather than four as with the embodiment of FIG. 1 . This would lower manufacturing costs appreciably.
Still another variation of the invention is shown in FIG. 5 . In this case the wash water tub 13 and the caddy 30 are separate and removable but the spray hose 40 and the wash brush 36 are mounted to the exterior of body 12 by the same means as shown in FIG. 4 . This feature provides the potential user with the alternative of having a station with more interior space for storage and for wash water.
The chief advantage of this invention is that it puts all the implements and facilities for washing a car or other similar object at the operator's fingertips. Everything needed for the operation is contained in the station. The station itself is readily movable and storable. It may be stored outdoors and still protect its components and contents from the weather. By keeping implements within easy reach the device saves the user a good deal of bending, squatting, and lifting. It is expected that the cost of manufacturing the station will put it within easy reach of the average household, where it will prove a boon for what heretofore has often been a disagreeable task.
While the invention is shown and described in particular arrangements, it should be obvious that other arrangements of the parts could be used. For example, the compartment for the spray hose 40 could be located in the front of the body 12 . Or the wash water tub could be arranged so it is accessible from the rear of the body rather than the front. | This invention is a station for aiding in the washing of automobiles and other similar objects. The station is a wheeled cart that contains everything needed for the job. Space is provided for storage on the station of wash or rinse water; hose for connecting the station to a local water supply and for applying water to the automobile; and any article, fluid, or tool which may be of use for the task. All such space and any article therein is protected from the weather so the station may be stored outdoors. The station is of such a configuration as to minimize or eliminate the bending, stooping, and squatting usually associated with car washing. It may be constructed of molded plastic to minimize production costs. | 0 |
BACKGROUND OF THE INVENTION
The invention relates to a medical apparatus for reducing intraocular pressure by acting upon the Schlemm's canal and the tissue of the trabecular network directly in contact with the Schlemm's canal, comprising a probe with a photoconductor connectable to a laser.
International Patent Application No. WO 92/17138 A2 discloses a medical apparatus of this type having a laser, to which a probe is connected by a photoconductor. The end of the photoconductor or fiber optic is disposed in a sleeve which is introduced into the probe housing, and inside the housing there are additional light conducting means such as lenses and prisms for adjusting and deflecting the beams. The apparatus and especially the probe are not easy to use in microsurgery due to their large size.
Moreover, a method and an apparatus for microsurgery on the eye by laser radiation are disclosed in published German Patent Application No. DE-OS 38 31 141. This apparatus includes a handpiece in which a fiber optic or photoconductor, on the one hand, and on the other an aspirating or flushing system for removing the tissue ablated by the laser beam, are provided. The light issues frontally from the free end of the photoconductor, the end of the photoconductor being disposed together with the aspirating or rinsing system in a special head piece. This apparatus too has appreciable dimensions which limit its use in microsurgery to special cases.
Glaucoma is one of the most frequent causes of blindness in the industrial countries. The common characteristic of this class of diseases in by far the greatest number of cases is an elevation of the intraocular pressure above a level tolerated by the optical nerve and nerve sheath. Untreated, a progressive atrophy of the optical nerve takes place. The progressive loss of nerve fibers results in the late stages of the disease in advancing losses of peripheral vision, and if untreated an irreversible, complete loss of function occurs, plus blindness. Treatment is based on the particular form of the glaucoma, the lowering of the intraocular pressure being the most prominent. The cause of the pressure increase is an elevated resistance in the aqueous humor drainage system. More than 80% of the aqueous humor, which is formed at a rate of approximately 2.5 μl/min, leaves the eye in the area of the corner of the anterior chamber, and more than 20% in the area of the ciliary body. Through the trabecular meshwork in the corner region of the chamber it reaches the Schlemm's canal and is carried through the aqueous humor veins under the conjunctiva, where resorption takes place in the vessels of the conjunctiva. The main resistance to drainage of the aqueous humor is in the inner wall of the Schlemm's canal and the adjacent trabecular meshwork. The treatment of glaucoma in the early stage of the disease is primarily with drugs. If sufficient pressure-reducing effect cannot be achieved, then surgical or laser surgery methods are employed. The methods heretofore available for intraocular pressure reduction other than by drug treatment are characterized by the fact that they do not act primarily at the locus of the most severe elevation of resistance.
Argon laser trabecular surgery is known, in which laser pulses are aimed through the anterior chamber at the trabecular meshwork via a contact glass with special lens systems on the slit lamp, which are intended to produce a stretching of the trabecular meshwork, and thus to improve the aqueous humor drainage into the Schlemm's canal. This procedure does result in a temporary reduction of intraocular pressure in most cases; however, due to the deflection of the laser beam by the anterior chamber onto the opposite side of the meshwork, the accuracy of aim is limited; the formation of adhesions (synechiae) in the area of the corner region of the chamber is one of the complications. In particular, it is difficult to control the depth of penetration of the laser pulses.
Also known is photoablation of the trabecular meshwork ab interno, in which either an erbium-Yag laser (Er:Yag) or a neodymium-Yag laser (Nd:Yag) or an excimer laser is used, whose pulses are aimed by means of fiber optics through the anterior chamber of the eye at the trabecular meshwork. Moreover, experiments have been undertaken to apply the laser pulses of an Nd:Yag laser through a contact glass at the opposite chamber corner region, without opening the eye. Alternately, ab interno sclerostomies also have been performed experimentally with pulsed dye lasers or argon lasers through a contact glass. Also in these methods it is difficult to control the depth of penetration of the laser pulses. Many experimenters are attempting a breakthrough effect through the adjacent sclera in order to open the subjunctival chamber (region directly under the pupil conjunctiva) and facilitate direct drainage in this region. Due to the scarring reactions these techniques have been unable to achieve any progress beyond a series of clinical experiments.
In the case of the known laser sclerostomy ab externo, a fistula for aqueous humor drainage under the conjunctiva has been created, in which after the ocular conjunctiva has been opened, the entire thickness of the sclera is penetrated. In this process an extensive defect is produced in the sclera. Any lasting resorption of the intraocular fluid requires that the access must not scar, but in this process it is a typical complication, the same as in the conventional operations performed manually. In contrast to the conventional surgical methods, however, the iris is not also partially removed (iridectomy) during laser sclerostomy, so that another possibility of complication is that the fistula may be closed by pulling in the iris. Attempts are often made to control the scarring from overshooting in the area of the conjunctiva through supplemental medication by antimetabolites, such as Mitomycin C or 5-fluorouracil. A serious disadvantage here is the toxicity of the substances used.
All of the experimentally tested medical devices and methods that are presently in clinical use have in common that they do not selectively achieve an improvement of the intraocular fluid drainage at the intraocular structures which are the locus of the main resistance in the system of drainage from the anterior chamber of the eye. In the known methods the laser pulse is aimed through the anterior chamber at the opposite tissue areas. In the known methods the first effects take place in the area of the trabecular meshwork, and the effects that likewise occur in the deeper structures cannot be evaluated.
SUMMARY OF THE INVENTION
It is the object of the invention to provide a medical apparatus which avoids the above disadvantage and which will be small and compact and yet be simple to operate.
Another object of the invention is to provide a medical apparatus which is to be used mainly in microsurgery and/or in ocular medicine.
It is also an object of the invention to provide a medical apparatus which can reduce the resistance to the drainage of the aqueous humor within the eye precisely at those structures which are responsible for the main component of the resistance to such drainage, while other ocular tissue components are protected.
These and other objects are achieved in accordance with the present invention by providing a medical apparatus for reducing intraocular pressure by acting upon the Schlemm's canal and the tissue of the trabecular network directly in contact with the Schlemm's canal, the apparatus comprising a probe comprising a photoconductor connectable to a laser, the photoconductor being provided with a surface coating having at least one emission window therein, and the at least one emission window being disposed in a curved or bendable section of the photoconductor.
The apparatus of the invention is characterized by a functional design and compact construction. It is suitable for use in microsurgery for the removal or alteration of tissues, and especially in ocular medicine for the reduction of intraocular pressure. In contrast to the known laser surgery equipment, the apparatus of the invention makes it possible to remove tissues in a sequence contrary to the direction of the drainage of a tissue fluid. Thus, by means of the apparatus of the invention, it is possible to perform a laser trabeculotomy of the Schlemm's canal (SKLT) with the aim of reducing resistance to intraocular drainage precisely at those structures which are responsible for the main component of such resistance. All other tissue components are to be spared insofar as possible. The medical apparatus enables intraocular pressure to be lowered by acting on the Schlemm's canal, and/or on the tissue directly deposited in the Schlemm's canal, by means of the photoconductor probe which has an arcuate and/or flexible section. By means of the apparatus of the invention, it is possible to produce pores in the tissue, especially in the trabecular meshwork, without detriment to adjacent tissue structures. This is quite generally the object in microsurgery and tissue manipulation.
In ophthalmology what is special in the method practiced according to the invention is seen in the fact that, in contrast to the laser surgery equipment which has long been tried and tested to date, the order in which the tissues are removed is contrary to the direction of flow of the aqueous humor. The aqueous humor leaves the eye by passing out of the anterior chamber through the trabecular meshwork and entering the Schlemm's canal through the inner wall of the latter, and, passing from there, it leaves the eye through the aqueous humor veins. In this identical order the tissue ablation is brought about by minimally invasive ab interno laser surgery techniques that have heretofore been tested. However, the depth of penetration is only poorly controlled, and an opening in the outer wall of the Schlemm's canal cannot be reliably assured. This has even been brought about deliberately by a number of working groups and the adjacent sclera has additionally been penetrated in order to achieve an additional drainage of aqueous humor. Laser trabeculotomy of the Schlemm's canal, on the other hand, has the purpose of leaving the Schlemm's canal as intact as possible, and to create only pores in the inner wall which is adjacent to the anterior chamber of the eye and is separated from it only by the trabecular meshwork. The structures to be treated in Schlemm canal laser trabeculotomy are the inner wall of the Schlemm's canal (the margin of the Schlemm's canal facing the anterior chamber) and the tissue of the juxtacanalicular (i.e., directly attached to the Schlemm's canal) trabecular meshwork. The laser treatment of the Schlemm's canal according to the invention is a combination of the known laser-induced tissue ablation from the area of the trabecular meshwork by the surgical access according to Harms and Mackensen.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described in further detail hereinafter with reference to illustrative preferred embodiments depicted in the accompanying drawings without limiting its scope. In the drawings:
FIG. 1 shows a first embodiment of the configuration of such an apparatus;
FIG. 2 shows an additional embodiment of the apparatus of FIG. 1;
FIG. 3 shows an apparatus with a photoconductor configured as a nearly closed circle; and
FIG. 4 shows a configuration of the embodiment depicted in FIG. 3.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
With the apparatus according to the invention, after the surgical preparation of the access to the Schlemm's canal, instead of the conventional surgical trabeculotomy probe, with which only an imprecise and largely uncontrolled tearing open of the fabric structures can be performed, a flexible photoconductor which comprises an elastic and/or plastic material is introduced into the Schlemm's canal. The Schlemm's canal is an annular structure; the circular diameter of the Schlemm's canal is slightly greater than the thickness of the cornea of the particular patient being treated. For insertion into the Schlemm's canal of eyes having a horizontal corneal diameter of 10 to 12 mm, the photoconductor probe 12 is flexible toward the inside curve 13. The maximum probe diameter is about 400 μm, preferably 320 μm, so as to be able to be inserted atraumatically into a normal Schlemm's canal. Since a few eyes have a Schlemm's canal diameter of only 200 μm, smaller photoconductor diameters may also come into use. In the embodiment shown in FIGS. 1 and 2, the photoconductor 12 extends over an arc of about 90° to 120° to the right and left for insertion from the right or left into the Schlemm's canal. The curvature or bending radius is on the order of a few millimeters and is especially greater than 4 mm, preferably greater than 5 mm; the said radius amounts to a maximum of 7 mm, preferably 6 mm. The photoconductor's tip 2 is rounded according to the invention.
The probe has a surface coating 3 which provides for the exit of the laser beam at an emission window 4 (FIG. 1) near the tip 2 of the probe, or at a plurality of emission windows 4 to 6 (FIG. 2), at an angle of 90° toward the inside curve 13 of the flexible photoconductor 12. A color coating absorbing the corresponding wavelength, or a mirror coating or other kinds of shielding, e.g.,made of carbon material or plastic, is used as the surface coating 3. The arcuate section of the photoconductor 12 adjoins a handle 14 in which the photoconductor 12 is embedded. The handle 14 can also extend out from the curvature defined by the probe at an angle of about 90°. The photoconductor has a laser terminal 15. According to the invention, at its end forming the probe, the photoconductor is made at least partially flexible and is provided with the surface coating 3 that is impermeable to light or laser beams. This surface coating 3 has at least one emission window through which the light or laser beams can issue laterally from the photoconductor. The photoconductor connected to the laser can be elastically and/or plastically shaped to an arcuate section. Even if the flexible and/or bendable and/or bent section of the section provided with the surface coating forms approximately an arc, still other curve shapes can be achieved, such as a parabola, ellipse or the like, can be defined or achieved in order to provide optimum conditions for a particular use of the medical apparatus of the invention. Independently of the particular concrete configuration of the bend, the at least one emission window lies preferably near the inside of the said section. According to the invention, the flexible and/or bendable and/or bent section is adjoined by the handle 14 through which the photoconductor 12 extends. The other end of the photoconductor 12 is connected to the above-mentioned laser terminal. The tip 2 is preferably provided with the surface coating essential to the invention, so that no laser light can issue lengthwise from the photoconductor.
This probe can be connected to a conventional commercial Er:Yag laser. At an energy of 4 mJ, it is possible with a pulse duration of 100 microseconds, 150 microseconds and 250 microseconds to produce tissue ablations in the trabecular meshwork with pore sizes of approximately 100 μm, 120 μm and 200 μm, respectively. The thermal effects in the margins of the pores are of a magnitude of up to 10 μm, 20 μm and as much as 60 μm. To achieve a number of pores within the inner wall of the Schlemm's canal, the probe 12 is inserted into the canal.
In the embodiments shown in FIGS. 3 and 4, the photoconductor 1 is in a virtually full circular form and can thus cover the entire Schlemm's canal. According to FIG. 3, an emission window 4 is located near the tip 2 of the probe.
In addition to the single laser beam emission window 4 near the tip of the photoconductor 2, a plurality of emission windows 5 to 11 can be opened simultaneously on the inner radius of the photoconductor (FIG. 4), at an angular spacing of, for example, 100°, 60° or 40°, for three, five or eight simultaneous laser pulses, for example.
A holmium laser or an Nd:YLF picosecond laser system can be used as the laser source. When an Nd:YLF laser system is used, the energy required for tissue ablation can be further reduced. It is possible to use a two-stage system which consists of a diode-pumped actively modem-coupled oscillator and a regenerative amplifier. The pulses produced in the oscillator at a wavelength of 1053 nm have a duration of about 25 ps at a pulse energy of 0.2 nJ. These pulses are coupled into the regenerative amplifier through a polarization circuit and amplified therein up to a pulse energy of 1.5 mJ. At pulse durations of about 30 ps the process of tissue ablation begins at energy densities of 20 J/cm 2 . These low energies permit a virtually local tissue removal with minimal damaging effect on surrounding structures.
Furthermore, it is readily possible to use a commercially available diode laser system in connection with the described method and apparatus, especially when a coagulation effect is desired due to special anatomical circumstances. The term for this variant of SKLT is laser trabeculocoagulation of the Schlemm's canal.
The tissue ablation takes place contrary to the direction of the aqueous humor drainage. This assures that only the regions of the greatest resistance in the aqueous humor drainage system are treated.
The method of laser trabeculotomy of the Schlemm's canal has been designed with the following criteria:
The introduction of the photoconducting fiber into the Schlemm's canal achieves the following principal effects:
(1) The tissue-removing laser beam is aimed directly against the inner wall of the Schlemm's canal and thus is in the immediate vicinity of the structure to be treated. It is assured that the inner wall of the Schlemm's canal is treated and also the adjacent (juxtacanalicular) trabecular meshwork can be operated on by laser surgery.
(2) The outside radius of the photoconductor extends along the outer wall of the Schlemm's canal, and this wall structure is thus simultaneously protected mechanically against undesired effects.
This procedure makes it possible to produce pores in the trabecular meshwork without damage to adjacent structures.
In contrast to the method described herein, it has been common practice heretofore to aim the laser pulse through the anterior chamber against tissue areas lying opposite. In the previously known methods, the first effects are produced in the area of the trabecular meshwork, and the effects that also occur in deeper structures cannot be estimated.
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed to include everything within the scope of the appended claims and equivalents thereof. | A medical apparatus especially for lowering intraocular pressure by acting on the Schlemm's canal and on the tissue of the trabecular meshwork directly in contact with the Schlemm's canal, including a probe containing a photoconductor which is curved or elastically or plastically deformable to a curved configuration and which is connected to a laser, the photoconductor having a surface coating having at least one emission window therein facing the inner curvature of the photoconductor, the emission window permitting a laser beam to issue from the photoconductor at an angle of 90° to the curvature of the photoconductor. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to respirators with particular reference to air-filtering cartridges for protection against aerosols.
2. Discussion of the Prior Art
Prior art respirator cartridges designed for protection against aerosols such as lead fumes notably rapidly load with the aerosol materials and correspondingly increase their resistance to inhalation, i.e. airflow. Furthermore, in order to meet current industrial standards for initial and final airflow resistance and penetration of aerosol contaminants with the heretofor cartridge design parameters, the cost of materials and their assembly has become excessive particularly with the reflection of short service life due to rapid aerosol loading.
It is, accordingly, a principal object of this invention to lower the production cost of air-filtering respirator cartridges which are designed for protection against aerosols and to improve the operational efficiency of such devices.
Another object is to accomplish the foregoing by providing for distribution of aerosol loading over greater surface area of cartridge filter material with less than the usual number and size of cartridge components; and
still another object is to accomplish a reduction in respirator cartridge production cost by simplification of assembly procedure.
Other objects and advantages of the invention will become apparent from the following description.
SUMMARY OF THE INVENTION
The foregoing objects and corollaries thereof are accomplished by provision of a respirator cartridge which is designed to eliminate the traditional screen between the perforated cartridge bottom and its adjacent filter component, substitute fiberglass for one of the usual two wool-felt components and minimize filter component-to-shell cementing operations along with reshaping of the initial aerosol contacting filter component for effecting greater than usual distribution of aerosol loading and lower inhalation resistance.
These and other details of the invention will become more readily apparent from the following description when taken in conjunction with the accompanying drawings.
IN THE DRAWINGS
FIG. 1 is an illustration in cross-section of a preferred embodiment of the invention;
FIG. 2 is a cross-sectional view of a typical prior art aerosol filter cartridge.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the drawings, the structural distinctiveness of the present invention over the prior art is illustrated with FIGS. 1 and 2 wherewith the present respirator cartridge 10 (FIG. 1), when compared with prior art cartridge 10a (FIG. 2), can be seen to embody less components and an unusual prefilter design.
With respect to the former, the present arrangement and design of prefilter components 12, 14 16 and final filter 18 permits elimination of the prior art fine mesh screen 20 (FIG. 2) and substitution of less expensive and lighter weight glass fiber material for one of the heretofor dual wool-felt filters 18a (FIG. 2).
In connection with the present prefilter design, its domed triple component array provides for greater than usual distribution of aerosol loading and a correspondingly lower resistance to inhalation, i.e. airflow.
Details of the present cartridge construction are as follows:
Cartridge 10 (FIG. 1) comprises the usual shell 22 of stamped, drawn or otherwise formed sheet metal, e.g. aluminum, with cover 24 crimped in place after the positioning of filters 14, 16 and 18 in shell 22. Bottom 26 of shell 22 and top 28 of cover 24 are perforated to permit inhalation of air in the direction of arrows 30 through cartridge 10. The threaded portion 32 of shell 22 is used to conventionally secure cartridge 10 in a respirator face mask (not shown) so that top 28 of cover 24 is exposed to the particular environment against which respiratory protection is sought, e.g. an aerosol. Perforated bottom 26 of shell 22 is, accordingly, disposed internally of the respirator facepiece to provide the user with a source of filtered air for breathing.
It is to be understood that shell 22 and cover 24 may be formed of plastic or other compositions of materials which may be cast, molded or pressed to final shape.
Referring more particularly to the construction and arrangement of filters 12, 14, 16 and 18, final filter 18 of wool/acrylic felt is preferably secured in place with cement 34 while the relatively low density (e.g. non woven glass fiber) prefilter assembly of components 12, 14 and 16 is pressed into shell 22 tightly against the shell inner wall. Filter, components 14 and 16 are formed to a somewhat larger diametral size than the internal diameter of shell 22 and become partially radially compressed when urged into shell 22 against final filter 18. Cement may also be used but is deemed unnecessary since the forces of inhalation which are in the direction of arrows 30 prevent displacement.
Filter 12 which is preferably cemented, stapled or otherwise attached to filter 14 domes the prefilter assembly with its edge 36 as well as face 38 exposed to incoming atmospheres, e.g. air containing an aerosol, for greater than usual surface distribution of aerosol loading.
Tests of performance of the present respirator cartridge (FIG. 1) and that of the prior art (FIG. 2) were conducted as follows with test times and conditions being identical for both structures:
Testing Atmosphere
Lead fume aerosol at a concentration of from 15 to 20 milligrams/cubic meter.
Temperature
78°-83° F.
Relative Humidity
30 to 40%
Test Flow Rate
16 liters/minute
Results
(1) The present cartridge construction (FIG. 1) showed an initial resistance to airflow of from 12 to 13 mm H 2 O and a final resistance to airflow of from 35 to 44 mm H 2 O.
(2) The prior art construction (FIG. 2) showed an initial resistance to airflow of from 16 to 17.5 mm H 2 O and a final resistance of from 47 to 66 mm H 2 O.
Neither the prior art construction (FIG. 2) nor that of the present invention (FIG. 1) exceeded a current standard for lead penetration which is set to be less than 1.5 Mg. Both cartridges remained considerably below this 1.5 Mg maximum.
From the foregoing, it can be seen that with greater than usual economy and simplification of aerosol respirator cartridge construction, the present invention contributes lowering of initial and final inhalation (airflow) resistance with high operating efficiency.
Various modifications and adaptations of the precise form of the invention described hereinabove may be made to suit particular requirements. For example, filters 12, 14 and 16 may be formed of a single unit of resin bonded non-woven glass fibers. Accordingly, it is intended that all modifications which incorporate the novel concept disclosed are to be construed as coming within the scope of the claims or the range of equivalency to which they are entitled in view of the prior art. | Lower inhalation resistance in respirator cartridges designed for protection against aerosols is accomplished with lower production cost and improved design distributing aerosol loading over greater surface area of filter material. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit of priority from Danish patent application No. PA 2000 01373 filed on Sep. 15, 2000.
BACKGROUND OF THE INVENTION.
The present invention relates to an apparatus for and a method of automatically separating at least one organ from a set of organs eviscerated from a carcass, which set of organs comprises a diaphragm and one or more organs.
EP-A-0 587 253 describes a method of separating one or more organs from a cluster of organs from a slaughtered animal, particularly a bird. According to this publication connective tissue can be broken by suspending a strong organ, such as a gullet, from a fixing device and influencing an organ in the cluster by a force in a direction away from the point of suspension. In one embodiment, two bend rods are closed around the gullet, and the fixing device is lifted, whereby the organs connected with the gullet are stripped off. In another embodiment, the suspended cluster is conveyed by a conveyor, parts of the cluster are passed between some rods and plates, and as these rods and plates diverge from the conveyor path, organs in the cluster are pulled away from other parts of the cluster during the conveyance.
It should be noted that the present invention relates to separation of organs in a set of organs comprising a diaphragm, and that birds, to which the above publication EP-A-0 587 253 relates, have no diaphragm. The invention is thus aimed particularly at sets of organs from carcasses of mammals, such as pigs, sheep, goats and cattle.
BRIEF SUMMARY OF THE INVENTION
The object of the invention is to provide an apparatus and a method of the type mentioned in the introduction, which render it possible to provide separated organs of good quality, that is, where the organs are whole and substantially free of other parts of the set of organs.
It is a particular object to provide separation of liver and/or kidneys from a set of organs containing these organs, whereby organs are obtained that require substantially no post-treatment, but can be used as they are.
It is a further object to provide an apparatus and a method that can utilize the conveyance of a set of organs of a pluck conveyor system in the slaughterhouse.
This is obtained by an apparatus which is characterized in comprising a running conveyor with hooks for suspending the set of organs by the diaphragm and conveying it in a conveying direction of the conveyor, a slit device arranged below the conveyor with a slit for guiding horizontally in the slit a connective tissue part of the set of organs during the conveyance of the set of organs on the conveyor with the said at least one organ located below the slit, a retaining device arranged in a conveying path which the said at least one organ follows with the connective tissue part guided by the slit, the retaining device being adapted to retain said at least one organ on the retaining device by means of the conveyor's pull in the set of organs, and means for causing separation of the said at least one organ and the connective tissue part when such retention has been provided.
The invention applies the fact that the organ is guided towards the retaining device and is here made to be retained by the conveyor's conveyance of the set of organs, whereupon a suitable separation of the organ can be made which keeps the organ intact while taking place in an area close to the organ. This more surely provides separation at the desired place in the set of organs.
In one embodiment, the slit device and the retaining device together comprise two portions which, between adjacent edges, define the slit for the connective tissue part with an inlet at an upstream end of the slit in relation to the conveying direction of the conveyor, this slit having a first section extending along the conveyor and a second section with retention surfaces on either side of the slit, which retention surfaces extend downwards in relation to the conveying direction of the conveyor so that the said at least one organ is retained on the retention surfaces by means of the conveyor's pull in the set of organs. This embodiment is suitable for pulling a liver off the diaphragm. Owing to the inclination of the retention surfaces in relation to the conveying direction of the conveyor, the liver will not, when it reaches the retention surfaces, let itself be pulled further in the longitudinal direction of the slit by the conveyor's pull in the diaphragm, so the diaphragm is gradually pulled free of the liver which remains at rest in relation to the retention surfaces until the diaphragm has been pulled free, whereupon the liver can fall down into a collection place.
In a second embodiment, the retaining device comprises a pair of curved surface parts which between them form a slit for the connective tissue part and are arranged in the conveying path of the said one organ, which surface parts form a cavity facing the said organ. In that connection a cutting device may also be provided behind the retaining device for cutting a connection between the connective tissue part and the said at least one organ. This embodiment is suitable for separating one kidney or two kidneys from the set of organs, the kidney or kidneys being retained securely while the connection to the connective tissue part, the so-called renal fat, is cut.
Other advantageous embodiments appear from the dependent apparatus claims.
The object is further obtained by a method which is characterized by the steps: the set of organs is suspended by the diaphragm in a running conveyor with hooks and conveyed in a conveying direction of the conveyor, a connective tissue part of the set of organs is guided horizontally in a slit in a slit device arranged below the conveyor during the conveyance of the set of organs on the conveyor with the said at least one organ located below the slit, the said at least one organ is retained on a retaining device arranged in a conveying path which the at least one organ follows with the connective tissue part being guided by the slit, the organ being retained on the retaining device by means of the conveyor's pull in the set of organs, and a separation is caused between the said at least one organ and the connective tissue part when the said retention has been provided. Advantageous embodiments appear from the dependent method claims.
In one embodiment, which is suitable for separation of a liver from the diaphragm, the connective tissue part is guided into an inlet of the slit which is located upstream in relation to the conveying direction of the conveyor and is found between adjacent edges of two portions comprised by the slit device and the holding device together, this slit having a first section extending along the conveyor and a second section with retention surfaces on either side of the slit, and the said at least one organ is retained on the retention surfaces by means of the conveyor's pull in the set of organs, these surfaces extending downwards in relation to the conveying direction of the conveyor.
In an embodiment suitable for separating one kidney or two kidneys from the set of organs, the at least one organ is guided into a cavity formed by a pair of curved surface parts comprised by the retaining device, the surface parts between them forming a slit for the connective tissue part and being arranged in the conveying path for the said one organ. The separation is then preferably provided by means of a cutting device behind the retaining device, the cutting device cutting a connection between the connective tissue part and the said at least one organ.
Other advantageous embodiments appear from the dependent method claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
Further advantages of the invention will appear from the following, in which preferred embodiments will be described in further detail as non-limiting examples with reference to the very scematical drawing.
In the drawing:
FIG. 1 shows a perspective view of an installation with two different apparatus according to the invention;
FIG. 2 shows a side view of the first apparatus of FIG. 1;
FIG. 3 shows a side view of the second apparatus of FIG. 1;
FIG. 4 shows a detail of the apparatus of FIG. 3 seen in the direction of the arrow IV,
FIG. 5 shows a detail of the apparatus of FIG. 3 seen in the direction of the arrow V, and
FIG. 6 shows a detail of a hook suspension.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a hollow rail 1 receiving a running chain of a conveyor system with a conveying direction 2 . A hook 4 is suspended from a bracket plate 3 , which extends from a chain link and out through a slot in the rail, and a set of organs 5 eviscerated from a carcass is suspended from the hook 4 . The set of organs 5 comprises a diaphragm 6 , through which the hook 4 has been thrust, a liver 7 and two kidneys 8 . The kidneys 8 are connected with the diaphragm 6 by a connective tissue part called renal fat 9 . This includes blood vessels and the ureter enclosed by a layer of fat.
The installation of FIG. 1 comprises a first apparatus 10 for separating the kidneys 8 from the set of organs 5 and a second apparatus 11 for separating the liver 7 from the diaphragm 6 .
The apparatus 10 comprises a set of inclined plates 12 defining a slit 13 between them by adjacent edges for receiving the renal fat 9 for guiding the latter horizontally, as will be explained in further detail below.
Furthermore, the apparatus 10 comprises a retaining device with a pair of curved plate parts constituted by a plate 14 formed in one piece and having a slit 15 . The plate 14 has a substantially cylindrical portion which forms a cavity 16 facing against the conveying direction 2 . The plate 14 is mounted on arms 18 pivotable about a horizontal axis 17 .
In a starting position shown in FIG. 2 by solid lines, the arms 18 of the retaining device are in frictional engagement with a resilient bracket plate 19 extending some distance in the downstream direction. There is a sensor 20 adapted to record when the arms 18 leave the starting position. Furthermore a pneumatic cylinder 21 is provided for returning the arms 18 to their starting position.
An oscillating knife 22 is mounted pivotably at the cylindrical portion of the plate 14 . The knife 22 is driven by a motor 23 and by pivoting can be passed closely along the external side of the cylindrical portion of the plate 14 while oscillating in a direction parallel with the axis of rotation.
Downstream of the cylindrical portion of the plate 14 there is a gripping member in the form of two jaws 24 , only one of which is visible in FIG. 2, the other being hidden behind the first one. The two jaws 24 can be moved towards and away from each other by the aid of means, not shown, such as a pneumatic cylinder.
At the inlet to the slit 13 , the plates 12 are cut off obliquely so as to form a funnel-shaped inlet. The inlet is partially filled out by a pointed end of a guide rail 25 in the form of an angularly bent strip of steel plate with an upward longitudinal ridge 26 .
Upstream of the guide rail 25 there is an oscillating rail 27 performing a wriggling motion 28 by means of a motor 29 in its assembly.
Downstream of the plates 12 there is another pair of plates 30 forming an extension of the slit 13 . Below this extension there is a second oscillating knife 31 , driven by means of a motor 32 in an oscillating motion transversely to the slit 13 and its extension.
The first apparatus 10 functions as follows:
The set of organs 5 is conveyed in the conveying direction 2 and reaches the oscillating rail 27 , which imparts a sideways motion to the set of organs 5 . The set of organs 5 is conveyed onwards along the guide rail 25 . At the end thereof, the renal fat 9 slides into the inlet of the slit 13 , while the liver 7 slides up along the inclined plates 12 . The sideways motion facilitates the entry into the slit 13 of the renal fat 9 , as the motion facilitates a positioning of the renal fat 9 relative to the liver 7 ensuring that the liver 7 is not between the renal fat 9 and the inlet.
The distance between the hook 4 and the apparatus 10 is adapted so that the kidneys 8 pass below the plates 12 and into the cavity 16 in the retaining device, the renal fat 9 sliding into the slit 15 located below the slit 13 . Since the kidneys 8 cannot pass the slit 15 , they are caught in the cavity 16 .
The further conveyance of the hook 4 causes the renal fat 9 to be stretched out and to pull the retaining device forwards, the arms 18 pivoting about the axis 17 . The first part of this pivotal motion occurs at a substantially constant tractive force in the renal fat 9 owing to the friction between the arm 18 and the resilient bracket plate 19 .
The motion of the arm 18 is recorded by the sensor 20 , which transmits a signal to control means, not shown, which again actuate the jaws 24 , which clamp around the renal fat 9 and retain it, and the oscillating knife 22 which oscillates while being pivoted along the cylindrical portion of the plate 14 thereby cuts the renal fat near the kidneys 8 , which then lie free in the cavity 16 .
While the kidneys 8 are being cut free, the arms 18 and together with them the retaining device tilt forwards due to gravity after the arm 18 is released from the frictional engagement with the resilient bracket plate 19 , The retaining device reaches the position shown in dashed lines, and the upper end of the renal fat 9 is swung towards the second oscillating knife 31 , which cuts the renal fat 9 near its connection to the diaphragm 6 .
The jaws 24 now separate and let the renal fat 9 cut free drop down on a renal fat conveyor or into a renal fat collection box 33 . The cylinder 21 , so far non-pressurized, is now actuated to bring the arms 18 and the retaining device back to the starting position. This alters the inclination of the plate 14 , and the kidneys 8 fall out of the cavity 16 and down on a kidney conveyor or into a kidney collection box 34 .
The set of organs 5 , now only comprising the diaphragm 6 and the liver 7 , continues to the second apparatus 11 .
The second apparatus comprises two bend rods 40 extending in parallel and between them defining a slit 41 . The bend rods 40 and thus the slit 41 have a first portion 42 extending horizontally and a second portion 43 extending obliquely downwards. Furthest upstream the bend rods 40 diverge in the direction opposite to the conveying direction 2 to provide an inlet 44 . One bend rod is fixed while the other can be moved away from and towards the first bend rod by means of a pneumatic cylinder 45 .
Under the bend rods 40 is a tray 46 that can be tilted by the aid of means, not shown, as will be explained below.
Downstream of the bend rods 40 there is a device for gripping the diaphragm 6 and pulling it forwards in cooperation with the hook 4 . This device comprises a carriage 47 with guide fins 48 which slide in guideways in guide rails 49 . The carriage comprises a U-shaped frame part 50 at its front end and a second, inclined, U-shaped frame part 51 at its back end. The latter frame part 51 carries two jaws 52 , 53 , the first jaw 52 of which is fixed, while the other jaw 53 can be moved towards the first jaw 52 by means of a pneumatic cylinder 54 to grip the diaphragm 6 , as will be explained below.
FIG. 4 shows how the bracket plate 3 is fastened to a chain link 55 of the chain running in the rail 1 . The bracket plate 3 has a keyhole-shaped hole 56 in which a pin 57 of the hook 4 provided with a recess 58 has been received in order to connect the hook 4 pivotably with the bracket plate 3 . Opposite the pin 57 , the hook 4 has a longer pin 59 acting as a guide and indicator, as will be explained below. On an upright pin, the pin 59 carries an indicator disc 60 shaped like a quarter of a circle and being pivotable about a vertical axis 61 between two positions, one of which is shown in FIG. 6 while in its other position the disc 60 is pivoted by 90° counterclockwise in relation to the Figure.
Along the rail 1 there are two further rails 62 and 63 . The top one thereof, the rail 62 , carries two inductive sensors 64 and 65 , whose function will be described below. The lower rail of the two, the rail 63 , is adapted to engage with the long pin 59 of the hook 4 to ensure that this pin 59 passes close by the sensors 64 and 65 .
The carriage 47 carries a pawl 66 which is pivotable about a vertical axis 67 to get into or out of engagement with the bracket plate 3 , as will be explained below.
The second apparatus 11 functions as follows:
After the set of organs 5 has passed the first apparatus 10 , the diaphragm 6 is passed into the inlet 44 of the slit 41 between the two bend rods 40 and onwards into the actual slit 41 , the liver 7 being passed underneath the first portion 42 of the bend rods 40 . As the liver 7 reaches the second portion 43 , it will be retained, and owing to the inclination of the second portion 43 of the bend rods 40 , the liver 7 will be retained and not slide along the second portion 43 , while the diaphragm 6 is stretched owing to the pull from the hook 4 .
At this time the long pin 59 has slid in over the rail 63 and has reached the sensor 64 , which detects the arrival of the pin 59 . This makes the sensor 64 transmit a signal which actuates the cylinder 54 and makes the jaws 52 and 53 grip and retain the diaphragm 6 , as well as makes a power means, not shown, swing the pawl 66 into engagement with the bracket plate 3 as shown in FIG. 4 . The latter causes the carriage 47 to follow the motion of the conveyor and, by means of the grip on the diaphragm 6 by the jaws 52 and 53 , to contribute to pulling the diaphragm 6 free of the liver 7 . The liver 7 then falls down on the tray 46 .
When the carriage 47 has moved a specified distance together with the conveyor, the pawl 66 is swung out of engagement with the bracket plate 3 , and the carriage reaches a stop, not shown. The further conveyance of the hook 4 causes it to be torn out of the diaphragm 6 . When the hook 4 is free of the diaphragm 6 , the jaws 52 and 53 open, and the diaphragm falls down into a diaphragm collection box 68 or on to a diaphragm conveyor. Then a power means, not shown, returns the carriage 47 to its starting position.
Before the set of organs 5 reaches the apparatus 10 , an operator has examined the quality of the liver 7 and set the indicator disc 60 in one of its two positions mentioned, one position indicating that the liver is flawless, the other position indicating that it is not flawless, but has spots, for example. The sensor 65 senses whether the indicator disc 60 is in one position shown in FIG. 6 or is not, as is the case in FIG. 4, and accordingly transmits a signal causing the tray 46 to tilt to one or the other side after having received the liver 7 , for example when the carriage 47 is returned to its starting position. Thus, a flawless liver 7 will fall into a liver collection box 69 or on to a liver conveyor, and a flawed liver 7 will drop down into another liver collection box 70 or on to another liver conveyor.
Finally, the bend rods 40 are moved away from each other and back again to release parts of the set of organs 5 that may have remained hanging there owing to faulty function. The tray is tilted to let such parts fall down into the second liver collection box 70 .
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. | The apparatus comprises: a running conveyor ( 1 ) with hooks ( 2 ) for suspending a set ( 5 ) of organs by the diaphragm ( 6 ) and conveying it in a conveying direction of the conveyor ( 1 ); a slit device ( 10; 11 ) arranged below the conveyor ( 1 ) with a slit ( 13; 44 ) for guiding horizontally in the slit a connective tissue part ( 9; 6 ) of the set ( 5 ) of organs during the conveyance of the set of organs on the conveyor with an organ ( 8; 7 ) located below the slit ( 13; 44 ), a retaining device ( 14-16; 40 ) arranged in a conveying path which the organ ( 8; 7 ) follows with the connective tissue part ( 9; 6 ) guided by the slit ( 13; 44 ), the retaining device ( 14-16; 40 ) being adapted to retain the organ ( 8; 7 ) on the retaining device by the conveyor's ( 1 ) pull in the set ( 5 ) of organs; and ( 22, 23; 49-51, 54 ) for causing separation between the organ ( 8; 7 ) and the connective tissue part ( 9; 6 ) when such retention has been provided. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to a process for desulfurization of ores, particularly coal, that is continuous and which recovers a high grade sulfur crystal.
A primary use of the process is for production of a sulfurless coal powder than can be fired in powder form, or further processed into briquettes by conventional means. The crystaline sulfur is suitable for general sulfur products or in continuous steps may be melted and cast into construction blocks. This process is adaptable to other ores for recovery of tungsten, cinabar, etc. which are relatively high in sulfur content.
The critical need and dependence on fossil fuels, particularly oil, has caused a reevaluation of fuel use priorities. It is requisite to examine the specific type of fuel to be consumed in each instance. Because oil and its refined products are a convenient source of power for vehicles, it is desirable to reserve the limited oil resources to such uses if it is to be used as a power source. Ideally oil should not be consumed as a power source but reserved for lubricants and other by-products such as solvents and plastics.
Natural gas similarly should not be used either as a power source or for heating. Because of its particularly clean burning, natural gas should be reserved for open flame uses such as cooking and other clean combustion applications.
Stationary power sources are ideally suited for burning of coal which is available in abundance in certain geographical areas and particularly throughout North America. However, much of the available coal is contaminated with sulfur, which generates a noxious pollutant when the coal is combusted. Expensive pollution control devices installed to wash the combustion gases are only partially successful in removing sulfur, sulfur compounds and oxidants before releasing such combustion gases to the atmosphere. Consequently, much of the coal mined that is not of low sulfur content or is otherwise highly contaminated with impurities is simply left in gob piles.
Ideally, the sulfur contaminant should be removed prior to combustion. Past processes are of limited efficiency and contribute excessively to the cost of coal as a common fuel.
The process devised is economical and is operable as a continuous rather than batch method. Furthermore, the process recovers and recycles the solvent used to separate sulfur from the ore maintaining solvent losses at a minimum. The large quantities of sulfur recovered are usable in a coupled process stage to produce building blocks at a cost competitive with similar concrete blocks. The process is particularly applicable to gob pile coal that has been abandoned and exists in huge quantities. Other features of this process are described in greater detail in the detailed description of the preferred embodiment hereinafter.
SUMMARY OF THE INVENTION
The desulfurization process of this invention is a continuous process for desulfurizing ores, particularly coal. The process recovers a high grade sulfur and extracts other solids which may be further refined for recovery of precious metals or by-products that are economically justifiable to recover. When used for desulfurization of coal, the principal application which is described herein in detail as an example of the process, the coal is refined to a high grade coal powder suitable for modern powder handling techniques which approximate the advantages of liquid handling.
The process begins by crushing the ore, a sulfur bearing coal ore in the preferred use, to approximately a 28 mesh size. The crushed ore is mixed with a solvent, preferably perchlorethylene, forming a solvent liquor in which the sulfur dissolves in solution. The solvent liquor is centrifuged separating the sulfur and solvent solution from the coal slurry in a continuous process centrifuging drum. A second centrifuging drum separates the lighter weight coal particles from the heavier earth tailings or sedimentary-type residuals in a continuous process.
It has been discovered that such residuals or tailings include a surprisingly high amount or rare metals, typical samples including close to one ounce of platinum, over a tenth of an ounce of gold and substantial traces of silver for each ton of coal ore. These elements can be profitably removed from the residual tailings by conventional refining. The separated coal is dried in a solvent recovery process and readied for use, shipment or further processing into briquettes.
The sulfur liquor, contaminated with a microparticle ash suspension is filtered to remove the ash. The sulfur in solution is crystalized by cooling and centrifugally separated from the solvent. The sulfur is dried and the remaining solvent recovered. The resultant sulfur is suitable for marketing or at this stage heated to a higher melting temperature and the liquid sulfur cast for building materials. All of the solvent from the separating and drying processes, less minimal losses, is recycled in the process. The desulfurization process is so effective that less than 0.01 percent sulfur remains in the final coal product after drying.
This process is designed to utilize standardized equipment in the various stages which can be shifted or stage rotated to maximize a uniformity of wear. The process is able to capitalize on gravity to convey materials and liquids from one stage to another wherever possible.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic illustration of the process.
FIG. 2 is a block diagram summary of the process.
FIG. 3 is a perspective view of a processor.
FIG. 4 is a perspective view of interlocked construction block.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to the schematic illustration of FIG. 1, the desulfurization process can be described with relation to the various circuits that make up the process when used for production of sulfur and the refining of coal for generating a coal product that is virtually sulfur-free.
The coal ore, high in impurities in bulk form is delivered by conventional handling equipment, for illustration, a dump truck 10 and front end loader 12, to an initial crushing station 14 which receives batch quantities of ore 16 in a jaw crusher 18 and by a feeder mechanism delivers aggregate size coal ore 22 in a continuous flow to a belt conveyer 24. The belt conveyer feeds the crushed coal ore 22 to a roll crusher 26 which reduces the aggregate size ore to a powder 28 of approximately 28 mesh size. A belt conveyer 30 transports the powder 28 to one or more heated mixer processors 32 into which a heated solvent is introduced. The mixer processor employed throughout this process must be continuous in nature and in certain cases must be capable of collecting products of evaporation where the processors function as dryers.
While not specifically required, certain processors manufactured under the trademark Holo-Flite by Joy Manufacturing Company are suitable for multiple processing functions involved herein. These processors, an exemplar 34 of which is shown in FIG. 3, employ double conveyance screws 36 rotatable in an elongated conduit 38. The augers 36 are hollow to provide for a heat transfer fluid for cooling or heating. The conduit 38 similarly includes a fluid jacket 40 for a heat transfer fluid to provide a controllable temperature or temperature gradient in the substance processed through the processor. The fluid, a liquid or gas, is supplied to the processors from external sources. Other features of the processor are detailed hereinafter.
The mixer processors 32 as in the schematic illustration of FIG. 1 are provided with steam from a supply line 42 to achieve a mix temperature, preferably approximately 245° F. The solvent, perchlorethylene is preheated and supplied from solvent supply line 44. The mixing process leaches and dissolves sulfur into the solvent solution, forming a hot mother liquor.
The steam for heating processors 32 is obtained from water storage tank 46, where water is supplied by a pump 48 through water supply line 50 to a filter 52 to remove impurities before delivery to a recirculating tank 54. In the recirculating tank, supply water if needed is preheated by system recirculated condensation water by pump 56 before added to water in a boiler 58. The boiler is fired by fuel from a fuel supply line 62. Connected incidentally to the steam supply line 42 to the mixer processors 32 is a heating line 64 for cold climates to steam heat the storage fuel to reduce viscosity.
The solvent is supplied from a steam heated solvent supply tank 66 by pump 68. Heating of the solvent to 250° F. is accomplished by a heat exchange jacket supplied with steam from the boiler 56 through line 70. Loses, which are minimal from the closed system design, are replenished from solvent storage tanks 72 through feed line 74.
The mother liquor with coal particles and heavier undissolvable suspended and sedimentary impurities is delivered through a conduit 76 to a continuous process centrifuge separator 78. The centrifuge separator 78 separates the sulfur and solvent solution from a coal and residue slurry. The slurry is drawn off and conveyed by a screw conveyer 79 to a second centrifuge separator 80 where the lighter weight coal slurry is separated from the heavier residue or tailings. The heavier residue or tailings are in many instances suitable for refining by conventional methods to recover valuable materials, particularly rare metals. The slurry is conveyed by a conveyer 81 to a continuous process dryer 82 which comprises a similar processor to the mixer processors 32, but equipped with a domed collector 84 for recovering solvent vapors generated by evaporation during the drying process. The dryer 82 includes a steam supply line 83 for the processor's heat exchanger and a condenser 86 to condense the solvent vapors collected by the domed collector.
From the dryer, the coal is delivered in a dry powder form for further processing into briquettes and the like, bagging, or bulk shipment.
When this process is used to refine sulfur from ores other than coal, the gradient centrifuge, which has the capability of separating suspensions of different mass, is not required. A more enconomical filter drum centrifuge with internal scrapers for continuous operation may be used to separate the suspensions or tailings as an aggregate from the sulfur liquor.
The hot sulfur solution together with microparticle suspensions from the centrifuge separator 78 is pumped by pump 88 through line 89 to a pair of pre-coat filters 90 for removal of the suspensions from the sulfur solution. Depending on the quantity of suspensions the filters can be of a continuous process-type with in process scrapers or a pair of intermittent filters that are periodically scraped in alternating fashion. The ash recovered is either used in fabricating construction materials or refined by conventional methods if analysis indicates the presence of recoverable materials.
The purified sulfur solution flows through line 92 to a receiving tank 94 where cooling begins for crystalization of the sulfur in solution. The actual crystalization occurs in a set of three series arranged processors 96 which are chilled by solvent pumped by pump 98 from a heat exchanger 100 to the processors in cooling lines 102. The three crystalization processors 96 are again similar to the processor of FIG. 3, with dual screw mechanisms constructed to function as a heat exchanger using a lean solvent as the cooling medium.
By the time the sulfur solution has reached the third processor, the temperature has been reached to 80° F. and the sulfur has crystalized, existing in part as a suspension and in part as a precipitate. The crystalized sulfur and solvent solution flow to a centrifugal separator 104 where the solvent is removed, leaving crystalized sulfur. The sulfur is conveyed directly to a dryer 106 similar to the dryer 82 for the coal. The dryer is heated by a steam line 83 from the boiler to a temperature of approximately 180° F. The dryer 106 recovers and collects solvent from the sulfur crystal by the domed collector 106. The solvent vapors are condensed in condenser 110 before returning to solvent recovery line 112. Any vapors that remain are condensed when the recovery line 112 joins the solvent return line 114 from the separator 104 where relatively cool solvent is introduced in large quantities. The solvent is returned to a preheater receiving tank 116. The preheater includes one or more vapor condensers 118 which act as pressure buffers as well as condensers to reduce to liquid form any solvent vapors that may exist. To maintain a gradual increase in temperature, the receiving tank 116 is heated by steam connection line 120 which taps the steam supply line 83. The immediate maintenance and subsequent raising of the solvent temperature is necessary to prevent any further crystalization of residue sulfur dissolved in the solvent which may interfere with free flow of the solvent in the flow lines. The presence of residue sulfur is unimportant since the solvent is immediately pumped by pump 122 through feed line 124 to the main solvent heating tank 66 where it is heated to a high temperature for introduction to the first stage mixing with the crushed ore in the mixer processors 32.
The dried sulfur crystals are either fully dried in the dryer 106, which is equipped with a heat exchange unit 126, for use in a conventional commercial manner for pesticides, soil amendments, chemical manufacture, etc. Alternately, the crystals are conveyed by a conveyer 128 from the dryer 106 to a hopper 130 for mixing with a preheated aggregate in a high temperature steam heated mixer 132. In such case, the dryer need not be as thorough, and its operation is dictated by economics as to the degree of solvent recovery since the sulfur in mixer 132 is raised to the melting point 285° F. The liquid sulfur and aggregate mix are poured into suitable molds for construction materials.
For example, the molds can produce construction blocks 136 having a configuration as shown in FIG. 4. The male and female ends, 138 and 140 are easily assembled by the simple interlock of the projection and recess.
A block diagram shown in FIG. 2 provides a summary for the process. Beginning from a primary crushing stage 200, ore passes to a secondary crushing stage 202. At a juncture 204, solvent is added to the crushed ore and a leaching stage 206 is encountered where sulfur is leached into solution. Following leaching, a separation stage 208 is encountered, where a coal and residue slurry is separated in one process line and conveyed to a second separation stage 210, and a sulfur liquor is separated in another process line and conveyed to a purification stage 212.
Continuing the coal process line to completion, in the separation stage 210 a residue is separated at 214 and is discarded, used in fabrication of construction materials, or is further refined at step 216, as indicated. The coal slurry is conveyed to a drying stage 218.
Accompanying the drying stage 218 is a solvent recovery step 220 where solvent is evaporated from the slurry, condensed and returned to the solvent supply at juncture 204. The dried coal is in powder form and is processed in a bulk or bagged step 216 before a final market stage 222.
The separated sulfur liquor in the purification stage 212 removes impurities as an ash residue by filtration. The separated ash 226 may be disposed or used in fabricating construction materials.
The purified liquor enters a crystalizing stage 228 where the dissolved sulfur in solution crystalizes as a precipitate. The separation of the crystalized sulfur is accomplished in a separation stage 230 where the liquid solvent is removed, preferably by a centrifuge separator. The crystalized sulfur in a slurry is conveyed to a drying stage 232 accompanied by a solvent recovery stage 234 in which the remaining solvent is evaporated recovered and condensed and subsequently returned to the solvent supply at juncture 204. The sulfur is ready for market at final stage 236.
Since the enconomics of the system is dependent on minimizing the loss of solvent, a relatively closed cycle solvent system is virtually essential for enconomic operation of the process.
While in the foregoing specification embodiments of the invention have been set forth in considerable detail for purposes of making a complete disclosure of the invention, it will be apparent to those skilled in the art that numerous changes may be made in such details without departing from the spirit and principles of the invention. | A continuous process of desulfurizing coal and other ores contaminated with sulfur and recovering the sulfur in relatively pure crystal form, the process for coal including the steps of crushing sulfur bearing coal ore, mixing the crushed ore in a solvent forming a solvent liquor in which the sulfur is dissolved, centrifuging the solvent liquor separating a coal slurry from the solvent liquor, centrifuging the coal slurry separating the coal from the tailings including rare metals for further refining to recover the rare metals, drying the coal slurry and recovering the solvent, filtering the remaining solvent liquor removing ash, crystallizing the sulfur in the filtered solvent, centrifugally separating the crystallized sulfur from the solvent and recovering the solvent, drying the crystallized sulfur and further recovering the solvent, heating the crystallized sulfur to form a sulfur liquid and casting the sulfur in preformed molds to produce building materials. | 2 |
This application is a continuation of application Ser. No. 08/292,568, filed Aug. 19, 1994, now pending, which is a continuation of application Ser. No. 08/215,012, filed Mar. 21, 1994, now abandoned, which is a continuation of application Ser. No. 08/124,992, filed Sep. 21, 1993, now abandoned, which is a continuation of application Ser. No. 08/048,576, filed Apr. 15, 1993, now abandoned, which is a continuation of application Ser. No. 07/803,797, filed Dec. 6, 1991, now abandoned, which is a continuation of application Ser. No. 07/292,517, filed Dec. 29, 1988, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 131,390 now abandoned, filed Dec. 10, 1987, the entire specification of which is incorporated herein by reference, now abandoned.
FIELD OF THE INVENTION
This invention relates generally to peptides and more specifically to peptides which are involved in cell adhesion systems.
BACKGROUND OF THE INVENTION
The adhesion of cells to other cells or to extracellular materials is important to the orderly development and functioning of cells in an organism. Cell adhesion is mediated by certain adhesive legands and corresponding receptors. Among such adhesive ligands are the glycoproteins fibronectin, vitronectin and collagen. All three contain the tripeptide sequence arginine-glycine-aspartic acid (Arg-Gly-Asp or R-G-D) which appears to function as the primary recognition site for receptors on the surface of cells binding to these molecules. When presented to cells as a peptide-covered surface, synthetic peptides containing the Arg-Gly-Asp sequence promote cell attachment in a manner similar to that of natural fibronectin or vitronectin. In solution, such peptides can inhibit cell attachment to a surface coated with fibronectin, vitronectin, collagen, the peptides themselves or some other adhesive protein having an Arg-Gly-Asp cell attachment site.
Several receptors have now been identified which recognize the Arg-Gly-Asp sequence of their respective ligands. While some of these receptors have affinity for only their specific ligand, others will interact to varying degrees with two or more ligands containing the tripeptide. It therefore appears that while the Arg-Gly-Asp sequence is sufficient for receptor recognition and binding, the remaining amino acid sequence of the peptide may nonetheless be important to the specificity of the ligand-receptor interaction. The precise manner in which the remaining sequence affects binding has, thus far, remained elusive.
One view that has been held by some investigators in the field is that the specificity of a given adhesive protein for its receptor may depend on the presence in the adhesive protein of one or more receptor binding sites other than their Arg-Gly-Asp site. According to this view, the Arg-Gly-Asp site would be a shared binding site and the additional site or sites would be responsible for the specificity (See, for example, Yamada et al., (1987) Biochem. and Biophys. Res. Comm. 144:35; Wright et al., (1987) PNAS 84:1965). An alternative possibility is that the Arg-Gly-Asp sequence provides essentially all of the information for the receptor binding and that it is the conformation of this sequence that gives an adhesion protein its receptor specificity. The binding sites of various peptide hormones are known to be small (Rose et al., (1985) Adv. in Chemistry 37:1) but these peptides generally comprise only about 10 amino acids in total. In contrast, each of the two fibronectin polypeptide chains comprises over 2000 amino acids. The idea that the conformation of a single amino acid triplet could be important to the function of a number of different proteins carrying it is novel.
Synthetic peptides containing the Arg-Gly-Asp sequence are useful in that they can both promote and inhibit cell attachment. There are at least ten different adhesion receptors that are known or suspected to recognize an Arg-Gly-Asp sequence in one or more of the various adhesive proteins. Peptides that reproduce with reasonable accuracy the function of such adhesive proteins or specifically inhibit that function offer a tremendous potential for the manipulation of important physiological events such as thrombosis, metastasis, inflammation, wound healing, and rejection of prosthetic implants.
There thus exists a need for peptides having an amino acid structure that provides the optimum specificity for the receptor of interest. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The present invention involves novel synthetic peptides which have high affinity and specificity for their receptors by virtue of restrictions on their stereochemical conformation. Such restrictions or stabilizations, can be provided, for example, by cyclization, by inclusion into a constraining conformational structure such as a helix, by providing an additional chemical structure such as an amide or an enantiomer of a naturally occurring amino acids, or by other methods. Such peptides can have a range of numbers of residues, but preferably between 3 and 100, more preferably 7 to 30. In particular, there is provided a cyclic peptide having increased affinity and selectivity for the vitronectin receptor over that of linear, Arg-Gly-Asp-containing synthetic peptides. The affinity and selectivity of the cyclic peptide approaches that of natural vitronectin.
In one aspect, the invention comprises a peptide having about 10 amino acids in which a bridge is formed between amino acids surrounding the Arg-Gly-Asp sequence. A suitable structure is ##STR1## The peptide may have about 1 to 4 amino acids between the Arg-Gly-Asp sequence and those residues forming the bridge. The bridging residues may be, for example, penicillamine and cysteine, or other amino acids capable of forming a bridge, such as a disulfide bridge.
Another suitable structure is ##STR2##
Alternatively, the peptide may be cyclerized through a peptide bond between amino acid residues. An appropriate structure is ##STR3##
The present invention provides evidence that, rather than the specificity of adhesion ligands residing in distinct binding sites outside the Arg-Gly-Asp site, such specificity results from the conformational structure imposed on the Arg-Gly-Asp sequence by the structure of the remaining peptide. At the practical level, the invention demonstrates that a conformationally restricted Arg-Gly-Asp-containing peptide can have different receptor specificity and higher binding affinity than its unrestricted counterpart. This demonstration permits the synthesis of other Arg-Gly-Asp conformations with variant receptor specificities and affinities.
The stabilized peptides of the present invention have various applications relating to their cell-adhesion properties. In one embodiment, for example, where the peptide structure is ##STR4## the peptide has increased affinity for the vitronectin receptor and decreased affinity for the fibronectin receptor over that of linear synthetic Arg-Gly-Asp-containing peptides and may therefore be effectively used to inhibit the binding of vitronectin receptor-containing cells to a substrate for cell culture. Alternatively, the stabilized peptide may be usefully employed to promote adhesion of cells expressing the vitronectin receptor by, for example, coating cell culture substrates. Additionally, the stabilized peptide may be used to coat materials for in vitro implantation, such as prothesis, where cell attachment is desired.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be described in connection with the accompanying drawings in which:
FIG. 1 is a graph of HPLC analysis of a crude preparation of cyclic peptide (a); and purified cyclic peptide (b).
FIG. 2 is a graph illustrating adhesion of normal rat kidney cells to fibronectin and vitronectin in the presence of a cyclic and a linear peptide having the same amino acid sequence.
FIG. 3 shows the sequence of the peptide of Example III and the recovery of its degradation products recovered by automated Edman degradation.
FIG. 4 records the change in optical rotation caused by a solution of the peptide of FIG. 3, as a function of increasing temperature, indicating its restricted conformation at the lower temperature.
FIG. 5 is an axial projection of the peptide of Example IV. Those residues above the dotted line are lipophilic while those below the line are hydrophilic.
FIG. 6 is a schematic representation of the cyclic peptide synthesized in Example VI.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "conformationally stabilized" or "conformationally constrained" refers to limitations imposed on the number of possible stereochemical structures which a peptide may assume. In the context of the present invention, such limitations are imposed on the conformation of the Arg-Gly-Asp binding site and result from the presence of chemical structures surrounding the binding site which limit the possible structural conformations of the binding site to less than those assumable by the tripeptide sequence alone. Such conformationally stabilized Arg-Gly-Asp-containing peptides still exhibit binding activity with at least one receptor. "Surrounding chemical structures" may refer either to amino acids or other chemical moieties, and may refer both to those moieties lying immediately adjacent the binding site as well as those separated from the binding site itself by the presence of intervening amino acids. The term "amino acids surrounding the Arg-Gly-Asp sequence" refers both to residues adjacent to the Arg-Gly-Asp sequence as well as to residues separated from the Arg-Gly-Asp sequence by intervening residues.
As used herein, references to "Arg-Gly-Asp containing peptides" are intended to refer to peptides having one or more Arg-Gly-Asp containing binding sites which may function as binding sites for a receptor of the "Arg-Gly-Asp family of receptors", i.e., those recognizing and binding to the Arg-Gly-Asp sequence. While the Arg-Gly-Asp sequence has bean found to necessarily be invariant in order to retain the binding activity, the composition of the remaining peptide as well as any other chemical moiety present in conjunction with the peptide may vary without necessarily affecting the activity of the binding site. Where specific chemical structures or sequences beyond the Arg-Gly-Asp sequence are presented, it is intended that various modifications which do not destroy the function of the binding site are to be encompassed without departing from the definition of the peptide.
As used herein, the term "bridge" refers to a chemical bond between two amino acids in a peptide other than the amide bond by which the backbone of the peptide is formed.
As used herein, the term "peptide bond" or "peptide linkage" refers to an amide linkage between a carboxyl group of one amino acid and the α-amino group of another amino acid.
The abbreviations for amino acids are used herein are given in the following table:
______________________________________Ala Alanine α-ABA α-Amino isobutyric acid Arg Arginine Asp Aspartic acid Cys Cysteine Glu Glutamic acid Gly Glycine Leu Leucine Lys Lysine Pen Penicillamine Pro Proline Ser Serine SuccAla Succinyl-alanine______________________________________
The present invention provides novel synthetic peptides which incorporate the sequence Arg-Gly-Asp in a conformationally stabilized form. In one embodiment, the peptide comprises the sequence X--R 1 --R 2 --Arg-Gly-Asp--R 3 --R 4 --Y in which R 1 and R 4 are amino acids forming or capable of forming a bridge, such as a disulfide bridge, or a peptide linkage, R 2 and R 3 are each a sequence of 0 to 5 amino acids, X is one or more amino acids or H and Y is one or more amino acids or OH or NH 2 and together X and Y preferably total about zero to 100 amino acids, although longer sequences may also be useful. In a preferred embodiment, R 1 is penicillamine, R 4 is cysteine, R 2 is glycine and R 3 is Ser-Pro. Additional amino acids can be present at the NH 2 and COOH termini, as represented by X and Y, respectively.
Such peptides may be synthesized by any suitable method, including well-known methods of chemical synthesis. Preferably, the linear sequence is synthesized using commercially available automated peptide synthesizers. The material so synthesized can be precipitated and further purified, for example by high performance liquid chromatography (HPLC). Although a purity of greater than 95 percent for the synthesized peptide is preferred, lower purity may be acceptable.
To obtain one of the stabilized peptides of the present invention which has high specificity and affinity for particular cell surface receptors related to the cell adhesion system, the synthesized peptide is cyclized using methods well known in the art. For example, where the residues contain a sulfhydryls, a disulfide bridge may be formed by oxidizing a dilute aqueous solution of the peptide with K 3 [F e (CN) 6 ]. Other means of cyclizing which are known in the art may also be utilized.
The stabilized cyclized peptides of the present invention can also be prepared by forming a peptide bond between non-adjacent amino acid residues. A procedure for forming such peptide bond is provided in Schiller et al., Int. J. Peptide Protein Res. 25:171(1985), which is incorporated herein by reference. Briefly, cyclic peptides can be synthesized on the Merrifield resin by assembling the peptide chain using N.sup.α -Fmoc-amino acids and Boc and tertiary-butyl protein.
The stabilized peptide can also be prepared by designing or treating it so as to form a helix such as an alpha (α) helix or a triple helix, according to methods well-known in the art.
The stabilized peptides described herein can be used as analogues to adhesion proteins including, for example, vitronectin. Because of the increased affinity for the vitronectin receptor of the cyclic peptide of the preferred sequence over that of the analogous linear sequence, the cyclic peptide may be used to inhibit binding of vitronectin without affecting the function of other receptors such as the fibronectin receptor. Alternatively, the cyclic peptide can be used to promote adhesion of cells expressing the vitronectin receptor, as by coating cell culture substrates.
Certain specific structures containing an Arg-Gly-Asp sequence have been found to confer particular specificity or other attribute on the binding site. Among such structures are the sequences --Arg-Gly-Asp--NH 2 , --D-Arg-Gly-Asp-- and --Arg-Gly-Asp-D-Ser--. The conformationally stabilized latter sequence exhibits useful affinity for the fibronectin receptor but not the vitronectin receptor. The presence of the enantiomeric forms of the naturally occurring amino acids has been shown to confer resistance to degradation enzymes, such as trypsin, in the case of D-Arg. Other useful peptides include the sequences Phe-Arg-Gly-Asp-Ser-Pro, Gly-Arg-Gly-Asp-Ser-Phe, and Phe-Arg-Gly-Asp-Ser-Phe.
The peptides of the present invention may be utilized industrially for in vivo uses such as coating of medical devices, including prostheses or implants, for example vascular implants, so as to facilitate the attachment of cells thereto. In addition, the peptides have in vitro uses in coating of substrates, such as cell culture substrates, to promote cell adhesion.
Other features and advantages of the present invention will become apparent from the following more detailed Examples which illustrate, by way of example, the principles of the invention.
EXAMPLE I
Peptide Synthesis
The peptide Gly-Pen-Gly-Arg-Gly-Asp-Ser-Pro-Cys-Ala was synthesized using an automated peptide synthesizer (Model 430A: Applied Biosystems, Foster City, Calif.) according to the directions provided by the manufacturer. After cleavage from the resin with hydrogen fluoride, the peptides were washed in cold ethyl ether and precipitated from solution in trifluoroacetate with ice cold ether. The peptides were then redissolved in distilled water and lyophilized. The peptides were further purified by HPLC using a Waters Bondapak™ C 18 (3×30 cm: 10 μm packing, Waters Assoc., Milford, Mass.).
EXAMPLE II
Cyclization of the Peptide
611 mg of the peptide synthesized as described in Example I were dissolved in 4 liters of water that had been previously boiled and allowed to cool. Immediately prior to addition of the peptide, nitrogen was bubbled through the water for 45 minutes. After the peptide was dissolved, a solution of 0.1 μg/ml of potassium ferrous cyanide K 3 [Fe(CN) 6 ] in water was added dropwise to the stirred peptide solution until the yellow color persisted for 5 minutes (approximately 5 ml). The pH of the solution was held at 7.0 throughout this procedure by addition of NH 4 OH. The solution was allowed to stand for 20 hours under low vacuum and then lyophilized. Excess K 3 [Fe(CN) 6 ] was removed by passing the cyclized material over a Sephadex G-15 column (1.8×120 cm). The peptide was purified by reverse phase HPLC using a Waters Bondapak™ C 18 column (3×30 cm; 10 μm packing) (Waters Assoc., Milford, Mass.). The peptide was loaded on the columnm in buffer A (20 mM ammonium acetate at pH 7.5) and eluted with a gradient of buffer B consisting of 60% acetonitrile and 40% buffer A. FIG. 1 depicts the result of purification of the cyclized peptide by reverse phase HPLC. Trace a represents purification of the peptide on the C 18 column. Fractions 1, 2 and 3 were pooled for testing of their ability to inhibit attachment of cells to fibronectin or vitronectin. Fraction 2, containing cyclic peptide, was rechromatographed by the same procedure on a C 18 column and yielded a single peak (trace b).
The major peak obtained from the C 18 column (fraction 2 in FIG. 1) constituted 90% of recovered peptide and was deduced to be a monomeric cyclic peptide because it was retained on the column for the length of time predicted for that sequence and because the uncyclized material and multimeric forms were well separated from the main peak.
EXAMPLE III
Formation of a Triple Helical Structure
The cell attachment promoting Arg-Gly-Asp sequence of the linear peptide generated in Example I was conformationally restrained by allowing the peptide to assume a helical structure, according to methods of Dedhar at al, (1987) J. Call Biol. 104:585, which is incorporated hereby reference. Briefly, a 33-amino acid peptide having the sequence (Pro-Hyp-Gly) 4 -Ala-Pro-Gly-Leu-Arg-Gly-Asp-Thr-Gly-(Pro-Hyp-Gly) 4 was synthesized using an automated peptide synthesizer (Model 430A; Applied Biosystems, Foster City, Calif.). The sequence was confirmed by automated Edman degradation using a gas phase sequencer (Moder 470A; Applied Biosystems, Foster City, Calif.) as shown in FIG. 3. The linear peptide was allowed to dissolve overnight in the smallest possible volume of 0.05% acetic acid at 4° C. Polarimetrical analysis was used to confirm that it had assumed a helical structure according to the method of Rhodes et al. (1978) Biochemistry, 17:3442, which is incorporated herein by reference. The peptide existed as a triple helix at low temperatures as judged by the high degree of negative optical rotation which underwent a sharp change as the temperature was increased, producing a "melting" curve having an inflection point (second derivative equal to 0: Tm) at 30° C., as shown in FIG. 4.
EXAMPLE IV
Formation of an Alpha Helical Structure
An Arg-Gly-Asp containing peptide was designed so as to have an amino acid sequence such that it would under appropriate conditions assume an alpha helical configuration. As demonstrated by Carbone et al., (1987) J. Immunology 138:1838, which is incorporated herein by reference, peptides comprising alternating α-aminoisobutyric acid (α-ABA) and alanine (Ala) residues adopt helical conformations in structure-forming organic solvents. Moreover, the presence of a negatively charged group at the amino terminus and a positively charged group at the carboxy terminus creates a dipole which acts to stabilize such a helix (Shoemaker et al., (1987), Nature 326:563, which is incorporated herein by reference). Further, the sequence of amino acids were chosen so as to create an amphiphilic secondary structure in which hydrophilic residues lie on one side, lipophilic residues on the other side of the helix (Kaiser et al., (1984) Science, 223:249, which is incorporated herein by reference).
The following linear sequence was produced by an automated peptide sequencer (Model 430A; Applied Biosystems, Foster City, Calif.) was: SuccAla-Leu-Glu-Glu-αABA-Ala-Lys-Arg-Gly-Asp-Ser-Leu-αABA-Gly-Lys-αABA-Ala-Lys.
The peptide was synthesized and purified according to the methods of Example 1. The alpha helical conformation of this peptide is depicted schematically in FIG. 5.
EXAMPLE V
Cell Adhesion Assay
Fibronectin and vitronectin were purified from human plasma according to the methods of Ruoslahti et al., (1982) Meth. Enz. 82:803; and Hayman et al., (1983) PNAS 80:4003, respectively, both of which are incorporated herein by reference. The adhesion of normal rat kidney cells to fibronectin and vitronectin was assayed as described in Ruoslahti et al., Meth. Enz. supra. Briefly, 0.1 ml solution of fibronectin or vitronectin at a concentration of 12 μg/ml in 0.1M PBS was placed in each well of 96-well plastic microtiter plates and left for 2 hours at room temperature. The unattached protein was removed by washing three times with PBS.
One day before the assay, a confluent culture of normal rat kidney cells was split 1:2 using standard tissue culture trypsin. The cells were washed three times with PBS, pH 7.2. 10 ml of 2×crystallized trypsin (Sigma, Type III), 0.1 mg/ml in PBS, was added, and the cells incubated at 37° C. until they detached. The detached cells were then collected by centrifugation and washed three times with a solution of 0.5 mg/ml of soybean trypsin inhibitor in PBS to ensure neutralization of the trypsin. Before the last centrifugation, a sample was taken and cell numbers and viability by trypan blue exclusion are determined. The cells were suspended in minimal essential medium (MEM) at a concentration of 10 6 cells/ml and dispersed by pipetting until a single-cell suspension was obtained.
To ensure even dispersal of the cells in the microtiter well, 0.1 ml of MEM was added to each well, followed by the addition of 0.1 ml of the cell suspension. The plate was incubated for 1 hour at 37° C.
The unattached cells were removed simply by removing the medium and washing the wells. The plate was flooded with PBS, and the washing solution was removed. The cells were then fixed with 3% paraformaldehyde in PBS and stained with 1% toluidine blue, paraformaldehyde in PBS, and attached cells counted. Their number was determined using a cell counter that is capable of counting cells attached to a surface (Dynatech Laboratories, Alexandria, Va.).
The ability of the cyclized peptide of the invention to inhibit adhesion of cells to the substrates was assayed by adding stock solutions of the peptide dissolved in MEM to give final concentrations in the wells of 0 to 10.0 mM. Prior to addition to the assay, the stock solutions were neutralized with sodium bicarbonate. Rat kidney cells were added and the wells incubated and assayed as described.
In order to more fully determine the ability of the cyclized peptide to inhibit the attachment of normal rat kidney cells to the fibronectin and vitronectin substrates, the binding of a non-cyclized, or linear, peptide having the sequence Gly-Pen-Gly-Arg-Gly-Asp-Ser-Pro-Cys was assayed. As shown in FIG. 2, the cyclic peptide of the invention inhibited attachment to vitronectin at a 10-fold lower molar concentration than the linear peptide, but it was ineffective at inhibiting attachment to fibronectin. The linear peptide, in contrast, inhibited attachment of cells to both substrates at relatively similar concentrations.
While not wishing to be bound by this explanation, the cyclic peptide of the invention appears to possess a different affinity for the binding site of fibronectin and vitronectin receptors. This is consistent with the fact that the rat kidney cells used in the assay are known to possess separate receptors for fibronectin and vitronectin.
EXAMPLE VI
Cyclization Through Peptide Bond
The peptide cyclo-(1-7)Gly-Arg-Gly-Asp-Ser-Pro-Asp-Gly was synthesized using a modification of the method of Schiller et al., Int. J. Peptide Protein Res. 25:171 (1985), which is incorporated herein by reference.
The synthesis was done using PAM resin-TFA; (Applied Biosystems, Inc., Foster City, Calif.) with t-Boc Gly-attached to the resin withd a substitution factor of 0.80 mmol/g (see FIG. 6). All amino acids were obtained from Bachem Bioscience, Inc., Philadelphia, Pa. 1.25 g (1.0 mmol) of resin was shaken with 20 ml dichloromethane (DCM) for 15 minutes to induce swelling and DCM removed with N 2 pressure the procedure repeated. The t-Boc protecting group was cleaved with 20 ml 20% TFA; (Applied Biosystems, Inc., Foster City, Calif.) in DCM (Pfizer, Groton, Conn.) for 15 minutes. This reaction was repeated, this time shaking for 30 minutes. Between the reactions, the resin was washed once with 20 ml DCM for 2 minutes. After the second reaction, the resin was washed six times with 20 ml DCM for 2 minutes each, followed by neutralization with 20 ml 10% triethylamine (TEA) in DCM two times for 3 minutes each. The resin was washed six times with 20 ml DCM for 2 minutes each and was then ready for the next reaction.
In a 50 ml round bottom flask equipped with stirring bar, Fmoc-Asp-t-butyl ester ((OtBu)OH) (1.03 g, 2.5 mol) was dissolved in 15 ml DCM followed by addition of 2.5 ml (1M) DIC (Aldrich Chem. Co., Milwaukee, Wis.) in DCM. The mixture diisopropyl carbodiimide was stirred for 5 minutes and followed by addition of 1.25 ml 2.0 M hydroxybenzotriazole (HOBT; Aldrich) in DMF (Pfizer) at 0° C. and stirred for 10-15 minutes more. This mixture was added to the resin and shaken 1 to 2 hours. This reaction was repeated once (double coupled) and the resin was washed 2 times with 20 ml DCM between couplings. After the second coupling was completed, the resin was washed three times with 20 ml DCM.
The cleavage of the Fmoc group was done with 20 ml 20% piperidine (Aldrich) in DCM (freshly made) and shaken for 15 minutes. This reaction was repeated for another 30 minutes. The resin was then washed once with DMF and five times with DCM for 2.0 minutes each. Then the resin was ready for the next coupling.
In a 50 ml round bottom flask equipped with stirring bar, Fmoc-Pro-OH (0.84 g, 2.5 mmol) was dissolved in 15 ml DCM followed by addition of 2.5 ml (1 M) DIC in DCM. The mixture was stirred for 5.0 minutes, followed by the addition of 1.25 ml (2M) HOBT in DMF at 0° C. and stirred for 10 to 15 minutes more. This mixture was added to the resin and shaken 1 to 2 hours. This reaction was repeated once (double coupled) and the resin was washed 2 times with 20 ml DCM between couplings. After the second coupling was completed, the resin was washed three times with 20 ml DCM. The Fmoc was cleaved using the same procedure as above and the material was then ready for the next coupling.
In a 50 ml round bottom flask equipped with stirring bar, Fmoc-Asp-benzyl ester ((OBzl)--OH) (1.11 g, 2.5 mmol) was dissolved in 15 ml DCM followed by addition of 2.5 ml (1 M) DIC in DCM. The mixture was stirred for 5.0 minutes, followed by addition of 1.25 ml 2.0 M HOBT in DMF at 0° C. and stirred for 10 to 15 minutes. This mixture was added to the resin and shaken 1 to 2 hours. This reaction was repeated once (double coupled) and the resin was washed 2 times with 20 ml DCM between couplings. After the second coupling was completed the resin was washed three times with 20 ml DCM. The Fmoc was cleaved using the same procedure as above and the material was then ready for the next coupling.
In a 50 ml round bottom flask equipped with stirring bar, Fmoc-Gly-OH (0.74 g, 2.5 mmol) was dissolved in 15 ml DMF followed by addition of 2.5 ml (1 M) DIC in DCM. The mixture was stirred for 5.0 minutes, followed by addition of 1.25 ml 2.0 M HOBT in DMF at 0° C. and stirred for 10 to 15 minutes more. This mixture was added to the resin and shaken 1 to 2 hours. This reaction was done twice (double coupled) and the resin was washed 2 times with 20 ml DCM in between coupling. After the second coupling was completed the resin was washed three times with 20 ml DCM. The Fmoc was cleaved using the same procedure as above and the material was then ready for the next coupling.
In a 50 ml round bottom flask equipped with stirring bar, Fmoc-Arg Tosilate ((Tos)OH) (1.37 g, 2.5 mmol) was dissolved in 15 ml DCM followed by addition of 2.5 ml (1M) DIC in DCM. The mixture was stirred for 5.0 minutes and followed by addition of 1.25 ml 2.0 M HOBT in DMF at 0° C. and stirred for 10 to 15 minutes more. This mixture was added in to the resin and shaken 1 to 2 hours. This reaction was repeated once (double coupled) and the resin was washed 2 times with 20 ml DCM in between coupling. After the second coupling was done the resin was washed three times with 20 ml DCM. The Fmoc deprotection was performed using the same as the procedure above and the material was then ready for the next coupling.
In a 50 ml round bottom flask equipped with stirring bar, t-Boc-Gly-OH (0.44 g, 2.5 mmol) was dissolved in 15 ml DCM followed by addition of 2.5 ml (1 M) DIC in DCM. The mixture was stirred for 5.0 minutes and followed by addition of 1.25 ml (2M) HOBT in DMF at 0° C. and stirred for 10 to 15 minutes more. This mixture was added in to the resin and shaken 1 to 2 hours. This reaction was repeated (double coupled) and the resin was washed 2 times with 20 ml DCM in between coupling for 2 minutes each. After the second coupling was done the resin was washed three times with 20 ml DCM for 2 minutes each.
The deprotection of the t-Boc Group of Gly 1 and the t-Butyl ester side chain of Asp 7 was performed at the same time by adding 20 ml 20% TFA in DCM for 15 minutes. This reaction was repeated once again for 30 minutes. Between reactions the resin was washed once with DCM for 2 minutes. After the second reaction, the resin was washed six times with 20 ml DCM for 2 minutes each, followed by neutralization with 20 ml 10% TEA in DCM two times for 3 minutes each. The resin was washed six times with 20 ml DCM for 2.0 minutes each.
The N-terminus of Gly 1 was cyclized to the side chain carboxyl group of Asp 7. The cyclization was accomplished by adding 10 ml of 1M DIC solution and 5 ml 2M HOBT in DMF and shaken for 4 days. Each day, old reagent was drained and the resin was washed with 20 ml DMF once and with DCM three times for 2 minutes each. Fresh reagent (DIC and HOBT) was then added.
The resin was cleaved with hydrogen fluoride using procedures well known in the art. After cleaving, the peptide-containing resin was were washed with cold ethyl ether then dissolved with 10% acetic acid to remove the peptide from the resin. The filtrate was frozen and lyophilized. The crude product recovered was 508 mg. This crude product was subjected to purification using HPLC through C 18 (1×20 cm; 10-μm packing) column. The peptide was loaded on the column in buffer A (10 mM ammonium acetate at pH 6.0) and eluted with a gradient of buffer B consisting of 60% acetonitrile and 40% buffer A. Yield after purification was 210 mg.
This compound was confirmed to have the desired cyclic peptide structure by proton NMR in DMSO-d6 as the solvent. The 1D and 2D (COSY, COSY-Relay, and NOESY) spectra of this compound were obtained by using a 360 MHz FT-NMR equipped with Nicolet software at the University of California, San Diego NMR facility. (See Wuthrich, K., NMR of Proteins and Nucleic Acids, John Wiley & Son, NY (1986), which is incorporated herein by reference).
Although the invention has been described with reference to the presently-preferred embodiment, it should be understood that various modifications can be made by those skilled in the art without departing from the invention. Accordingly, the invention is limited only by the following claims. | Novel synthetic Arg-Gly-Asp containing peptides which have high affinity and specificity for their receptors by virtue of restrictions on their stereochemical conformation. Such restrictions can be provided by cyclization, by inclusion into a constraining conformational structure such as a helix, by providing an additional chemical structure such as an amide or an enantiomer of a naturally occurring amino acid, or by other methods. In particular, there are provided cyclic peptides having increased affinity and selectivity for the certain receptors over that of linear, Arg-Gly-Asp-containing synthetic peptides. | 2 |
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to novel quinoxaline derivatives and herbicidal compositions containing the same.
Description of the Prior Art
Various compounds have been practically used as herbicides as a result of various studies on herbicides for long years. These herbicides have been proposed and practically used to contribute for elimination of agricultural labour works and to improve productivities of agricultural and horticultural crop plants.
It has been still awaited to find novel herbicides having superior herbicidal characteristics. The herbicides for agricultural and horticultural purposes are preferably compounds which selectively control the object weeds at a small dose without a toxicity to the crop plants. The known herbicides do not always have the optimum herbicidal characteristics.
The inventors have studied to develop novel useful herbicides especially on herbicidal characteristics of various heterocyclic compounds.
Substituted pyridyloxyphenoxy fatty acid herbicides have been known as heterocyclic ether type phenoxy fatty acid derivatives in Japan Unexamined Patent Publication No. 106735/1976.
Benzimidazole, benzthiazole, and benzoxazole derivatives and herbicidal effect of these compounds have been known in Japanese Unexamined Patent Publication No. 40767/1978.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel quinoxaline derivatives,
It is another objects of the present invention to provide a herbicidal composition which has excellent selective herbicidal activity to various weeds especially gramineous weeds but substantially non-phytotoxicity to broad leaf crop plants.
The foregoing and other objects of the present invention have been attained by providing novel compounds having the formula ##STR4## wherein X represents a halogen atom; R represents ##STR5## --CN or --CH 2 OH, and R 1 represents
--S--R 3 (R 3 represents a C 1 -C 4 alkyl or alkenyl group or phenyl or chlorophenyl group), --NH--R 4 (R 4 represents a C 1 -C 4 alkoxy carbonylalkyl group, hydroxy alkyl group, phenyl group, C 1 -C 4 alkoxy alkyl group or di C 1 -C 4 alkyl amino group).
The present invention provides also herbicidal compositions comprising the novel quinoxaline derivative as an active ingredient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The quinoxaline derivatives having the formula (I) of the present invention are the novel compounds.
The quinoxaline derivatives having the formula (I) of the present invention are significantly unique compounds which are effective for controlling gramineous weeds without any phytotoxicity to broad leaf crop plants as well as broad leaf weeds especially in a post-emergence treatment. Such unique characteristics have not found,
Typical compounds of the present invention having the formula (I) are shown in Table (1) together with the physical properties. The present invention are not limited to the typical compounds shown in Table 1.
__________________________________________________________________________ ##STR6##Comp. No. X R Physical Property__________________________________________________________________________ 1 F ##STR7## N.sub.D.sup.22 = 1.4666 Colorless liq. 2 " COO(CH.sub.2).sub.2 N(CH.sub.3).sub.2 mp 69-71° C. W.C. 3 " ##STR8## N.sub.D.sup.22 = 1.5513 Colorless liq. 4 " COSCH.sub.3 mp 111-113° C. W.C. 5 " CONHCH.sub.2 COOC.sub.2 H.sub.5 mp 143-145° C. W.C. 6 " CONHCH.sub.2 CH.sub.2 OH W.C. 7 " ##STR9## mp 159-161° C. W.C. 8 " ##STR10## mp 95-97° C. W.C. 9 " CN mp 104-105° C. W.C.10 " CH.sub.2 OH mp 93-94° C. W.C.11 Cl COO(CH.sub.2).sub.2 SCH.sub.3 Colorless liq.12 " COONC(CH.sub.3).sub.2 mp 128-130° C. W.C.13 " COSCH.sub.3 mp 109-110° C. W.C.14 " COSC.sub.2 H.sub.5 mp 92-93° C. W.C.15 " COSCH.sub.2 CHCH.sub.2 mp 103-104° C. W.C.16 " ##STR11## N.sub.D.sup.20 = 1.6390 Colorless liq.17 " ##STR12## mp 107-108° C. W.C.18 " ##STR13## mp 130-132° C. W.C.19 " CONHCH.sub.2 CH.sub.2 OCH.sub.3 mp 134-135° C. W.C.20 " CONHN(CH.sub.3).sub.2 mp 182-183° C. W.C.21 Cl ##STR14## mp 173-174° C. W.C.22 " CN mp 125-126° C. W.C.23 " CH.sub.2 OH Colorless liq.24 " CH.sub.2 OH N.sub.D.sup.20 = 1.5530 Colorless liq.25 " ##STR15## mp 143-145° C. W.C.__________________________________________________________________________ Note: W.C.: white crystal
The compound (I) of the present invention can be produced by the following processes.
A) The compound of the present invention can be produced by a condensation of a compound having the formula ##STR16## wherein X and Hal designate a halogen atom; with 4-hydroxyphenoxy derivative having the formula ##STR17## wherein R is defined above, in the presence of an inorganic or organic base such as sodium hydroxide, potassium hydroxide or potassium carbonate, at suitable temperature.
The reaction can be carried out in an inert solvent such as dimethylformamide, dimethylsulfoxide, or acetonitrile.
B) The compound of the present invention can be produced by a condensation of a compound having the formula (II) with a hydroquinone monobenzyl ether having the formula ##STR18## in the presence of an inorganic or organic base to produce a compound having the formula ##STR19## and then a hydrogenation of the product with a catalyst such as palladium-carbon catalyst to result a debenzylation and to obtain a compound having the formula ##STR20## and then a condensation of the product with a faloakyl derivative having the formula ##STR21## in the presence of an inorganic or organic base such potassium carbonate in a polar organic solvent such as methyl ethyl ketone, acetonitrile or dimethyl-formamide.
C) The product obtained by the process A) or B) is converted into the other compounds of the present invention by a hydrolysis, an esterification, an ester interchange, a salt or an amidation.
In the esterification, it is possible to use the conventional coupling agents as well as unique coupling agents such as imido coupling agents especially dicyclohexyl carboirnide. The concentrations of the reagents and the temperatures in the reactions and kinds of the inert solvents can be selected as desired.
In the process A), the reaction is preferably carried out at 50° to 200° C. especially at 80° to 100 ° C., at a molar ratio of the compound (II): 4-hydroxyphenoxy derivative (III) of 1:0.2 to 5.0 preferably 1:0.5 to 2.0 especially 1:0.8 to 1.5. The inorganic or organic bases can be any base which is useful for the condensation of the compound (II) and the compound (III). The concentration of the starting materials in the inert solvent can be in a range of 5 to 50 wt. % preferably 10 to 30 wt. %.
In the process B), the reaction is preferably carried out at 50° to 200° C. especially at 100° to 150° C. at a molar ratio of a compound (II): a hydroquinone monobenzyl ether (IV) of 1:0.2 to 5.0 preferably 1:0.5 to 2.0 especially 1:0.8 to 1.5. The inorganic or organic base can be any base which is useful for the condensation of the compound (II) and the compound (IV). The reaction is preferably carried out in an inert solvent at a concentration of the starting material of 5 to 50 wt. % preferably 10 to 30 wt. %.
The hydrogenation of the resulting intermediate (V) is carried out in the condition for the debenzylation to obtain the compound (VI). The hydrogen pressure is preferably in the range of 1 to 5 atm. preferably 1 to 2 atm.
The reaction of the compound (VI) with the compound (VII) is preferably carried out at 80° to 100 ° C. at a molar ratio of the compound (VI): the compound (VII) of 1:0.2 to 5.0 preferably 1:0.5 to 2.0 especially 1:0.8 to 1.5. The inorganic or organic base can be the same ores. The concentration of the starting materials in the inert solvent can be in a range of 5 to 50 wt. % preferably 10 to 30 wt. %.
In the process C), the conditions of the hydrolysis, the esterification, the ester interchange, the neutralization and the amidation can be selected as desired. These conditions can be considered by a person skilled in the art.
Certain examples for the preparations of the present invention will be described.
Preparation 1
2-[1-[4-(6- fluoro-2-quinoxalyoxy)phenoxy]-ethyl-4,4-dimethyl-2-oxazoline
(Compound 8)
In 20 ml. of dimethyl-formamide, 2.0 g. (0.0070 mol) of 6-fluoro-2-(4-hydroxyphenoxy)-quinoxaline, 1.8 g. (0.0087 mol) of 2-(1-bromoethyl)-4,4-dimethyl-2-oxazoline and 1.3 g. (0.0094 mol) of potassium carbonate were dissolved and the mixture was heated at 90° C. for 8 hours to react them. After cooling, the reaction mixture was poured into water and the product was extracted with benzene and the benzene layer was washed with 2% aqueous solution of sodium hydroxide and then with water and the benzene layer was dehydrated over sodium sulfate. The solvent was distilled off. The resulting crude crystal was washed with n-hexane to obtain 0.8 g (yield 27%) of the object compound.
Preparation 2
2-[4-(6-fluoro-2-quinoxalyloxy)phenoxy]propanol
(Compound 11)
In 50 ml. anhydrous ethyl ether, 0.5 g. (1.5 m mol) of methyl 2-[4-(6-fluoro-2-quinoxalyloxy)phenoxy]propionate was dissolved and 10 ml. of a solution containing 0.11 g. (3.0 m mol) of LiAlH 4 in anhydrous ethyl ether was added dropwise and the mixture was refluxed for 12 hours. After the reaction, 10 ml. of water and 7 ml. of 2N-H 2 SO 4 were added to the reaction mixture and the organic layer was separated and washed with water and dehydrated over anhydrous sodium sulfate and the solvent was distilled off to obtain viscous liquid. This viscous liquid was crystallized and the crystal was washed with n-hexane to obtain 0.25 g. of the object compound (yield of 54%).
Preparation 3
2-[4-(6-chloro-2-quinoxalyloxy)phenoxy]propionic thioethyl ester
(Compound 15)
In 50 ml. of tetrahydrofuran, 1.0 g. (2.90 m mol) of 2-[4-(6-chloro-2-quinoxalyloxy)phenoxy]propionic acid, 0.66 g. (3.2 m mol) of N, N-dicyclohexyl carbodiimide, 0.43 g. (3.2 m mol) of 1-hydroxybenzotriazole and 0.32 g. (3.2 m mol) of triethylamine were dissolved. Into the solution, 0.20 g. (3.2 m mol) of ethyl mercaptane was added and the mixture was stirred at the ambient temperature for 24 hours. After the reaction, N, N-dicyclohexyl urea was separated by a filtration and tetrahydrofuran was distilled off under a reduced pressure and a residue was dissolved in chloroform. The chloroform layer was washed with an aqueous solution of sodium bicarbonate and then, dehydrated over anhydrous sodium sulfate and concentrated and dried to obtain 1.1 g. of a crude product. The crude product was purified by a silica chromatography with chloroform to obtain 0.45 g. of white crystal of the object compound having a melting point of 92° to 93° C. (yield of 40%).
The compound of the present invention can be used as a herbicidal composition.
In the preparation of the herbicidal compositions, the compound of the present invention can be uniformly mixed with or dissolved in suitable adjuvants such as solid carrier such as clay, talc, bentonite, diatomaceous earth; liquid carrier such as water, alcohols (methanol, ethanol etc.), aromatic hydrocarbons (benzene, toluene, xylene etc.) chlorinated hydrocarbons, ethers, ketones, esters (ethyl acetate etc.), acid amides (dimethylformamide etc. ) if desired, with an emulsifier, a dispersing agent, a suspending agent, a wetting agent, a spreader, or a stabilizer to form a solution, an emulsifiable concentrate, a wettable powder, a dust, a granule or a flowable suspension which is applied if desired, by diluting it with suitable diluent.
It is possible to combine the compound of the present invention with the other herbicide, or an insecticide, a lungicicle, a plant growth regulator, a synergism agent.
Certain examples of the herbicidal compositions of the present invention will be illustrated. In the examples, the part means part by weight.
Solution
Active ingredient: 5 to 75 wt. % preferably 10 to 50 wt. % especially 15 to 40 wt. %
Solvent: 95 to 25 wt. % preferably 88 to 30 wt. % especially 82 to 40 wt. %
Surfactant: 1 to 30 wt. % preferably 2 to 20 wt. %
Emulsifiable concentrate
Active ingredient: 2.5 to 50 wt. % preferably 5 to 45 wt. % especially 10 to 40 wt. %
Surfactant: 1 to 30 wt. % preferably 2 to 25 wt. % especially 3 to 20 wt. %
Liquid carrier: 20 to 95 wt. % preferably 30 to 93 wt. % especially 57 to 85 wt. %
Dust
Active ingredient: 0.5 to 10 wt. %
Solid carrier: 99.5 to 90 wt. %
Flowable suspension
Active ingredient: 5 to 75 wt. % preferably 10 to 50 wt. %
Water: 94 to 25 wt. % preferably 90 to 30 wt. %
Surfactant: 1 to 30 wt. % preferably 2 to 20 wt. %
Wettable powder
Active ingredient: 2.5 to 90 wt. % preferably 10 to 80 wt. % especially 20 to 75 wt. %
Surfactant: 0.5 to 20 wt. % preferably 1 to 15 wt. % especially 2 to 10 wt. %
Solid carrier: 5 to 90 wt. % preferably 7.5 to 88 wt. % especially 16 to 56 wt. %
Granule:
Active ingredient: 0.5 to 30 wt. %
Solid carrier: 99.5 to 70 wt. %
The emulsifiable concentrate is prepared by dissolving the active ingredient in the liquid carrier with the surfactant. The wettable powder is prepared by admixing the active ingredient with the solid carrier and the surfactant and the mixture is pulverized.
The flowable suspension is prepared by suspending to disperse a pulverized active ingredient into an aqueous solution of a surfactant. The dust, the solution, the granule etc. are prepared by mixing the active ingredient with the adjuvant.
In the following compositions, the following adjuvants are used.
______________________________________Sorpol-2680POE-hormylnonylphenolether 50 wt. partsPOE-nonylphenolether 20 wt. partsPOE-sorbitan alkyl ester 10 wt. partsCa-alkylbenzenesulfonate 20 wt. partsSorpol-5039POE-alkylarylether sulfate 50 wt. partsSilica hydrate 50 wt. partsCarplex 100 wt. partsSilica hydrateZeeklite 100 wt. partsClaySorpol W-150 100 wt. partsPOE-nonylphenoletherComposition 1: Wettable powder:Active ingredient 50 wt. partsZeeklite A 46 wt. partsSorpol 5039 (Toho Chem.) 2 wt. partsCarplex 2 wt. parts______________________________________
These components were uniformly mixed and pulverized to prepare a wettable powder. The wettable powder was diluted with water at 50 to 1,000 times and the diluted solution was sprayed at a dose of 5 to 1,000 g. of the active ingredient per 10 ares.
______________________________________Composition 2: Emulsifiable concentrate:______________________________________Active ingredient 20 wt. partsXylene 75 wt. partsSorpol 2680 (Toho Chem.) 5 wt. parts______________________________________
The components were uniformly mixed to prepare an emulsifiable concentrate. The emulsifiable concentrate was diluted with water at 50 to 1,000 times and the diluted solution was sprayed at a dose of 5 to 1000 g. of the active ingredient per 10 ares.
______________________________________Composition 4: Wettable powder:______________________________________Active ingredient 30 wt. partsOther herbicide 20 wt. partsZeeklite A 46 wt. partsSorpol 5039 (Toho Chem.) 2 wt. partsCarplex 2 wt. parts______________________________________
As the other herbicide, the following known herbicides were respectively used 2-(2,4-dichlorophenoxy)propionic acid, 2,4-dichlorophenoxyacetic acid, 3-(3- trifluoromethylphenyl) -1,1 -dimethylurea, 3-(4-methylphenethyloxyphenyl)-1-methyl-1-methoxy urea, 3-(methoxycarbonylamino)-phenyl-N-(3-methylphenyl) carbamate, 3-(ethoxycarbonylamino)-phenyl-N-phenylcarbamate, 3-isopropyl-1H-2,1,3-benzo thiadiazine-(4)-3H-one-2, 2-dioxide, 5-amino-4-chloro-2-phenylpyridazine -3-one, 3- cyclohexyl-5,6-trimethyleneuracil, 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine,2-chloro-4,6-di(ethylamino)-1,3,5-triazine, 2-methylthio-4,6-bis(isopropylamino)-1,3,5-triazine, 4-amino-4, 5-dihydro-3-methyl- 6-phenyl-1,2,4-triazine-5-one, 4-amino-6-t-butyl-4,5-dihydro-3-methylthio-1,2,4-triazine -5-one, 2- chloro-4-trifluoromethylphenyl- 3'-ethoxy-4'-nitrophenyl ether or sodium-5-[2-chloro-4-(trifluoromethyl) phenoxy]-2nitro benzoate.
It is also possible to combine the compound of the present invention with the other herbicidal compounds which are described in "Weed Control Handbook" (Vol. I 6th edition 1977; Vol. II 8th edition 1978 ) issued by the British Crop Protection Council edited by J. D. Fryer MA & R. J. Makepeace BSc. Blackwell Scientific Publication.
The quinoxaline derivatives of the present invention impart excellent herbicidal effect to various weeds especially gramineous weeds in a soil treatment or in a foliage treatment, without any phytotoxicity to broad leaf crop plants such as cotton, soybean, radish, cabbage, eggplant, tomato, sugar beet, ground nut, peas, beans, line seed, sun flower, safflower, potato, tabacco, alfalfa, onion etc. Therefore, the quinoxaline derivatives of the present invention are suitable for selective control of gramineous weeds in a culture of a broad leaf crop plant as herbicide for an agricultural and horticultural field especially up-land.
The quinoxaline derivatives of the present invention are also effective as herbicides for controlling various weeds in the agricultural and horticultural fields such as up-land, paddy field and orchard as well as non-culturated lands such as playground, vacant land, and railway sides, etc.
The herbicidal composition is usually contains 0.5 to 95 wt. % of the compound of the present invention as the active ingredient and the remainder of the adjuvants in the concentrated form. The dose of the compound of the present invention is depending upon a weather condition, a soil condition, a form of a composition, a season of an application and a kind of a crop plant and kinds of weeds and it is usually in a range of 1 to 5000 g. preferably 5 to 1000 g. of the compound of the invention per 10 ares.
The herbicidal activities of the quinoxaline derivatives of the present invention will be illustrated in the following tests.
In the following tests, the herbicidal effects of the compounds of the present invention to gramineous weeds including rice are shown together with non-phytotoxicity of the same compounds to broad leaf crop plants as well as broad leaf weeds especially, non-phytotoxicity of the same compounds to broad leaf weeds in post-emergence. These remarkable selectivities have not been found by the other compounds.
Test 1: Tests for Herbicidal Effect in Soil Treatment
Each plastic box having a length of 15 cm, a width of 22 cm and a depth of 6 cm was filled with a sterilized diluvium soil and seeds of rice (Oryza satira), barnyard grass (Echinochloa crus-galli), large crab-grass (Digitaria adscendens), lambsquarters (Chenopodium ficifolium), common putslane (Postuloca oleracea), hairy galinsoga (Galinsoga ciliata), yellow cress (Rorippa atrovirens) were sown in a depth of about 1.5 cm. Each solution of each herbicidal composition was uniformly sprayed on the surface of the soil to give the specific dose of the active ingredient.
The solution was prepared by diluting, with water, a wettable powder, an emulsifiable concentrate or a solution described in examples of the composition except varying the active ingredient. The solution was sprayed by a small spray. Three weeks after the treatment, the herbicidal effects to rice and various weeds were observed and rated by the following standard. The results are shown in Table 2.
Standard rating:
5: Growth control of more than 90% (substantial suppression)
4: Growth control of 70 to 90%
3: Growth control of 40 to 70%
2: Growth control of 20 to 40%
1: Growth control of 5 to 20%
0: Growth control of less than 5% (non-herbicidal effect)
Note:
Ri: Rice
Ba.: Barnyard grass
L.C.: Large crab grass
La. : Lambsquarters
C.P.: Common putslane
H.G.: Hairy galinsoga
Y.C.: Yellow cress
TABLE 2______________________________________ Dose ofComp. Comp.No. (g/a) Ri Ba L.C. La. C.P. H.G. Y.C.______________________________________1 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 02 100 5 5 5 3 3 3 3 50 5 5 5 2 1 1 2 25 5 5 5 0 0 0 03 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 04 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 05 100 5 5 5 2 2 2 2 50 5 5 5 0 1 1 1 25 5 5 5 0 0 0 06 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 07 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 08 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 09 100 5 5 5 1 2 1 2 50 5 5 5 0 1 0 1 25 5 5 5 0 0 0 010 100 5 5 5 2 3 2 2 50 5 5 5 1 2 1 1 25 5 5 5 0 0 0 011 100 5 5 5 2 1 2 2 50 5 5 5 1 0 1 1 25 5 5 5 0 0 0 012 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 013 100 5 5 5 1 2 2 2 50 5 5 5 0 1 1 1 25 5 5 5 0 0 0 014 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 015 100 5 5 5 2 1 2 2 50 5 5 5 0 0 1 1 25 5 5 5 0 0 0 016 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 017 100 5 5 5 2 3 2 2 50 5 5 5 1 2 1 0 25 5 5 5 0 0 0 018 100 5 5 5 1 2 3 2 50 5 5 5 0 1 2 1 25 5 5 5 0 0 0 019 100 5 5 5 2 1 2 2 50 5 5 5 1 0 1 1 25 5 5 5 0 0 0 020 100 5 5 5 2 2 1 2 50 5 5 5 1 1 0 1 25 5 5 5 0 0 0 021 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 022 100 5 5 5 1 2 2 2 50 5 5 5 0 1 1 1 25 5 5 5 0 0 0 023 100 5 5 5 1 2 2 2 50 5 5 5 0 1 1 1 25 5 5 5 0 0 0 024 100 5 5 5 3 2 1 2 50 5 5 5 2 1 0 1 25 5 5 5 0 0 0 025 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 0______________________________________
Test 2: Tests for Herbicidal Effect in Foliage Treatment
Each plastic box having a length of 15 cm, a width of 22 cm, a depth of 6 cm was filled with a sterilized diluvium soil and seeds of rice, barnyard grass, large crab-grass, lambsquarters common purslane, hairy galinsoga, yellow cress and tomato were sown in a form of spots in a depth of about 1.5 cm. When the weeds were grown to 2 to 3 leaf stage, each solution of each herbicidal composition was uniformly sprayed to foliages at each dose of each active ingredient shown in Table 3. The solution was prepared by diluting, with water, a wettable powder, an emulsifiable concentrate or a solution described in examples of the composition except varying the active ingredient and the solution was uniformly sprayed by a small spray on all of foliages of the plants.
Two weeks after the spray treatment, the herbicidal effects to the weeds and tomato were observed and rated by the standard shown in Test 1. The results are shown in Table 3.
TABLE 3______________________________________ Dose ofComp. Comp.No. (g/a) Ri Ba L.C. La. C.P. H.G. Y.C.______________________________________1 100 5 5 5 2 2 2 3 50 5 5 5 1 1 0 2 25 5 5 5 0 0 0 02 100 5 5 5 3 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 03 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 04 100 5 5 5 1 1 1 1 50 5 5 5 0 0 0 0 25 5 5 5 0 0 0 05 100 5 5 5 2 3 2 2 50 5 5 5 1 2 1 1 25 5 5 5 0 0 0 06 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 07 100 5 5 5 2 1 1 2 50 5 5 5 1 1 0 1 25 5 5 5 0 0 0 08 100 5 5 5 2 1 1 1 50 5 5 5 1 0 0 1 25 5 5 5 0 0 0 09 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 010 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 011 100 5 5 5 2 3 2 2 50 5 5 5 1 2 1 1 25 5 5 5 0 0 0 012 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 013 100 5 5 5 3 2 1 2 50 5 5 5 1 1 0 1 25 5 5 5 0 0 0 014 100 5 5 5 1 1 1 1 50 5 5 5 0 0 0 0 25 5 5 5 0 0 0 015 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 016 100 5 5 5 1 1 1 1 50 5 5 5 0 0 0 0 25 5 5 5 0 0 0 017 100 5 5 5 2 2 2 3 50 5 5 5 1 1 1 2 25 5 5 5 0 0 0 018 100 5 5 5 1 2 2 2 50 5 5 5 0 1 1 1 25 5 5 5 0 0 0 019 100 5 5 5 2 2 2 2 50 5 5 5 1 1 0 1 25 5 5 5 0 0 0 020 100 5 5 5 2 1 2 2 50 5 5 5 1 0 0 1 25 5 5 5 0 0 0 021 100 5 5 5 2 1 1 1 50 5 5 5 1 0 0 0 25 5 5 5 0 0 0 022 100 5 5 5 2 2 2 2 50 5 5 5 1 1 1 1 25 5 5 5 0 0 0 023 100 5 5 5 3 2 2 2 50 5 5 5 2 1 1 1 25 5 5 5 0 0 0 024 100 5 5 5 1 1 1 2 50 5 5 5 0 0 0 1 25 5 5 5 0 0 0 025 100 5 5 5 2 2 2 1 50 5 5 5 1 1 1 0 25 5 5 5 0 0 0 0______________________________________
Test 3: Tests for Phytotoxicity to Crop Plants (Foliage Treatment):
Each plastic box having a length of 15 cm, a width of 22 cm, and a depth of 6 cm was filled with a sterilized diliuvium soil and seeds of cotton, soybean, radish, cabbage and eggplant were sown in a form of spots in a depth of about 1.5 cm. When the plants were grown to leaf-emergence stage, each solution of each herbicidal composition was uniformly sprayed to foiliages at each dose of each active ingredient shown in Table 4. The solution was prepared by diluting, with water, a wettable powder, an emulsifiable concentrate or a solution described in examples of the composition except varying the active ingredient and the solution was uniformly sprayed by a small spray on all of foliages of the plants.
Two weeks after the spray treatment, the phytotoxicities to the plants were observed and rated by the following standard. The results are shown in Table 4.
Standard rating:
5: Complete death of plant
4: Serious phytotoxicity to plant
3: Fair phytotoxicity to plant
2: Slight phytotoxicity to plant
1: Only slight phytotoxicity to plant
0: Non phytotoxicity
Note:
Cot.: Cotton
Soy.: Soybean
Rad.: Radish
Cab.: Cabbage
Egg.: Eggplant
TABLE 4______________________________________Compound Dose of CompoundNo. (g/a) Cot. Soy. Rad. Cab. Egg.______________________________________ 1 50 0 0 0 0 0 25 0 0 0 0 0 2 50 0 0 0 0 0 25 0 0 0 0 0 3 50 0 0 0 0 0 25 0 0 0 0 0 4 50 0 0 0 0 0 25 0 0 0 0 0 5 50 0 0 0 0 0 25 0 0 0 0 0 6 50 0 0 0 0 0 25 0 0 0 0 0 7 50 0 0 0 0 0 25 0 0 0 0 0 8 50 0 0 0 0 0 25 0 0 0 0 0 9 50 0 0 0 0 0 25 0 0 0 0 010 50 0 0 0 0 0 25 0 0 0 0 011 50 0 0 0 0 0 25 0 0 0 0 012 50 0 0 0 0 0 25 0 0 0 0 013 50 0 0 0 0 0 25 0 0 0 0 014 50 0 0 0 0 0 25 0 0 0 0 015 50 0 0 0 0 0 25 0 0 0 0 016 50 0 0 0 0 0 25 0 0 0 0 017 50 0 0 0 0 0 25 0 0 0 0 018 50 0 0 0 0 0 25 0 0 0 0 019 50 0 0 0 0 0 25 0 0 0 0 020 50 0 0 0 0 0 25 0 0 0 0 021 50 0 0 0 0 0 25 0 0 0 0 022 50 0 0 0 0 0 25 0 0 0 0 023 50 0 0 0 0 0 25 0 0 0 0 024 50 0 0 0 0 0 25 0 0 0 0 026 50 0 0 0 0 0 25 0 0 0 0 0______________________________________ | Quinoxaline derivatives having the formula I ##STR1## wherein X represents a halogen atom; R represents ##STR2## --CH═CH--COOR 2 (R 2 represents a C 1 -C 4 alkyl group); --CN or --CH 2 OH, and R 1 represents ##STR3## --S--R 3 (R 3 represents a C 1 -C 4 alkyl or alkenyl group or phenyl or chlorophenyl group), --NH--R 4 (R 4 represents a C 1 -C 4 alkoxy carbonylalkyl group, hydroxy alkyl group, phenyl group; C 1 -C 4 alkoxy alkyl group or di C 1 -C 4 alkyl amino group), are remarkably effective as selective herbicides. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to flexible elastomeric articles, for example, gloves and condoms, processes for their manufacture and formers for use in the manufacturing processes.
2. Scope of the Prior Art
The manufacture of elastomeric gloves by vacuum molding is known from U.S. Pat. No. 3,124,807. The methods described therein comprise the vacuum molding and heat sealing of two sheets of a thermoplastic elastomeric material. However, gloves made from this method will generally possess one or more seams which may be a source of rupture or leakage.
More conventional methods of manufacturing synthetic. elastomeric gloves which overcomes the problem of having seams comprises solvent dipping of an appropriately shaped former into a suitable polymer solvent mix, withdrawing the polymer coated former and then drying off the solvent before stripping the glove therefrom. There are a number of disadvantages with this method, in particular the use of large amounts of solvent is undesirable. Equally, the method of dipping is both time consuming and costly since it is necessary to have a series of formers for dipping which cannot be rapidly reused. Additionally, gloves produced by this method are likely to have residual solvent in them which is toxic and therefore an unacceptable containment.
Blow molding of rigid plastic articles is known, eg. in the manufacture of rigid plastic bottles. However, such techniques have not been used with thin walled flexible elastomeric articles.
WO89/11258 discloses condoms comprising a blow formed tubular main sheath. However, WO89/11258 does not disclose the use of such technology in relation to gloves.
SUMMARY OF THE INVENTION
The present invention seeks to overcome the abovementioned disadvantages by providing flexible elastomeric articles, especially thin walled articles, a method of manufacturing an article body and then stretching the article body in order to produce a flexible elastomeric article.
According to the invention we provide a flexible elastomeric body comprising a flexible elastomeric material the body of which is adapted to be stretched beyond the yield point of the flexible elastomeric material to produce a flexible elastomeric article.
By the term article we include, inter alia, gloves and condoms.
According to a further feature of the invention, we provide a flexible elastomeric body to comprising a glove body comprising hand and cuff portions wherein the finger and thumb portions are stumps which stumps are adapted to be stretched beyond the yield point of the flexible elastomeric material to produce a glove.
With reference to gloves, the finger and thumb stumps may be a stretched by applying stretching means. Such stretching means may be a mechanical means, such as a system of mechanical plungers which stretch the finger and thumb stumps to form the fingers and thumb of the glove, or alternatively a system of clamps which pull the finger and thumb stumps.
Preferably, since the finger and thumb stumps have inner and outer surfaces, they may be stretched by creating a pressure differential between the inner surface and outer surface of the stumps. That is, stretching may be carried out either by applying a pressure, eg. blow molding, to the inner surface, or by applying a vacuum, eg. vacuum molding, to the outer surface of the stumps. It is particularly preferable to apply pressure or vacuum to the glove form.
Conventional molding techniques may be used in the manufacture of the flexible elastomeric body, ie. molding a flexible elastomeric material into an appropriately shaped body. Molding techniques such as blow molding, eg. of a parison of a flexible elastomeric material or injection molding may be used. Conventional conditions known per se could be used in the manufacture of a flexible elastomeric body.
The glove body as hereinbefore described may be manufactured by conventional methods known per se, such as methods described in Handbook of Thermoplastic Elastomers edited by Benjamin M Walker, which is incorporated herein by reference. Preferably the glove body is manufactured by blow molding a parison of plastics material to produce a glove body comprising hand and cuff portions wherein the finger and thumb portions are stumps.
A condom body may be manufactured by techniques analogous to those used for glove manufacture.
In order that the finger and thumb portions of the glove are of smaller thickness to the hand and cuff portions, the finger and thumb stumps body will generally be of at least equal thickness or preferably greater thickness than the remainder of the hand and cuff portions created.
During the stretching, the polymer used to produce the gloves undergoes "strain hardening" (the alignment of the long chains of the polymer), which at a low thickness actually increase the strength of the flexible elastomeric polymer.
Thus, a glove produced using the glove body described may comprise hand and cuff portions of greater thickness than the finger and thumb portions. Preferably the finger and thumb portions are of a thickness less than 50 μm and the remainder of glove body is of a thickness less than 200 μm. As an alternative, the cuff portion may be greater in thickness than the hand portion which will be beneficial in the donning of the gloves as the additional thickness provides additional strength and tear resistance to the glove.
Whereas in the traditional method of manufacturing a glove form the hand and cuff portions may generally be of the same thickness as the finger and thumb stumps, ie. less than 200 μm.
According to yet a further aspect of the present invention there is provided a glove made by the process as hereinbefore described. In particular we provide a glove made from a polyetherester block copolymer such as HYTREL™.
A variety of polymers may be used in the manufacture of the articles and flexible elastomeric bodies of the present invention. The material used in the invention may be any thermoplastic elastomer which material may be stretched beyond their yield value to a point such that the material will be permanently deformed, but at the same time still displays elastic properties in the new deformed state.
According to the invention, we provide a glove as hereinbefore described comprising a thermoplastic elastomer.
By the term thermoplastic elastomer (TPE), we mean compounds which show intermediate behavior between a thermoplastic and an elastomer. They are provided with crosslinks derived from physical means rather than chemical means, as in the case with true rubbers. Consequently, they can be processed as thermoplastics, including, eg. blow molding which is impossible for rubbers. After processing they return to their original state with the crosslinks reforming.
There are a number of different types of TPEs and their distinction is typically made on the method of crosslink. They invariably have a two phase system comprising of rubbery matrix, or sort block embedded in which is a stiff phase comprising a glassy or crystalline polymer, or hard block.
In particular, we prefer thermoplastic elastomers which comprise hard and soft block copolymers, eg. di-block and tri-block copolymers. Typical di- and tri- block copolymers include styrenic di- and tri-block copolymers, eg. styrene-butadiene-styrene and styrene-ethylenebutadiene-styrene. Preferred polymers of this type include those sold by Shell in the UK under the names KRATON and CARIFLEX (Trade Marks).
Other preferred thermoplastic elastomers include polyurethanes where a polyol comprises the soft block and a polyester or polyether glycol the hard block. Polyether polyurethanes are preferred since they tend to be more flexible. Specifically preferred polyurethanes include those available in the UK, ELASTOLLAN (Trade Mark) from BASF, ESTANE (Trade Mark) from BF Goodrich and AVALON (Trade Mark) from ICI.
Thermoplastic polyetheresters may also be mentioned. Such copolymers comprise a polyether soft block and a polyester hard block. Preferred polyetheresters include HYTREL (Trade Mark) available from Du Pont.
In addition to hard and soft block copolymers, thermoplastics for use in the present invention include alloys and blends. For example, blends of polyurethane and vinyl acetate which are polymerised, eg. having a vinyl acetate content of from 10-30% w/w, may be used. Other materials include blends such as polyurethane/high impact polystyrene (PU/HIPS) and EVA/HIPS, copolyamides, eg. polyether block amides, and silicones.
Thus, in particular, hard and soft block copolymers may include those where the soft block may be selected from dienes, eg. alkyldienes such as butadienes, polyols, such as polyether or polyester polyols, polyethers, and vinyl acetates. The hard blocks may be selected from styrenes, glycols, polyesters and polyethylenes.
According to the invention we provide the use of a polymer or polymer blend as hereinbefore defined in the manufacture of a flexible elastomeric article body, or a glove, according to the invention.
According to the invention, we also provide the use of a polyetherester in the manufacture of an article, such as a glove.
The mold for use in the manufacture of the glove form according to the invention is also novel per se. Thus, according to yet a further aspect of the present invention there is provided a mold adapted for use in the production of a blow molded glove form which mold has internal dimensions in the form of glove, hand and cuff portions and with chambers for fingers and thumb stumps.
The mold as hereinbefore described preferably comprises two portions which may be separated to facilitate removal of the glove form.
Further, there is provided a second mold adapted to receive a glove body comprising a hand and cuff portion and finger and thumb stumps which second mold is provided with finger and thumb shaped chambers adapted to correspond with the finger and thumb stumps in the glove. The finger and thumb chambers also optionally are provided at the end distal from the hand portion with conduits for the evacuation of the finger and thumb chambers.
Preferably, the mold is a hollow mold in two parts in the shape of a glove body with finger and thumb stumps. Advantageously, a second hollow mold is provided in the form of a complete glove with finger cavities in order that a glove produced in the first mold may subsequently be stretched into a complete glove in this second mold.
The invention will now be described, but in no way limited, by way of example, with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a sectional view of a mold for the manufacture of a glove form as hereinbefore described;
FIG. 2 is a sectional view of the mold of FIG. 1 illustrating the blow mold of a glove body;
FIG. 3 is a sectional view of a mold for the manufacture of a glove as hereinbefore described illustrating a glove body in position ready to be stretched; and
FIG. 4 is a sectional view of a glove after stretching of the glove body within the mold shown in FIG. 3.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIGS. 1 and 2, there is illustrated a hollow mold generally designated 10, which hollow mold 10 comprises two halves 12 and 14 respectively. There is also shown in position between the two halves 12 and 14 a parison 9. Each half 12, 14 of the mold 10 is internally shaped in the form of two halves of a glove having internal walls 16 and 18 and having finger and thumb stump chambers generally designated 20.
The two halves 12 and 14 co-operate with each other in such a manner that in union the walls 16 and 18 of the mold form a space defining a glove body 22, with an opening 24 providing a cuff portion 26 to the glove. A parison transport mounting 28 into which a blowing pin 30 is fitted co-operates with the opening 24 and acts as a seal.
In use, a molten parison tube 9, eg. of polyetherester block copolymer such as HYTREL™ is placed between the two halves 12 and 14 of the hollow mold 10. The parison tube 9 is produced by a conventional method of pin extrusion known in the field of blow molding. Once the parison tube 9 is in position and mounted around the parison transport mounting 28, the two halves of the mold 12 and 14 are clamped together to form a space defining the glove body chamber. As a consequence of the two halves 12 and 14 engaging and being clamped, the parison tube 9 is sealed and the waste end of the parison 38 of the tube trimmed away. The blow pin 30 is then placed into the transport mounting 28 and air is injected into the parison tube 9 which expands until it comes into contact with walls 16 and 18 of the hollow mold 10 takes the shape of glove form chamber 21. The mold 10 can then be opened to remove the glove body 40.
FIG. 3 illustrates a second hollow mold 32 in the form of a complete glove 34 with finger and thumb cavities generally designated 36. The finger and thumb cavities 36 of the glove 34 has its tip remote from the glove body 40 and conduits 39 which form a connection between the fingers 36 of the mold 32 and a means of suction (not illustrated).
The glove body 40 which is still mounted on the transport mounting 28 and which still contains the air injected into it, is then placed in the second hollow mold 32. In position in the mold 32 each of the protrusions 20 correspond with a respective finger cavity 36. In this cold state each of the protrusions 20 are stretched by the use of suction into their respective finger cavities 36. Each protrusion 20 is stretched to a point where the polymer such as HYTREL exhibits a yielding phenomenon whereby the polymer is permanently deformed, but still displays elastic properties in the new deformed state.
Referring to FIG. 4, as a result of the suction applied to the finger and thumb stumps are formed. During the stretching, the polymer used to produce the gloves undergoes "strain hardening" (the alignment of the long chains of the polymer), which at a low thickness actually increase the strength of the polymer.
Having stretched the finger and thumb stumps as illustrated in FIG. 3 and 4 a glove 46 is produced which can then be released from the mold 32. | There is disclosed a method of manufacturing flexible elastomeric articles such as gloves, which comprises molding the glove body from a parison of the elastomeric material and stretching the stump portions into finger and thumb portions. | 1 |
REFERENCE TO CORRESPONDING APPLICATIONS
The present application is the 371 national stage application based on International Application No. PCT/AU2014/000512, filed May 12, 2014, which claims priority to Australian Patent Application No. 2013901675, filed May 13, 2013, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to methods for determining the amount of residual sterilant remaining on the surface of an object at the end of a disinfection process.
BACKGROUND
“Sterilization” has been defined as the process of destroying all microorganisms, spores and their pathogenic products. A 6 log reduction in the amount of such pathogens is generally required to provide a suitable sterility assurance level. “Disinfection” is a similar process, the difference being that it results in a lesser degree of biocidal effect, particularly on bacterial spores. Disinfection is thus easier to achieve than sterilization.
The term “sterilant” will be used throughout although it is understood to encompass both “sterilant” and “disinfectant”.
Heat has traditionally been one option for carrying out sterilization. However, heat sterilization is not always practical, for example, when sterilizing heat-sensitive articles, such as certain medical instruments, or when sterilizing large areas, as in the case of room sterilization. For this reason, low-temperature sterilization is often the best option.
Low-temperature sterilants are usually liquids and can be applied to articles requiring disinfection or sterilization in a variety of ways. In recent years, the use gas or aerosol dispensing technologies to dispense sterilants has become widespread. Gas or aerosol processes are particularly attractive since they reduce the amount of liquid sterilant used. The primary benefit of using micro volumes of liquid is that rinsing steps can sometimes be eliminated and drying times are often significantly reduced compared to using say, soaking baths. This shortened cycle time reduces the turnaround time for any given instrument which in turn translates into a much smaller capital outlay tied up in instruments.
Gas or aerosol processes also tend to be conducted in closed systems, which means that operator safety is also enhanced relative to conventional methods that expose workers to large volumes of open sterilant solutions.
In recent years the use of hydrogen peroxide or peracetic acid as a sterilant has become greatly preferred. Hydrogen peroxide has been used in the vapour phase for disinfection or sterilization. Vapour phase systems generally employ small volume chambers such as sterilizers that can be evacuated since the vapours are more effective at very low pressures or as plasmas. At the end of the treatment cycle, residual hydrogen peroxide vapour is pumped out by a vacuum pump and exhausted to the atmosphere directly or via a catalytic destroyer which decomposes any residual peroxide vapour into harmless oxygen and water.
Peroxide vapours have also been used at atmospheric pressure but in that case longer treatment times are generally involved than in vacuum systems and efficacy against bacterial spores has been shown to be limited. After treatment in small scale peroxide vapour systems, air is circulated through the chamber and any residual peroxide is either flushed directly into the atmosphere through a HEPA-filter, or is flushed into the atmosphere via a catalytic destructor so that the peroxide is catalysed to oxygen and water prior to disposal. In some recirculating systems the flow may be diverted after the treatment and recirculated by an air pump though a catalytic destroyer placed in parallel with the treatment circuit until peroxide is eliminated.
Others have endeavoured to use peroxide aerosols (rather than vapour) as the biocidal agent for sterilization or disinfection of small chambers. Aerosols have a number of major advantages over vapour process. A much higher concentration density of active species is obtainable at atmospheric pressure for aerosols than for vapours. Aerosols also eliminate the need for costly vacuum equipment. In some such cases the aerosol flow may be diverted through a catalytic destructor after the treatment cycle is completed to remove any peroxide residues.
While such stable aerosols of aqueous biocides, preferably hydrogen peroxide, can be employed at atmospheric pressure and above which avoid the need for vacuum equipment, elimination of residual hydrogen peroxide on the surface of sterilized articles nevertheless remains a significant problem.
In the food sterilization field, even trace amounts of hydrogen peroxide can affect the flavour or colour of the product. Food packaging regulations now limit hydrogen peroxide residues on containers to a maximum of 0.5 ppm in the United States.
In the case of medical instruments, even a small amount of residual peroxide on an ultrasound probe or similar could have potentially serious consequences for a patient if the probe were to be placed in direct contact with the patient's skin or mucosa. Peroxide in high concentrations is highly corrosive and can result in severe wounding. For similar reasons, the use of peroxide as a sterilant means that occupational health and safety measures need to be in place to ensure the safety of staff working in disinfected environments.
Surface residues of peroxides in operating theaters or on surgical instruments should be below 100 mkg/cm 2 . To achieve such levels by blowing or sucking air even though small chamber volumes for sterilizing instruments or the like can add significantly to process times, especially when the incoming air needs also to be HEPA-filtered to maintain sterility. The removal step thus adds greatly to treatment times because the residual balance of peroxide reduces asymptotically. The larger the volume of space treated the more difficult the removal problem becomes.
Similar considerations apply to biocides other than peroxides.
In addition, it is not feasible to check every sterilization cycle of every apparatus or every room or space treated in order to ensure complete sterilization. Certification of sterilant removal, i.e. guaranteed removal of the sterilant or reduction of the sterilant to a certain level is highly desirable. Following the stated protocol as a way to achieve a guaranteed or certified outcome is very efficient mode of operation. However, it can still be highly desirable to perform a quick test to confirm experimentally whether a guaranteed level of certification of sterilant removal is actually achieved. Ideally, such a test would be “on/off” or ‘go/no-go”, meaning that the when the test is conducted, a clear answer would be given as to whether a certain level of residual was present or not.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
SUMMARY OF THE INVENTION
In a broad first aspect the invention provides a method of determining the amount of residual sterilant on a test piece after a sterilization regime in a sterilization space, the method comprising the steps of:
placing a test piece having a predetermined surface area into the sterilization space;
subjecting the test piece to the sterilization regime;
collecting the residual sterilant from the test piece in a collector solution; and
measuring the amount of residual sterilant in the collector solution.
Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.
The sterilization space can in one embodiment the sterilization chamber of a sterilization apparatus. In another embodiment, the sterilization space can be a larger space or room which is being disinfected.
In a particularly preferred aspect, the invention provides a method of determining whether the amount of residual sterilant on a test piece after a sterilization regime in a sterilization space exceeds a predetermined threshold.
In one embodiment, the step of collecting the residual sterilant from the test piece in a collector solution is performed by placing the test piece into a collector solution. In another embodiment, the step of collecting the residual sterilant from the test piece in a collector solution is performed by washing the test piece with a collector solution
Preferably, the collector solution is used in a predetermined amount.
In one embodiment, the step of measuring the amount of residual sterilant in the collector solution is by direct measurement of the sterilant.
In another embodiment the step of measuring the amount of residual sterilant in the collector solution is by indirect measurement of the sterilant.
According to second aspect the invention provides a method of determining whether the amount of residual sterilant on a test piece after a sterilization regime in a sterilization space exceeds a predetermined threshold; the method comprising the steps of:
placing a test piece having a predetermined surface area into a sterilization space;
subjecting the test piece to the sterilization regime;
placing the test piece into a first solution containing a known amount of a first species reactive with the sterilant;
adding to the first solution a known amount of a second species reactive with the first species,
whereby the first species and second species are reactive to provide a result having a first visual appearance if the amount of residual sterilant is above a predetermined level or having a second visual appearance if the amount of residual sterilant is below a predetermined level; and wherein the first visual appearance and second visual appearance are non-identical.
In an alternative embodiment, the first species is reactive with the sterilant to provide a result wherein the an appearance can be correlated with the amount of residual sterilant.
In another alternative embodiment, the first solution and sterilant are reactive and the first solution and second solution are reactive to provide a result wherein the an appearance can be correlated with the amount of residual sterilant.
In a preferred embodiment, the sterilant is hydrogen peroxide.
For preference, the test piece is peroxide resistant plastic or glass. It may have any shape, but ideally the shape is simple
The predetermined threshold would be any regulatory or practical level of residual sterilant that was the minimum amount considered to be harmful to humans. Typically, such residual thresholds are expressed in terms of mass per unit area, (e.g., μg/cm 2 ).
In one embodiment, the sterilization regime comprises contacting the test piece with an aerosol of hydrogen peroxide in a sterilization space followed by removal of the aerosol from the sterilization space. Most preferably, the sterilization regime comprises contacting the test piece with an aerosol of hydrogen peroxide in a sterilization space followed by removal of the aerosol from the sterilization space.
Preferably the first solution contains sulfuric acid and iodide. The first solution is preferably prepared immediately prior to use by mixing a precursor solution comprising sulfuric acid with a precursor solution comprising iodide.
Preferably the first species reactive with the sterilant is iodide. Preferably the second species reactive with the first species is thiosulfate.
Preferably the first species and second species when mixed are monitored for a visual appearance at a predetermined time after mixing, for example 5 seconds.
Preferably the first visual appearance if the amount of residual sterilant is above a predetermined level is a yellow or brown color. Preferably the first visual appearance is caused by the presence of I 2 or I 3 − .
Preferably the second visual appearance if the amount of residual sterilant is below a predetermined level is a colorless appearance.
DETAILED DESCRIPTION
The method of the present invention enables a measurement of the amount of residual sterilant on a test piece after a sterilization regime in a sterilization space. It can be used to quantify the amount of sterilant or to determine whether the amount of residual sterilant meets or exceeds a predetermined threshold value.
The method involves placing a test piece having a predetermined surface area into the sterilization space or subjecting the test piece to the usual sterilization regime, removing the test piece from the sterilization space and collecting the residual sterilant from the test piece by way of a collector solution. In one embodiment, for example, a test piece of known area is placed in a chemical sterilizer (which may be bulk liquid, vapour or aerosol) and sterilized under the normal operating conditions (including time, concentration, temperature, aerosol removal and cycling) for that space that would be considered sufficient to certify sterilization.
The test piece is desirably of simple construction, such as a small strip or square that can easily be supported in the space. The test strip could be made of a one or more materials, including but not limited to plastics and metals that are commonly sterilized.
Once the sterilization process is finished, the test piece is removed carefully so as not to disturb any residual sterilant, but also as quickly as practicable so as not to allow for evaporation of sterilant peroxide which could provide a false negative.
The most preferred approach for collecting the residual sterilant is for the test piece simply to be immersed in the collector solution. Ideally, it is not removed from the collector solution for the remainder of the test. Alternatively however, the test piece can be rinsed with a collector solution and the total rinse volume collected.
The collector solution is preferably used in a predetermined amount, so that the concentration of the sterilant collected can be determined.
The step of measuring the amount of residual sterilant in the collector solution can be by direct or indirect means. The choice of direct or indirect measurement will depend upon the nature of the sterilant.
For example, direct measurement may be applicable for a sterilant that is UV active (having an aromatic ring or forming a charge transfer complex, for instance) directly subjecting the collector solution or a treated collector solution to UV spectroscopy. The use of a calibration curve will enable the concentration of the residual sterilant in the collector solution to be determined. Because the volume of collector solution is known, the total amount of sterilant can thus be determined. Because the area of the test piece is known, a figure for the amount of sterilant per unit area can be determined.
Any species which can have its concentration determined spectroscopically can have the amount of residual sterilant measured in this way.
Direct measurement may also be possible if the sterilant can be analysed via titration (for instance, in the case of acidic or basic sterilants) where an endpoint can be used to determine the concentration of sterilant present in the collector solution.
For species which are difficult to quantify directly, indirect measurement of the sterilant may be possible. An example of indirect measurement would be in the case of a sterilant reacting stoichiometrically with an agent that was quantifiable.
An important sterilant which is difficult to quantify by direct measurement is hydrogen peroxide. It is preferred if peroxide can be determined indirectly, via its stoichiometric reaction with iodide, and subsequent titration with a reductant. The following nonlimiting explanation is provided by way of example.
The present invention in a particular embodiment relates to a test to determine whether the amount of a sterilant, particularly hydrogen peroxide on a surface is above or below a certain predetermined threshold level. The test may be used for example to determine the level of peroxide residue (in terms of mass/unit area) left on a sterilized article at the completion of the sterilization process.
In principle, a test piece of known area is placed in a chemical sterilizer (which may be bulk liquid, vapour or aerosol) and sterilized under the normal operating conditions (including time, concentration, temperature, aerosol removal and cycling) for that space that would be considered sufficient to certify sterilization.
The test piece is desirably of simple construction, such as a small strip or square that can easily be supported in the space. The main thing is that the test piece is of precisely known surface area. The test strip could be made of a one or more materials, including but not limited to plastics and metals that are commonly sterilized.
Once the sterilization process is finished, the test piece is removed carefully so as not to disturb any deposited peroxide, but also as quickly as practicable so as not to allow for evaporation of peroxide which could provide a false negative.
The test piece is then subject to the following:
An aqueous solution of sulfuric acid and iodide is prepared immediately before use by mixing sulfuric acid with a sodium iodide solution in a suitable container. The test strip is then placed into this solution and a further solution containing thiosulfate is then added. The whole container, including the test strip in the liquid is then shaken for about 5 seconds. It is important that any loss of liquid is minimised during the mixing and shaking procedure.
The quantities of each component are decided beforehand depending upon the desired threshold level that is chosen. The chemistry and method of calculation will be illustrated below for the example.
If the amount of residual peroxide per unit area on the test strip exceeds the calculated threshold, then the solution will turn yellow. If the solution does not turn yellow, the level of peroxide per unit area on the test strip does not exceed the calculated value.
To explain further, the chemistry of the present invention involves the following two reactions:
H 2 O 2 +2NaI+H 2 SO 4 →I 2 +NaSO 4 +2H 2 O
and then
I 2 +2Na 2 S 2 O 3 →Na 2 S 4 O 6 +2NaI
In this system, water, sodium iodide and sulfuric acid are provided in comfortable excess. However, other alkali metal iodides, for example, potassium iodide, may be used as an alternative source of iodide to sodium iodide. The amount of iodine produced will be in an equimolar to the amount of peroxide present, which is the variable being measured. The amount of iodine thus produced acts as a visible proxy for the amount of peroxide present on the test piece.
Thus, it can be seen that if the molar amount of peroxide:thiosulfate equals 1:2 (and consequently, the ratio of iodine:thiosulfate is 1:2), then the reaction will be balanced, and the net amount of iodine produced will be zero, since the two equations will cancel each other out.
If the molar ratio of peroxide:thiosulfate is less than 1:2 ratio (and consequently, the ratio of iodine:thiosulfate is less than 1:2), then there will be excess thiosulfate, meaning that all iodine will be consumed, and reduced to I − .
However, if the molar ratio of peroxide:thiosulfate exceeds a 1:2 ratio (and consequently, the ratio of iodine:thiosulfate exceeds 1:2), then there will be a deficit of thiosulfate to reduce the iodine. Some, but not all, of the iodine will be reduced to I − . There will thus be an excess of iodine, which will present a visible colour (the visible colour is actually caused by iodine and iodide forming soluble, I 3 − which is brown at high concentrations and yellow at lower concentrations).
The above chemistry can be exploited in a manner which can test for a predetermined molar amount of peroxide.
In the present case, the test is to determine whether the amount of peroxide in grams per unit area on the test piece falls above a certain amount. The molecular weight of peroxide is known, as is area A of the test piece, so it becomes only necessary to determine whether the total molar amount of peroxide is at Q moles or above. The amount of sulfuric acid and alkali metal iodide (for example, sodium iodide or potassium iodide) are chosen to be comfortably in excess of Q, but an exact quantity of 2Q moles of thiosulfate is required when testing for a total of Q moles of peroxide residue. If more than Q moles of peroxide are present, the test will show a positive colour for iodine. If Q or less than Q moles of peroxide are present, the test will not show any iodine colour.
EXAMPLE
The following example illustrates the present invention:
Health regulations vary from jurisdiction to jurisdiction and application to application as to the level of residual hydrogen peroxide on the surface of a sterilized article following sterilization that would be considered safe. For the following purposes, we will define the safe concentration as 250 ng per square centimeter of article.
In the present example, a test piece, being a strip of smooth plastic, of area 10 cm 2 is placed in the sterilizer and is subjected to the sterilizer's standard sterilization regime.
Whilst the sterilizer is completing its process, the following two solutions are mixed in a separate container:
Precursor solution A containing 1M sulfuric acid, 20 mL. Precursor solution B containing 10% sodium iodide or potassium iodide Solution, 3 mL.
The solutions A and B are provided in unmixed two part form for maximum accuracy. The solutions should be mixed just prior to their intended use, since the quantity of free iodine can reduce over long term storage.
Once the standard sterilization regime is complete, the test piece is removed from the sterilizer and introduced into the container containing the mixed precursor A and B solutions.
To this mixture, the following solution is then added as soon as practicable:
Solution C containing 0.05N sodium thiosulfate solution, 3 mL
The container, including the test strip, is then shaken for 5 seconds. It is desirable if the containers are closed, since loss of liquid during shaking can result in errors.
If the solution remains clear/colourless, the residual peroxide on the test carrier is at or below the predetermined threshold limit, in this case 250 μg/cm 2 .
If the solution turns a yellow colour, the residual peroxide on the test carrier was above the 250 μg/cm 2 threshold limit.
The above concentrations are specifically formulated to determine whether there is more or less than 250 μg/cm 2 over a 10 cm 2 surface, but these can be adapted to different surface areas and levels of residue.
250 μg/cm 2 of hydrogen peroxide on a 10 cm 2 surface equates to a total mass of 2520 μg of hydrogen peroxide. Hydrogen peroxide has a molecular mass of 34 g/mol, so the threshold test is in effect looking to determine whether the test strip carries in excess of 7.4×10 −5 moles of hydrogen peroxide.
The amount of I − used is around 0.002 moles, comfortably in excess of the peroxide level being tested. The amount of sulfuric acid is also in comfortable excess.
However, the amount of thiosulfate is carefully chosen to give a stoichiometric reaction with the iodine produced—in this case 0.00015 moles (twice the molar amount of peroxide threshold being tested, which is the exact stoichiometric ratio to give the desired result).
These calculations could be readily modified to adjust for the changes in the predetermined threshold value and/or test strip area.
In addition, the current test is highly sensitive. The visual detection limit of (I 2 /I − ) systems (I 3 − ) has been estimated to be of the order of 5×10 −6 M. The exemplified solution has 7.4×10 −5 moles in 26 mL total volume, which translates to a molarity of 0.0028M. Thus, the relative precision of this test (5×10 −6 in 3×10 −3 ) is extremely high.
The counter ions and acid can be varied, substituting equivalents as necessary or desired.
This method can thus allow ready onsite re-validation of certified residual amounts of peroxide, in a “go/no-go” fashion.
Alternatively, this method can also provide a quick test for certification of an instrument prior to release for sale.
The test can also be worked in a semi-quantitative manner in which a number of test pieces are removed from the sterilizer and placed into a graded series of solutions prepared with different quantities of thiosulfate intended to capture different peroxide residues. Alternatively, a suite of differently sized test pieces could be used in a number of parallel tests. In this way, a wider range of peroxide residues could be evaluated, each discrete point giving a “go/no-go” result.
The present invention, using a test strip and a small number of solutions, is highly portable and very suitable for end user on-site testing. This invention allows for an accurate test to be conducted relatively inexpensively and can be carried out by following simple instructions, with no training required. | Methods for determining the amount of residual sterilant remaining on the surface of an object at the end of a disinfection process are described. One method of determining the amount of residual sterilant on a test piece after a sterilization regime in a sterilization space includes the steps of: placing a test piece having a predetermined surface area into the sterilization space; subjecting the test piece to the sterilization regime; collecting the residual sterilant from the test piece in a collector solution; and measuring the amount of residual sterilant in the collector solution. | 0 |
FIELD OF THE INVENTION
[0001] This invention refers to a liquid fertilizer of origin mineral and organic where it is used sabila and humic acid as source of organic matter, to which have been added the micronutrients iron, zinc, copper, manganese, boron, calcium and magnesium in form of soluble compound, furthermore of an chelating agent and a surface active agent to make that the nutrients are more assimilable for the cultivations.
BACKGROUND OF THE INVENTION
[0002] The use of fertilizers is essential for the good growth and the high production of the crops. Of the basic nutrients that the plants need to have a healthy development, most of the cultivations and soils require big quantities of nitrogen (of from NO 3 − or NH 4 + ), phosphor (of from H 2 PO 4 − ), and potassium (of from K + ) (Wichmann, W., et al, IFA World Fertilizer Use Manual). Such quantities of nitrogen, phosphor and potassium are provided mainly in form of mineral fertilizers, be already processed of natural or produced minerals chemically (K. F. Isherwood, 1998, Mineral Fertilizer Use and the Environment, United Nations Environmental Programme Technical Report No. 26). The development and use of the mineral fertilizers from the decade of the 1940's have allowed significant increments in the production of the crops.
[0003] In spite of the importance of the mineral fertilizers, in the last years the damage made to the atmosphere has been recognized by its use. The future challenge it is to use the fertilizer with more efficiency and the systems of integrated handling of the production provide a road toward the rationalization in the use of the inputs. (Fertilizer and the future, by Louise O. Fresco, Assistant Director-General, FAO Agriculture Department, http://www.fao.org/AG/magazine/wfspdf/0306sp1.pdf).
[0004] The mineral fertilizers, in occasions, they can damage to the soil. For example, the excessive use of the chemically synthesized nitrogen can inhibit the natural activity of the responsible microorganisms of fixing the nitrogen and, therefore, to diminish the natural fertility of the soil. The extensive use of the mineral fertilizers can cause contamination. For example, the nitrogen loss and phosphate of the fertilizers due to the erosion could contaminate soils and underground waters.
[0005] In the search of a solution to these problems, some Agricultural Engineers have recaptured the use of organic fertilizers or of the fertilizers in a half point between the minerals and the organics, the organic-minerals fertilizers, produced; by combining some minerals with organic matter coming mainly of plants and they have had very satisfactory results as for the enrichment of the plants and the soil.
[0006] Today in day, the organic fertilizers and the organic-minerals fertilizers can be made of matters varied cousins. Some of the first used materials were the municipal organic residuals due to their low cost and great macronutrients content, such it is the case of the U.S. Pat. Nos. 6,828,137 and 6,352,569. Other fertilizers use the cow manure, horse, chicken, lamb or pig like organic base, like in the U.S. Pat. No. 6,852,142. However, although the organic matter coming directly of the plants it is one of the more abundant, very few fertilizers use this source like base of their formulation. The present invention uses the sabila as source of its organic matter, furthermore other nutrients, for its fabrication.
DESCRIPTION OF THE INVENTION
[0007] The present invention intends to provide an ecological fertilizer that promotes the growth of the cultivations and improve the quality of the crops and the characteristics of the soil.
[0008] The present invention consists on a liquid fertilizer that with-has organic matter and lignin; amino acids, nitrogen, iron, zinc, manganese, copper, boron, calcium, magnesium, humic acid, a chelating agent, a surface active agent and a conservative.
[0000]
COMPONENT
CONCENTRATION (%)
Organic matter
25-35
Lignin
0.5-5
Amino acids
0.01-2
Nitrogen
1-6
Iron
1-6
Zinc
0.5-5
Manganese
0.5-5
Copper
0.1-2
Boron
0.01-3
Calcium
0.01-3
Magnesium
0.01-3
Humic acid
10-30
Chelating Agent
1-6
Surface active agent
1-6
[0009] The percentages in weight are based on the total weight of the fertilizer; where the organic matter is obtained of the sabila extract ( Aloe Vera ) and of the humic acid, the lignin of the sabila extract, the nitrogen source is from urea, the iron is from ferrous sulphate monohidrated, the zinc is from the zinc sulphate monohidrated, the manganese is from manganese sulphate monohidrated, the copper is from copper sulphate heptahidrated, the boron is from liquid fertilizer of Boron to 10%, the calcium is from the liquid fertilizer of calcium nitrate, the magnesium is from magnesium sulphate, the chelating agent such as epoxidated soybean oil, the surface active agent such as nonilphenol poliglicolic eter and the conservative such as formal.
[0010] The use of the sabila extract is one of the essentials characteristics of the invention, since it provides to the fertilizer organic matter and lignin of great importance for the soils, furthermore other essential nutrients as calcium, potassium, sodium, aluminum, iron, zinc, copper, chromium, phosphor and amino acids.
[0011] Furthermore the use of the extract of the sabila as source of natural organic matter is added liquid humic acid concentrated (humus) that gives bigger enrichment contribution to the soil in organic matter and more assimilation and exchange of nutrients in the soil
DESCRIPTION OF THE SABILA PLANT
[0012] The genus Aloe belongs to the tribe Aloineae of the family Liliaceae, which is a fundamentally African tribe, but some of the genus which comprise it can be found in any other part of the world, either for natural dispersion, or because they were introduced by its multiple advantages and actually they are being objects of commercial cultivation.
[0013] Of the genus Aloe they have been described 320 species approximately, among which it highlights the sabila ( Aloe Vera (L) Burm.) (Table 1) In Mexico the most frequent cultivated species are: A. Vera and A. ferox.
[0014] The plants of this species are herbaceous of short shaft, vivacious, perennial, with aspect rosetted (basal rosettes) of grizzly green colour that presents reddish stains by the lingering exhibition to the sun. In their mature stage they end up measuring 65-80 cm of height.
[0015] ROOT. It is fairly superficial, with scaly structure.
[0016] LEAVES. They are lineal (long and narrow), acuminadas (finished in tip), the margins are thorny-jagged; of coriaceous texture (similar to the leather, resistant but flexible); succulent (juicy, fleshy); of 30-60 cm of longitude, they are usually cone-shape packed in a dense rosette; of intense colour in variable tones of green.
[0000]
Taxonomic clasification
Kingdom
Vegetable
Division
Embriophyta-siphonogama
Subdivision:
Angiosperma
Class
Monocotiledoneae
Order
Liliales
Family
Liliaceae
Subfamily
Asfondeloideae
Tribe
Aloinaeae
Genus
Aloe
Specie
vera
Synonymous
barbadensis
[0017] INFLORESCENCE. Of 1-1.3 m of high, simple or barely ramified (one or two lateral ramifications).
[0018] FLOWERS. Of yellow-greenish colour; accompanied by a membranous bract, lanceolate (in form of lance tip—longer than wide—), of white, rosy colour, with dark lines of 6 mm; cylindrical, curved perianth, segment erect; stamens with 6 filaments, as long as the perianth anthers oblong base-fixed; ovary sésil, oblong-triangular, with several ova in each cavity; filiform style; small stigma.
[0019] The flowering happens in different times depending on the species, it can happen from the end of the winter until the summer.
[0020] FRUIT. It is a capsule loculisidal or septicidal, with inconsistents walls and it conforms to of three valves loculizadas, oblong and triangular.
[0021] This plant presents characteristic such as the succulency and its metabolism acid crasuláceo that indicate an important adaptation to areas characterized by the shortage of water.
[0022] The plants in wild state or generally naturalized form dense colonies, being the central plant the plant mother. Each plant produces 20 lateral rosettes on the average (sprouts) where difficultly reach the 40 cm of height.
Geographical Localization
[0023] In Mexico, the sabila can be found in almost the whole country, as of ornament in the domestic gardens and in some places as wild plants, they obtain in plantations.
[0024] Particularly, in the states of San Luis Potosi, Hidalgo, Tamaulipas and Guanajuato, the wild colonies of sabila are bigger. However, the natural populations of this genus have not been defined and quantified in our country.
[0025] For their easiness of adaptation and their properties the sabila has wakened up the interest like cultivation, there being you established plantations in 1,752 hectares of the country, of those which 780 (44.5%) they are of storm and the remaining ones 972 (55.5%) they understand watering cultivations. The distribution of the sabila in cultivation is given in the following table.
[0000]
Cultivated surface of sabila by states (ha)
Watering
%
Storm
%
Total
%
San Luis
—
—
362
46.5
362
20.66
Potosí
Tamaulipas
946
97.3
418
53.6
1,364
77.85
Nuevo León
13
1.4
—
—
13
0.74
Zacatecas
3
0.3
—
—
3
0.19
Guanajuato
5
0.5
—
—
5
0.28
Chiapas
5
0.5
—
—
5
0.28
Total
972
780
1,752
Source: CONAZA, 1991
[0026] Previously plantations had been reported in Oaxaca, Yucátan, Sonora, Baja Calif. Sur and Veracruz, same that are not considered in the official information upgraded at 1993, being ignored the situation of such plantations.
[0027] In the agronomic area, the sabila juice has been used experimentally as repellent and insecticide in larvas present in some tuberous plants, being obtained very good results. In a same way the experimentation has been reported for the control of illnesses viral in potato, presenting an action inhibitory stocking in comparison with other extracts of vegetable origin. Reference: Indexes Http://www.sabilinaza.com/sabila.php
Chemical Composition of the Sabila
[0028] The species of the genus Aloe contains a mixture of glucosides called collectively Aloin, which is the active principle of the plant. The aloin content in the plant can vary according to the species, the region and the gathering time.
[0029] The main constituent of the Aloin is the barbaloin, a yellow pale soluble in water. Other constituents are the emodina isobarbaloin, betabarbaloin and resins. The characteristic scent of the plant is due to traces of an essential oil.
[0030] In a general way, the proportion of the compounds before mentioned it is the following one:
[0031] Two yellow brilliant, very active resins, possibly identical, soluble in bicarbonate of sodium, 30%.
[0000] A soluble very active resin in bicarbonate of sodium 6.8% Aloin, lightly active, 20.0%
[0032] Emodine, lightly active 1.5 to 1.8%
[0033] Substances inactive hidrosolubles, 15.2%
[0034] Amorphous substances that produce stomach alterations but that they don't arrive to the purgative effect, 5.1%
[0035] The different analyses carried out to the plant and their extract had allowed to know the nature of the substances that they compose it. Some of them are mentioned next.
Polysaccharides: glucose, mannose, galactose, xilose, arabinose Acids: Glucuronic, citric, succinic, malic Enzymes: oxidase, cellulose, bradiquinase, catalase, amilase Tannins Steroids Proteins: only one, not hydrolyze, contains 19 amino acids Biogenic stimulative Saponin Magnesium Esterols: three
Chemical Composition of the Acibar or Sabila Juice
[0046] The acibar is the juice or perspired of the leaves of the sabila when these suffer wounded or they are practiced incisions. It presents an appearance mucilaginous, glutinous and of dark greenish yellow colour, it has a strong scent and of very bitter flavour.
[0047] The contained resin varies from 40 to 80% and it is composed of an ester of paracumaric acid and a resinic alcohol called Aloeresinetanol. The content of Aloin is, approximately, of 20% and when hydrolyzed the pentosides that contains, are obtained derived of the antraquinone.
[0048] The protein content in the juice is low (0.013%), it presents a composition of 18 amino acids; however it possesses a great quantity of vitamins and minerals. The vitamins found in the juice are A, C, E, and B-12, carotenes, folic acid, niacin, riboflavin and tiamin. In the case of the minerals they are reported: calcium, magnesium, potassium, sodium, iron, aluminum.
[0049] The sabila acibar contains 12 enzymes. These enzymes consist of a protein fraction or apoenzyme and a prosthetic group or coenzyme. The enzyme acts forming a complex with the skin (or “sustrate”), the part of the protein that unites to this becomes an active center; in most of the cases the action of the enzyme depends on the coenzyme and specifically for the sustrate type (open skin, hairy leather, etc.,) of the apoenzyme.
Extraction of the Acibar to Apply it to the Fertilizer
[0050] The process for the extraction of the juice, consists on subjecting to the leaves of Aloe to a court treatment, mill and compression so that you can extract the biggest quantity in possible juice and this way to be able to obtain the biggest use in the liquid fertilizer and in turn in the application to the field.
[0051] This process considers the following steps:
[0000] a) As first point it is the selection of the leaves they should be young leaves and they don't should dry with the purpose of that are richer in nutrients
b) They intersect the thorns and that this dry one or under bad conditions
c) Laundry of the selected leaves and very cut with detergent
d) Laundry with water to eliminate the detergent
e) It blunts of the leaves (manual)
f) It cuts (manual)
g) Mill with industrial blender
h) Filtered for mesh of #110
i) Filtered for mesh of #325
j) The obtained juice is added to the previously formulated fertilizer
k) It is packed in drums of 19 lt. for their sale and distribution
[0052] When an abundant quantity of organic matter is introduced in a soil where the concentration of difficultly assimilable materials is bigger than the easily degradable ones, immediately a great change takes place. The multiplication of the micro organisms of the soil suddenly increases in a prodigious way, with that which a quick energy liberation takes place in form of cations and anions and great detachment of anhydride carbonic. Finally, as the easily assimilable energy it is used and the nutrients reservations diminish, the microbial activity descends gradually. In this point they are in the soil simple products as nitrates, sulphates and humus (Buckman and Brady, 1991, Naturaleza y Propiedades de los Suelos).
[0053] Apart from the great energy contribution and of the detachment of CO 2 , the decomposition of the organic matter gives place to the liberation of other important simple products as the carbon (in form of CO 2 , carbonates and bicarbonates), nitrogen (in form of nitrates and ion ammonium), sulphur (in form of sulphates) and phosphor (in form of phosphates).
[0054] Another important product of organic dissolution is the humus that is a mixture of complex compounds, be already resistant material that have only been modified starting from the fabric vegetable native or compounds synthesized with microbial fabric with remains of dead organisms. The humus when it is saturated with ions H + , the assimilation of certain bases it increases as the Ca, K and Mg; being the humus-H the one that acts as ordinary acid and the one that reacts with minerals of the soil in the form required to extract their bases (Buckman and Brady, 1991, Naturaleza y Propiedades de los Suelos).
[0055] The lignin is one of the compounds main point of the organic matter as of the humus and it also plays an important paper in the soil. Because they are more resistant than other compounds they spread to persist in condition modified in the soil. The lignin is oxidized partially and the groups responsible for the cationic exchange increase in number.
[0056] The relationship in which they are the micronutrients is from supreme importance when speaking of fertilizers. For example, an excess of Cu, Mn or Zn can induce a deficiency of Fe, but in turn the Mn, in certain grade, helps to that the Fe is assimilated (Mortvedt, J. J., et al, 1982, Micronutrientes en Agricultura). It is for that reason that the proportions in those that are the micronutrients in this fertilizer have been evaluated being based on the experience in the use of fertilizers carefully.
[0057] Another significant characteristic of the fertilizer is the use of a chelating agent. The chelate increases the solubility of the metallic ions and they favourable their transport inside the plant. Furthermore, after binding to the metallic ion and later on to give it in the place where the plant requires it, the organic part of the chelate returns to solubilize more ions, that makes that the use of the micro nutrients of the soil is more lingering.
[0058] Another important aspect is the use of a surface active agent, since for its high one to be able to moist and its capacity of decreasing the superficial tension of the water, the assimilation of the nutrients is facilitated. On the other hand, due to their emulsificable power, it gives stability to the fertilizer.
THE BEST METHOD TO CARRY OUT THE INVENTION
Example 1
[0059] To produce 1000 liters of fertilizer they mix 67 Kg of ferrous sulphate monohidrated, 30 Kg of zinc sulphate monohidrated, 20 Kg of copper sulphate heptahidrated, 35 Kg of manganese sulphate monohidrated, 4 Kg of borax, 20 Kg of magnesium oxide, 70 Kg of chelant agent, 30 Kg of surface active agent, 70 Kg of urea, 1 Kg of amino acids, 30 Kg of sabila extract, 200 Kg. of humic acid, 6 Kg. of calcium nitrate, 4 Kg. of formal, 430 Kg. of water and 11 liters of antifoam, until obtaining a homogeneous mixture.
Example 2
[0060] The obtained fertilizer can be applied in several ways:
[0061] To the floor, of 10-30 Lts/Ha applying in band or spurt. To the watering, of 30-90 Lts/Ha. every 14 days or according to those requirements of the cultivation.
[0062] In the leak of 3 to 5 liters dosed in each application of the fertilizer watering program.
[0063] When applying 5 Lts/Ha to intervals of 6 days, in a cultivation of tomato (jitomate) during their development stage, differences significant were observed in the colour and size of the leaves of the cultivation, those with the leaves of the area witness (where fertilizer was not used)
[0064] With this dose they were possible to correct the micro elements deficiencies, however, effect some was not observed on the flowering.
[0065] Increasing the dose to 6-10 Lt/Ha leaving 8 days of rest among each application, they were possible to correct the deficiencies in young leaves, there were a good development and colour of the foliage, and, also, it improved the flowering and the quantity of fruits increased. | The invention relates to a liquid fertiliser of mineral-organic origin, in which aloe vera and humic acid are used as a source of organic matter, to which is added iron, zinc, copper, manganese, boron, calcium and magnesium micronutrients in the form of soluble compounds, as well as a chelating agent and a surfactant to make the nutrients more available to the crops. The invention comprises a mineral-organic liquid fertiliser, the organic base of which is extracted from aloe vera and/or humic acid. The mineral is formed by different salts added so that the fertiliser contains the micronutrients essential for every type of soil (iron, zinc, copper, manganese, boron, calcium and magnesium). In addition, the fertiliser contains a chelating agent and a surfactant which improve the availability of the nutrients to the crops. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a card case mounted within the vicinity of the driver's seat of an automobile for accommodating and holding therein a magnetic card such as, for example a prepaid type charge or credit card.
2. Description of the Prior Art
In recent years, prepaid cards have come into wide use for paying fees at toll houses, gas stations, and the like. Most drivers keep their prepaid cards in the glove compartment, the center console or the sun visor pocket.
In view of the inconvenience encountered heretofore in inserting a prepaid card into and taking it out of any one of these receptacles, the inventor has proposed a card case provided within the vicinity of the driver's seat for the exclusive use by means of the driver (Japanese Utility Model application No. 1-153049).
However, since the proposed card case has a relatively small card insertion slot, it is difficult to locate the card insertion slot under darkness conditions.
OBJECT OF THE INVENTION
The present invention has been accomplished to overcome the foregoing problem. The main object of the present invention is to provide a card case for an automobile which makes it possible to readily find the card insertion slot even under darkness conditions.
SUMMARY OF THE INVENTION
To achieve the aforementioned object, according to the present invention there is provided a card case mounted within the vicinity of the driver's seat of an automobile for accommodating and holding therein a magnetic card, which has a card accommodation portion provided upon the inner surface thereof an illuminating means and which further includes within the card accommodation portion a push member which is made of a light conductive material and which is adapted to be pushed inwardly by means of the insertion of a card, biasing means for biasing the push member in the direction of extracting the card, and a latch device for latching the push member at a card accommodation position within the card accommodation portion and, when the push member is pushed in further from the card accommodation position, for releasing the latched push member within the card accommodation portion.
With the construction described above, since the inner surface of the card accommodation portion is illuminated by the illuminating means, the card insertion slot can be easily located even under darkness conditions. Furthermore, since the push member is made of a light conductive material, the portion of the card accommodation portion along which the push member extends can be uniformly illuminated. Thus, it is possible to illuminate the inside of the card accommodation portion over a wide area using a single light source.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, characteristic features and advantages of the present invention will become more apparent from the following description made hereinbelow with reference to the accompanying drawings in which like reference characters designate like or corresponding parts throughout the several views, and wherein:
FIG. 1 is a perspective view illustrating one embodiment of the card case constructed according to the present invention and as applied to the inside of an automobile door.
FIG. 2 is a front view illustrating the card case mounted upon the inside door handle.
FIG. 3 is a partially sectioned left side view illustrating the card case of FIG. 2.
FIG. 4 is a cross-sectional view taken along line 4--4 in FIG. 3.
FIG. 5 is a partially cutaway, exploded perspective view illustrating the relationship defined between the card holder and the latch cam.
FIG. 6 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at one position.
FIG. 7 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at another position.
FIG. 8 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at still another position.
FIG. 9 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at yet another position.
FIG. 10 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at a further position.
FIG. 11 is a cross-sectional view illustrating the relationship defined between the card holder and the latch cam at a still further position.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention will now be described in detail with reference to the illustrated embodiment.
FIG. 1 illustrates the inner surface of an automobile door 1 to which one embodiment of the card case constructed according to the present invention is applied. The inner surface of the door 1 is provided at a vertically central portion thereof with an elongated arm rest 2 extending in the horizontal or lateral direction. The top surface of the arm rest 2 is provided therein with an inside door handle 3 at a substantially central position thereof as considered in the longitudinal direction thereof.
As illustrated in FIGS. 2 and 3, the inside door handle 3 is injection molded from a synthetic resin so as to have the shape of a cup open at the top and which is flat in the lateral direction so that the door 1 can be pulled shut by means of a person seated inside the automobile with the finger tips of the person inserted into the inside door handle 3. The inside door handle 3 has a flange or support member 4 defined around the top opening thereof. The flange or support member 4 has a rectangular hole 5 formed within a portion thereof disposed close to the door 1 and which is elongated in the lateral direction for a support member 4 permitting insertion of a card case 6 from a position above the hole 5 and flange. The inside door handle 3 having the card case 6 fitted within the rectangular hole 5 thereof is attached from above to the arm rest 2.
The card case 6 has a substantially rectangular shape and comprises a pair of thin plate members 6a and 6b, which are joined together and wherein each has a concave portion for constituting a card accommodation portion 7 having an elongated top slot 8 for permitting insertion of a card 10 and an arcuate notch 9 formed at a central portion thereof as considered along the longitudinal direction of the top slot 8 for use in pushing the card 10 deep into the card accommodation portion.
The card case 6 is provided at one end of the bottom portion thereof with a light emitting element 11, such as, for example, an LED, having a light emitting portion 11a directed toward the interior of the card accommodation portion 7. The light emitting element 11 is connected by means of lead wires 11b to a battery (not shown) and the light emitting portion 11a can be turned on and off as a result of operating a separate control switch (not shown).
The open end of the slot 8 of the card case 6 is formed with a flange 12 extending over the entire periphery thereof so as to abut the peripheral surface of the rectangular hole 5 formed within the flange or support member 4 of the inner door handle 3. The outer surfaces of the plate members 6a and 6b are each formed with a pair of engaging claws 13 disposed at intermediate positions along the lengthwise direction thereof so as to face or abut the lower surface of the flange 12. The periphery of the rectangular hole 5 of the inner door handle 3 is interposed between the lower surface of the flange 12 and the engaging claws 13 so as to fix the card case 6 within the inner door handle 3.
As is illustrated in FIG. 4, a substantially U-shaped card holder 14 serving concurrently as a push member is accommodated within the card accommodation portion 7 of the card case 6 and comprises a pair of arms 14a which are directed toward the open end of the card accommodation portion 7 and a main body 14b connecting the proximal ends of the arms 14a. The card holder 14 is made of a light conductive material such as, for example, transparent acryl resin. The main body 14b of the card holder 14 is provided with a block member 15 projecting in the card inserting and extracting directions and which, as shown in FIG. 3, is slidably disposed with a guide groove 16 formed within the inner surface of the plate member 6b at a lower position thereof and extending in the card inserting and extracting directions. The slidable movement of the card holder 14 is regulated by means of the guide groove 16.
Between the inner bottom portion of the card accommodation portion 7 and the lower surface of the main body 14b of the card holder 14, a pair of compression coil springs 17 are interposed so as to bias the card holder 14 in the card extracting direction. When no force is applied to the card 10 accommodated within the card accommodation portion 7, the card holder 14 is retained by means of the biasing force of the compression coil springs 17 at the uppermost position of the guide groove 16 regulating the slidable movement of the card holder 14. In this state, as shown in FIG. 4 the lower end of the card 10 is supported upon the card holder 14 and the upper end thereof projects outwardly from the open end of the card accommodation portion 7.
The arms 14a of the card holder 14 are provided upon the free ends thereof with pawls 14c which project inwardly toward each other. When a card 10 is inserted into the card accommodation portion 7 so as to abut against the pawls 14c, the arms 14a are flexed away from each other so as to resiliently pinch the opposite sides of the card 10 between the pawls 14c. When the card 10 is pushed downwardly from this position against the biasing force of the compression coil springs 17, the lower end of the card 10 abuts against the main body 14b of the card holder 14 so as to push the card holder 14 downwardly.
As is illustrated in FIG. 5 to FIG. 11, the surface of the block member 15 which is disposed opposite the surface thereof facing the guide groove 16 is formed with stepped portions 18a and 18b which are spaced apart vertically with respect to each other. The plate member 6a is integrally provided with a resilient piece 20 which has an inward projection 19 at the free end thereof. When the card 10 is substantially entirely accommodated within the card accommodation portion 7, the inward projection 19 engages the lower stepped portion 18b of the block member 15 as a result of the resiliency of the resilient piece 20. In this state, the card holder 14 is prevented from undergoing slidable movement in the card extracting direction and the card 10 is retained within the card accommodation portion 7 as shown in FIG. 9.
A latch cam 21 is attached to the block member 15 so that it is freely movable from its position in contact with the upper stepped portion 18a to its position in contact with the lower stepped portion 18b as shown in FIGS. 8 and 11, respectively. However, while the reverse movement of the latch cam 21 is permitted until the latch cam 21 abuts a triangular projection 22 formed between the upper and lower stepped portions 18a and 18b, further reverse movement thereof is prevented by means of the triangular projection 22.
To be more specific, as illustrated in FIG. 5, the latch cam 21 comprises a pair of legs 21a and a bridge portion 21b connecting the legs so as to form a substantially inverted U shape. The bridge 21b is located between the upper and lower stepped portions 18a and 18b of the block member 15 and the legs 21a are disposed at the lateral sides of the lower stepped portion 18b. The upper portion of the bridge 21b of the latch cam 21 facing the block member 15 is formed with a triangular groove 23 in which the triangular projection 22 of the block member 15 is complementarily fitted when the bridge 21b of the latch cam 21 abuts the upper stepped portion 18a of the block member 15 (FIG. 8). The lower portions of the legs 21a of the latch cam 21 facing the block member 15 are formed with slopes 21c. For this reason, the bridge 21b of the latch cam 21 can be disposed in an inclined mode with respect to the plate member 6a until the slopes 21c come into contact with the flat surface of the block member 15 (FIG. 7). When the bridge 21b has been inclined, the latch cam 21 moves upwardly, passes beyond the triangular projection 22 and contacts the upper stepped portion 18a of the block member 15. The legs 21a of the latch cam 21 are provided at their respective proximal ends with engaging grooves 21d which are disposed between the triangular projection 22 and the lower stepped portion 18b when the bridge 21b of the latch cam 21 abuts either the triangular projection 22 of the block member 15 or the upper stepped portion 18a of the block member 15 and are adapted to receive the inward projection 19 formed upon the resilient piece 20 of the plate member 6a (FIGS. 8 and 9).
The operation of the card case 6 according to the present invention will now be described.
Prior to the insertion of a card 10, the card holder 14 is retained in contact with the upper end of the guide groove 16 by means of the biasing force of the compression coil springs 17, whereas the latch cam 21 is disposed so as to be slidable downwardly from the triangular projection 22 to the lower stepped portion 18b of the block member 15 (FIG. 6).
Insertion of a card 10 into the card case 6 through means of the slot 8 allows the lower end of the card 10 to abut the card holder 14 and the upper end thereof to project outwardly from the open end of the card accommodation portion 7. When the card 10 is pushed inwardly from the inserted position against the biasing force of the compression coil springs 17, the card holder 14 is pushed toward the deepest possible position, at which the block member 15 abuts the lower end of the guide groove 16.
When the free ends of the legs 21a of the latch cam 21 are brought into contact with the inner projection 19 within the card accommodation portion 7 as a result of the card holder 14 being pushed downwardly, the latch cam 21 is pressed upwardly and moves in a sliding fashion to a position at which the top of the bridge 21b of the latch cam 21 abuts the triangular projection 22 of the block member 15. As soon as the upward slidable movement of the latch cam 21 is restricted by means of the triangular projection 22, the free ends of the legs 21a of the latch cam 21 are pressed against the inclined surface of the inner projection 19 and consequently the latch cam 21 continues to move in an inclined mode until the slopes 21c of the latch cam 21 abut the flat surface of the block member 15 (FIG. 7). This inclined disposition allows the latch cam 21 to pass beyond the triangular projection 22.
Since the inner projection 19 still abuts the free ends of the legs 21a so as to push the latch cam 21 upwardly, the latch cam 21 moves upwardly until the upper end of the bridge 21b abuts against the upper stepped portion 18a, whereas the card holder 14 is pushed downwardly. At this time, since the resilient piece 20 is flexed outwardly, the lower end of the block member 15 clears the inner projection 19 and, while the lower ends of the legs 21a of the latch cam 21 slide upon the inner projection 19, the card holder 14 is pushed inwardly so as to reach the deepest possible position, at which the lower end of the block member 15 abuts the lower end of the guide groove 16 (FIG. 8).
At the deepest possible position, the bridge 21b of the latch cam 21 abuts the upper stepped portion 18a of the block 15 and the engaging grooves 21d of the latch cam 21 are disposed between the triangular projection 22 of the block member 15 and the lower stepped portion 18b so as to receive the inner projection 19 due to the resiliency of the resilient piece 20.
In this state, when the application of pressure upon the card 10 is released, the card holder 14 is urged upwardly by means of the biasing force of the compression coil springs 17. At this time, since the inner projection 19 is engaged within the engaging grooves 21d of the latch cam 21, the latch cam 21 and the card holder 14 move in opposite directions. Consequently, the lower stepped portion 18b of the block member 15 is stopped by means of the inner projection 19 at a position slightly higher than the deepest possible position. At this position the latch cam 21 is retained between the lower stepped portion 18b and the triangular projection 22 (FIG. 9). As a result, the card 10 is substantially entirely accommodated within the card accommodation portion 7. In the accommodated state of the card 10, since the card 10 is clamped between the arms 14a of the card holder 14 due to the resiliency of the arms 14a, the card 10 is prevented from rattling within the card accommodation portion 7.
The accommodated card 10 can be extracted from portion by again pushing the card 10 downwardly utilizing the notch 9, thereby pushing the card holder 14 to the deepest possible position within the card accommodation portion 7 (FIG. 10). As a result, the latch cam 21 is pressed by means of the triangular projection 22 so as to move the latch cam 21 downwardly along with the card holder 14 and, at the deepest possible position, the card holder 14 is pressed by means of the bridge 21b of the latch cam 21 so as to disengage the inner projection 19 from the engaging grooves 21d of the latch cam 21 within the card accommodation portion 7.
Then, by releasing the pushing force impressed upon the card 10, the card holder 14 is pushed backwardly toward the initial position shown in FIG. 4 from the deepest possible position. At this time, as a result of the friction between the latch cam 21 and the inner projection 19, the latch cam 21 abuts the lower stepped portion 18b and the surfaces of the bridge 21b and lower stepped portion 18b which are both facing the inner projection 19 become flush with each other. Therefore, the inner projection 19 cannot catch the lower stepped portion 18b during the upward movement of the card holder 14, thereby permitting the card holder 14 to be pushed backwardly toward the initial position by means of the biasing force of the compression coil springs 17. Consequently, the upper end of the card 10 increasingly projects from the slot 8 of the card accommodation portion 7 so as to make it possible to readily extract the card 10.
The switch for the light emitting element 11 used as the illuminating means for illuminating the card accommodation portion 7 may be ganged with the switch for the automobile headlights or the like. An LED is desirably used as the light emitting element 11 in consideration of power consumption and may be set to emit light all the time during the illumination of the headlights or clearance lamps. Furthermore, in the case where the movement of the card holder 14 is sensed by means of a separate limit switch, the LED may be arranged so as to emit light only when a card is not accommodated within the card accommodation portion 7. The card holder 14 is desirably formed in the shape of a prism or lens in order to enhance the diffusion of light therethrough.
According to the present invention, as described above, since the card accommodation portion is illuminated with light, the location of the card insertion slot can be readily confirmed even under darkness conditions. Furthermore, since the card holder extending laterally within the card accommodation portion is made of a light conductive material, the light from a single light source can be diffused so as to illuminate the card insertion portion over the entire bottom portion thereof. Thus, the card case of the present invention can be advantageously utilized.
Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the present invention may be practiced otherwise than as specifically described herein. | A card case is mounted within the vicinity of the driver's seat of an automobile for accommodating and holding therein a magnetic card. The card case has a card accommodation portion which is provided upon the inner surface thereof with an illuminating means. The card accommodation portion is also provided therein with a push member pushed inwardly by means of the insertion of a card, biasing means for biasing the push member in the direction of extracting the card, and a latch device for latching the push member at a card accommodation position within the card accommodation portion and, when the push member is pushed in further from the card accommodation position, for releasing the latched push member within the card accommodation portion. The push member is made of a light conductive material. | 1 |
This is a continuation, of application Ser. No. 254,731 filed Apr. 16, 1981.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a nail polish composition which imparts moisture upon application to human nails.
2. Description of the Prior Art
It has long been recognized that when nail polish is applied to a human nail, the nail becomes dry and brittle. The polish draws out moisture from the nail and prevents moisture from being absorbed by the nail.
Nail polishes have been proposed which contain water. But no nitrocellulose polishes have been suggested which contain water, urea, and polyvinyl butyral resin.
SUMMARY OF THE INVENTION
Objects of the Invention
It is one of the objects of the invention to provide a nail polish composition which eliminates the drawbacks of the prior art nail polishes.
It is another object of the invention to provide a nail polish composition which prevents the polished nail from becoming dry and brittle.
It is a further object of the invention to provide a nail polish composition which moisturizes the human nail.
Yet a further object of the invention is to provide a nail polish composition which although softening the nail, forms a hard and durable lacquer coat.
A further object of the invention is to provide a nail polish composition containing water but which does not have a cloudy appearance due to the formation of precipitates.
Other objects of the invention in part will be obvious and in part will be pointed out hereinafter.
BRIEF DESCRIPTION OF THE INVENTION
In keeping with these objects, and others which will become apparent hereinafter, one feature of this invention resides, briefly stated, in an improved nail polish composition which moisturizes a polished human nail. A conventional liquid nail polish composition includes: nitrocellulose, one or more plasticizers, one or more hardeners, and a solvent system. The ingredients typically are ethyl acetate, isopropyl alcohol, butyl acetate, butyl alcohol, toluene, toluene sulfonamide/formaldehyde resin, dibutyl phthalate, camphor, nitrocellulose, and an ultra violet absorber. The improved polish additionally contains as the improvement, a combination of ingredients essentially constituting polyvinyl butyral resin, water and urea.
Both the water and the urea serves to moisturize the nail. The urea aids in the absorption of the water into the nail. The polyvinyl butyral resin is used to harden the nail polish coating which is softened by the addition of water. Further, the polyvinyl butyral resin increases the adhesion of the nail polish coating to the nail.
There are preferred weight percentages of polyvinyl butyral resin, water, and urea in the improved composition. For example, if too much water is used the wearability of the nail polish coating is adversely affected and precipitates are formed in the nail polish composition. If the percentage of water is too low, the moisturizing property of the nail polish composition is adversely affected.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Set forth below are components of a typical conventional nail polish composition to which the aforementioned ingredients are added to provide a moisturizing function.
______________________________________ Example I Preferred weight by percentage of liquid nail polish TypicalIngredient composition ranges______________________________________Ethyl Acetate 36.7% 20%-40%Isopropyl Alcohol 24.2% 15%-30%Butyl Acetate (solvent 9.9% 3%-25%Butyl Alcohol system) 1.4% 0.5%-10%Toluene 7.4% 2%-30%Toluene Sulfonamide/Formal- 14.4% 5%-20%dehyde Resin (hardener)Camphor 0.9% 0.5%-8% (plasti-Dibutyl Phthalate cizers) 1.2% 0.5%-8%Nitrocellulose (film former) 3.6% 2%-15%Ultra violet absorber 0.1% 0.1%-0.5%______________________________________
The water may be deionized or tap water. The polyvinyl butyral resin, the water, and the urea are added in a preferred weight percentage. However, there is an acceptable weight percent range. If these ingredients are used in an amount falling within said weight percentage range, a commercially acceptable product is obtained.
A preferred weight percent and an acceptable weight percentage range are as follows:
______________________________________ Preferred weight by Weight percent percent of liquid range of liquid nail polish composi- nail polishIngredient tion (Example II) composition______________________________________Water 6% 3%-10%Urea 0.1% 0.02%-0.5%Polyvinyl butyral resin 2.2% 1%-3%______________________________________
Urea, or any precursor thereof, can be used in the moisturizing composition. Urea is an organic compound with the chemical formula:
NH.sub.2 CONH.sub.2
It has a molecular weight of 60.06 and a melting point of 135° C. It is a weakly basic compound.
Some properties of polyvinyl butyral resins are:
______________________________________Property Units ASTM method______________________________________Tensile strengthYield 10.sup.3 psi D638-58T 6.3-7.3Break 10.sup.3 psi D638-58T 5.6-6.6ElongationYield % D638-58T 8Break % D638-58T 110Modulus ofelasticity(apparent) 10.sup.5 psi D638-58T 3.1-3.2Flexural strength,yield 10.sup.3 psi D790-59T 11-12Hardness,RockwellM -- D785-51 110E -- D785-51 20Impact strengthIzod,notched 1/2" × 1/2" ft.lb/in D256-56 0.7______________________________________
It has been found that when the nail polish composition of this invention is applied to human nails, the nails have a higher moisture content than nails polished with a conventional nail polish composition. Nails polished with the moisturizing composition of this invention are less brittle and do not break as frequently as nails polished with a conventional nail polish composition.
In tests of the moisturizing composition of this invention versus a conventional clear nail polish, the results indicated that nails coated with this moisturizing composition had a higher percentage of moisture than nails coated with a standard commercially available polish.
The first fourteen subjects on the test results of Table 1, were treated as follows: the first seven had the nails on their right hands coated with the moisturizing composition (the liquid nail polish of Example I mixed with the moisturizer additive of Example II) and the nails on their left hands coated with a conventional liquid clear polish (Example I). The second group of seven had the nails of their left hands coated with said moisturizing composition and the nails on their right hands coated with said standard clear polish.
The last six subjects of Table 1 had the nails of one hand coated with the nail polish of Example 1 mixed with the moisturizing additive of Example II and the nails of the other hand coated with the clear nail polish of Example I. The nails of both hands then were overcoated with the nail polish of Example I mixed with color.
The moisture content of the nails of all 20 subjects were determined by the following procedure: The nails were allowed to dry for 24 hours. It was previously determined that in this period of time the nail polish coats were fully dried. Then the nails from both hands of the subjects were clipped and weighed. The nail clippings next were placed in an oven maintained at a temperature of about 100° C. in order to evaporate moisture in the clippings. Sample nail clippings were periodically removed from the oven to determine when their weight remained constant to establish substantially complete removal of moisture. This occured in approximately 11/4 hours. The nail clippings then were weighed a second time. The difference in weight between the weight after the 24 hour period and the weight after the oven drying period was taken as the moisture content of the clippings before oven drying. The moisture content of the nail clippings to which the non-moisturizing coats were applied was used as a control. Results are set forth in the following Table 1:
TABLE I__________________________________________________________________________ MOISTURE CONTENT MOISTURE CONTENT OF NAILS W/ OF NAILS W/ STANDARD CLEAR MOISTURIZING % INCREASE NAIL POLISH BASE COAT IN MOISTURESUBJECT (% BY WEIGHT) (% BY WEIGHT) CONTENT__________________________________________________________________________S.A. 5.0 6.17 23.4A.B. 4.8 5.87 22.3D.F. 5.1 6.19 21.4C.H. 5.3 6.17 16.4R.K. 5.2 6.275 20.67J.L. 4.9 5.96 21.6K.M. 4.5 5.45 21.1B.P. 5.2 6.37 22.5M.S. 5.3 6.34 19.6V.S. 5.1 6.08 19.2A.W. 5.3 6.5 22.6G.H. 4.9 5.4 10.2M.C. 5.2 6.46 24.23L.F. 4.9 5.72 16.7__________________________________________________________________________ MOISTURE CONTENT MOISTURE CONTENT OF NAILS W/ OF NAILS W/ STANDARD CLEAR MOISTURIZING BASE NAIL POLISH AND COAT AND % INCREASE REVLON OVERCOAT REVLON OVERCOAT IN MOISTURESUBJECT (% BY WEIGHT) (% BY WEIGHT) CONTENT__________________________________________________________________________J.S. 5.2 6.23 19.8A.J. 5.3 5.94 12.1C.Y. 5.1 6.22 22.0L.R. 4.8 5.6 16.7A.L. 4.4 5.2 18.2P.W. 4.9 5.88 20.0__________________________________________________________________________
The moisturizing composition of this invention may be any liquid nail polish composition which is applied directly to the nail, i.e. as a colorless "base" coat or as a colored coat. In a preferred embodiment, the moisturizing polish is a base coat and it is intended that additional coats of polish will be applied over said base coat.
It has been found that the wearability of the nail polish composition is not adversely affected by the inclusion of water in the composition. As heretofore explained, it is believed that the polyvinyl butyral resin preserves the wearability of the composition by hardening the polish which has been softened by the addition of water.
Tests were run to determine wearability of the moisturizing liquid nail polish composition in comparison with a standard liquid nail polish composition, specifically the liquid polish composition of Example I. The tests were conducted as follows: Fourteen women were used as subjects. They were employed in light to heavy manual jobs such as typing and factory work. Each woman had applied to alternating nails of both her hands; (a) a base coat of Example 1, overcoated with two coats of a nail polish of Example I in which a color had been mixed; and (b) a moisturizing base coat constituting a mixture of Example I and Example II, overcoated with two coats of a nail polish of Example I in which a color had been mixed. The nails of these women were examined at the end of the first day after application and then again at the end of the second day after application. Wear was evaluated by ascribing a rating to the individual nails on the fingers of both hands, ranging from 0-5, 0 being no visible chipping and wear, 1 being a slight chipping and wear and so on up to 5 which was indicative of heavy chipping and wear. After the first day the nails which had the non-moisturizing base coating of Example I, plus two overcoats of Example I with color mixed in, had a total wear rating for all such nails (based on the wear rating above) of 80, in contrast to the total wear rating for the nails having the moisturizing base coat of Example I mixed with Example II and overcoated with two coats of Example I with color mixed in of 79. At the end of two days, the total wear rating for the nails having the standard nail polish overcoated with two coats of a colored nail polish was 109 as compared to 104 for the nails coated with a moisturizing base coat overcoated with two coats of a colored nail polish. Thus, the addition of the moisturizing constituents did not increase chipping or reduce wearability. Further, the percentage of water in the composition was low enough so that precipitates were not formed.
As various possible embodiments might be made of the present invention and as various changes might be made in the embodiment set forth, it should be understood that all matters herein described are to be interpreted as illustrative and not in a limiting sense. | An improved nail polish composition for application to human nails which allows a polished nail to retain and absorb moisture thereby preventing brittleness and breakage of polished nails. Water and urea are used in the composition to impart moisture to the polished nail and polyvinyl butyral resin is used to harden the nail polish composition which is softened by the addition of water and to increase the adhesion of the nail polish composition to the nail. | 0 |
This is a continuation-in-part of U.S. application Ser. No. 732,872, filed May 10, 1985, now abandoned.
BACKGROUND AND PRIOR ART
Swine dysentery is a severe mucohaemorragic diarrhea primarily affecting pigs post weaning. Control of the disease has been generally accomplished through use of chemobiotics and antibiotics. To date, there has been no effective nondrug prophylactic agent to control this disease. The anaerobic spirochete, Treponema hyodysenteriae, is recognized to be the primary etiological agent of swing dysentery. U.S. Pat. No. 4,100,272 discloses the use of a vaccine or bacterin containing killed cells of T.hyodysenteriae to increase the resistance of swine to swine dysentery.
This prior art method has not resulted in commercial acceptance, because the bacterin product has relatively low activity. The described treatment schedule includes six intravenous injections. It is desired to have a bacterin that can be used in a treatment schedule involving fewer intramuscular injections.
Cholesterol-rich fractions are known to be useful as growth promoters for some organisms. J.Bacteriol., Vol. 135, No. 3, pp. 818-827 (1978) describes the use of a cholesterol-rich fraction as a growth promoter for Mycoplasma pneumoniae and Mycoplasma arthritidis. J.Gen.Microbiology, Vol. 116, pp. 539-543 (1980) describes the use of USP cholesterol in the growth of T.hyodysenteriae.
There is no known prior art that suggests the specific use of cholesterol-rich bovine fractions to enhance the yield of cells of T.hyodysenteriae for subsequent inclusion in a bacterin suitable for control of swine dysentery.
SUMMARY OF THE INVENTION
In accordance with the present invention, a process is provided for the growth of Treponema hyodysenteriae in an appropriate nutrient medium for subsequent use of the resulting cells in a bacterin, wherein the nutrient medium contains a cholesterol-rich bovine fraction.
DESCRIPTION OF THE INVENTION
The process of the present invention can be practiced with any virulent strain of T.hyodysenteriae. A virulent strain is one which is capable of producing a typical swine dysentery infection. Two particular strains (B204 and B234) have been found useful for this purpose. These have been deposited with the American Type Culture Collection and have designations ATCC No. 31212 (B204) and ATCC No. 31287 (B234).
The T.hyodysenteriae strain can be grown in media comprising a mixture of Tryptic Soy Broth (Difco Laboratories) supplemented with fetal calf serum or lamb serum, dextrose, 1-cysteine HCl, vitamin B-12, and yeast extract. The improvement of the present invention is including a cholesterol-rich bovine fraction in such media for growth of the T.hyodysenteriae cells. The cholesterol-rich bovine fraction is preferably present in an amount of 1.0 to 2.5 volume percent based upon the volume of the media, but it can be used in an amount from 0.1 to 5.0 volume percent.
Cholesterol-rich bovine fractions suitable for use in the process of this invention are available from several sources. Cholesterol Concentrate Code 82-010 available from Miles Scientific Division of Miles Laboratories, Inc. and prepared from bovine serum according to the process disclosed and claimed in U.S. Pat. No. 4,290,774 is useful. Bovine Cholesterol Concentrate List 3200 available from Biocell Laboratories is another useful material. The preferred cholesterol-rich bovine fraction useful in the process of this invention is prepared by a process comprising the steps of:
(a) contacting a liquid cholesterol-containing bovine plasma or serum or fraction thereof with a silica adsorbent to adsorb the cholesterol-rich fraction;
(b) separating the adsorbed cholesterol-rich fraction from the remaining liquid plasma or serum;
(c) freezing and thawing the adsorbed cholesterol-rich fraction;
(d) eluting the adsorbed cholesterol-rich fraction at a pH from 9.0 to 11.5;
(e) either before or after step (f) and prior to step (g) adjusting the pH of the cholesterol-rich solution to a value in the range from 11.0 to 13.0;
(f) concentrating the cholesterol-rich solution by ultrafiltration;
(g) dialyzing the concentrated cholesterol-rich solution sequentially against sodium carbonate and water;
(h) further concentrating the dialyzed cholesterol solution by ultrafiltration;
(i) adjusting the pH of the concentrated cholesterol-rich solution to a value in the range from 7.0 to 11.0;
(j) heating the concentrated cholesterol-rich solution at 50° to 100° C. for 30 minutes to 24 hours; and
(k) recovering therefrom a purified cholesterol-rich bovine fraction.
This specific fraction and its production process are described and claimed in copending U.S. application Ser. No. 923,850 filed concurrently herewith.
The starting material for use in the production of the cholesterol-rich fraction can be any bovine blood plasma or serum or fraction thereof containing cholesterol. The preferred starting material is bovine serum. If the starting material is serum, it is preferred to add a soluble salt, such as sodium citrate, to an ionic strength of 0.25 to 1.0. Other suitable salts include sodium chloride, sodium phosphate, potassium phosphate, ammonium sulfate and sodium sulfate. The addition of a soluble salt to the above concentration will increase the amount of cholesterol adsorbed in the subsequent silica adsorption step. Bovine plasma is normally collected by a method which includes addition of citrate as an anti-coagulant. This salt concentration is usually sufficient for the adsorption step and no additional salt is needed.
The plasma or serum starting material is maintained at a temperature of from 0° C. to 50° C. preferably from 20° C. to 25° C. The pH is adjusted to a range of from 5.5 to 9.0, preferably from 7.0 to 8.0.
The silica adsorbent useful in this invention does not have a critical composition. Appropriate silica materials are the microfine silica available under the trademark Cabosil from Cabot Corporation and the powdered silica available under the trademark Aerosil 380 from Cary Company. The silica is added to the liquid plasma or serum in an amount of 1 to 50 g/l., preferably from 10 to 20 g/l. The silica suspension in the liquid plasma or serum is then mixed for about 3 to 4 hours. It is preferred to add to the silica suspension about 10 g/l of a polyethylene glycol having a nominal molecular weight of about 3350 daltons. A suitable material is Union Carbide Corporation Carbowax PEG 3350. The polyethylene glycol aids in the subsequent separation of the silica.
The silica containing adsorbed cholesterol-rich fraction is then separated from the remaining liquid plasma or serum preferably by centrifugation, and the liquid phase is discarded. The silica paste is then frozen at -20° C. and held at this temperature for at least one week and preferably two weeks. The frozen paste is then thawed to room temperature (about 20°-25° C.) for 24 to 48 hours until no visible ice crystals are present. Any liquid that is expressed from the thawed paste is discarded.
The silica paste is washed to remove any undesirable proteins. This is accomplished by suspending the paste in an aqueous salt solution containing about 0.15 M sodium chloride. Other useful salts are sodium acetate and sodium phosphate. The salt solution is used in an amount about 2 liters for each kilogram of the paste. The paste is separated from the liquid. This washing procedure using a salt solution is preferably repeated at least two times to remove occluded proteins.
The washed paste is suspended in about 2 liters of deionized or distilled water per kilogram of paste, and the pH is adjusted to 9.0 to 11.5, preferably 10.4 to 10.6, by the addition of appropriate amounts of sodium hydroxide or hydrochloric acid. The suspension is stirred for about 2 hours during which time the pH is maintained at the desired level by periodic additions of the above alkaline or acid material. This treatment elutes the desired cholesterol-rich fraction from the silica. The suspension is then allowed to settle for 12 to 24 hours, preferably 12-18 hours. The supernatant containing the cholesterol-rich fraction is siphoned off for further treatment. It is preferred to use only this first elution for production of the desired cholesterol-rich fraction product. However, it is possible to repeat the above alkaline suspension, elution, stirring and settling steps two more times and pool the supernatants from the second and third elutions with the first elution material. The silica is discarded.
The cholesterol-rich solution is clarified by filtration and centrifugation to remove any traces of silica and then preferably frozen at -20° C. and stored at that temperature for 48-72 hours. The frozen material is then thawed at room temperature for at least 24-48 hours until no visible ice crystals are present. The resulting liquid product is clarified by centrifugation and any solid material is discarded. This freeze-thaw cycle assists in removal of silica which otherwise interferes with subsequent processing steps. The clarified liquid is then concentrated to 15 to 50 percent, preferably 20 to 25 percent, of its initial volume, by ultrafiltration techniques.
The concentrated cholesterol-rich solution is then dialyzed against an alkaline material, such as aqueous sodium carbonate, to further remove silica. In order to improve the effectiveness of this dialysis step, it is desirable for the cholesterol-rich solution to be at pH 11.0 to 13.0, preferably pH 12.0. The pH can be adjusted to this value by alkaline addition. This can take place just prior to the dialysis step, but it is preferred for operating convenience to adjust the pH to this value before the cholesterol-rich solution is subjected to the above-discussed ultrafiltration concentration step.
In the dialysis step, the cholesterol-rich solution is dialyzed against 6-7 volumes of 0.01-0.3 M sodium carbonate to remove silica followed by dialysis against 6-7 volumes of deionized water to remove the sodium carbonate. The resulting solution is then concentrated by ultrafiltration to its volume prior to dialysis.
The pH of the concentrated cholesterol-rich solution is then adjusted to a value in the range from 7.0 to 11.0, preferably pH 8.6.
The concentrated cholesterol-rich solution is heated to 50° to 100° C., preferably 80° C., for 30 minutes to 24 hours, preferably 30 minutes to 5 hours, in order to increase the storage stability of the cholesterol-rich fraction. The solution is then cooled to about 30° C. It is convenient for handling purposes that the desired product contain about 0.50 to 30 mg./ml, preferably 10 to 20 mg./ml, of cholesterol. It is preferred to analyze the above cooled product for cholesterol using known techniques and to dilute the product with deionized water to the desired concentration.
While it is not necessary in the process for production of the cholesterol-rich fraction, it is convenient that the product contain about 8.5 g/l sodium chloride and have a pH adjusted to 7.7-7.9 so that it is generally compatible with media employed for cell culture. The product is then sterile filtered to recover a purified cholesterol-rich fraction. This product is not pure cholesterol, but it is mixed with minor amounts of unidentified materials which passed through the production process.
Pure cholesterol is not suitable for use in this invention since it does not appreciably affect the growth of T.hyodysenteriae in the way achieved by the cholesterol-rich bovine fractions.
The T.hyodysenteriae cells are grown in the media containing the cholesterol-rich bovine fraction under conditions well-known to those skilled in the art. The resulting cells are then killed in a well-known manner by using agents, such as formalin, merthiolate, or beta-propiolactone. The cells are then harvested and suspended in an appropriate carrier medium to produce a desired bacterin.
The activity of the bacterin can be further enhanced by the use of an adjuvant. An adjuvant that is preferred for use with the T.hyodysenteriae cells produced by the process of the present invention is the combination of an acrylic acid polymer cross-linked with a polyallyl saccharide and a specific emulsion system disclosed and claimed in U.S. Pat. No. 3,919,411. Such adjuvant is marketed by the Bayvet Division of Mobay Corporation under the trademark HAVLOGEN.
It has been found that the T.hyodysenteriae bacterin produced in the above manner can be injected intramuscularly in only two doses at three week intervals to significantly increase the resistance of pigs to swine dysentery.
The invention will be further described in the following examples.
EXAMPLE 1
Cholesterol-rich bovine fraction was prepared in the following manner. Fresh bovine serum was brought to a temperature of 20°-25° C. and 14.7 g/l of sodium citrate (serum ionic strength of 0.5) was added. The resulting solution was agitated for 30 minutes, and the pH was adjusted to 7.0 by addition of an appropriate amount of 1N sodium hydroxide. Finely-divided silica was added in an amount of 10 g/l and the resulting slurry was agitated for 3 hours at room temperature. The silica containing adsorbed material was then separated from the liquid phase by centrifugation, and the liquid was discarded. The silica paste was then frozen at -20° C. and stored at that temperature for 2 weeks. The frozen paste was then thawed at room temperature for 48 hours. The expressed liquid was discarded. The silica paste was then suspended in 2 liters of 0.85 percent (weight/volume basis) aqueous sodium chloride solution (0.146M NaCl) for each kilogram of silica paste. It was mixed gently for 15 minutes and allowed to settle for at least 3 hours. The supernatant liquid was siphoned off and discarded. This washing step was repeated two times. The washed paste was then suspended in 2 liters of deionized water per kilogram of silica paste with agitation at room temperature. The resulting suspension was then carefully warmed to 20°- 25° C. The pH was adjusted to 10.5 with addition of 1N sodium hydroxide. The resulting suspension was stirred at room temperature for 2 hours while readjusting pH to 10.5. The stirring was stopped, and the suspension was allowed to settle for 18 hours. The supernatant was removed by siphon and clarified by filtration and centrifugation. The silica was discarded. The clarified solution was then concentrated to 20 percent of its initial volume by ultrafiltration. The pH of the concentrated material was adjusted to 11.2 by addition of 1N sodium hydroxide. The concentrated material was then dialyzed against 6 volumes of 0.01M sodium carbonate at pH 11.2. It was then dialyzed against 6 volumes of deionized water. The cholesterol level of the concentrate was analyzed by known techniques and further concentrated by ultrafiltration to a cholesterol level of 10 mg./ml. The pH was then adjusted to 7.6 by addition of 1N hydrochloric acid, and the resulting solution was heated at 80° C. for 1 hour. The solution was then cooled to room temperature. Sodium chloride was added in an amount of 8.5 g/l and the resulting solution was sterile filtered. The filtered material was then recovered as a purified cholesterol-rich bovine fraction.
Frozen seed of T.hyodysenteriae strain ATCC No. 31212 was inoculated into a glass tube containing 13 ml. of Tryptic Soy Broth (Difco Laboratories,, 27.5 g/l), 10 percent fetal calf serum, 0.5 percent dextrose, 0.05 percent 1-cysteine HCl and 0.25 mcg/ml vitamin B-12. Such percents were on a weight/volume basis. The tube was then sealed and incubated under an anaerobic atmosphere containing 10 volume percent hydrogen, 80 volume percent nitrogen, 10 volume percent carbon dioxide at 37° C. for 72 hours. The resulting seed culture was then passaged to 2 tubes containing the same media which were incubated at 37° C. for 24 hours under the same conditions. The contents of the tubes were pooled. A 7 ml portion of the pooled active seed culture was then added to each of two 500 ml. bottles each containing 200 ml. of Tryptic Soy Broth, 1 percent yeast extract, 5 percent lamb serum, 0.5 percent dextrose, 0.05 percent 1cysteine HCl and 0.25 mcg/ml. vitamin B-12. Such percents were on a weight/volume basis. The bottle contents were then incubated under the above-described anaerobic atmosphere at 37° C. until turbid (about 24 hours).
The resulting expanded seed cultures were then divided into two portions, and each portion was used alone to inoculate one of two 14 liter pilot fermenters each containing 7 liters of Tryptic Soy Broth, 1 percent yeast extract, 3 percent lamb serum, 1 percent dextrose, 0.05 percent 1-cysteine HCl and 0.25 mcg/ml. vitamin B-12. Such percents were on a weight/volume basis. One of the fermenters was further supplemented with 2.5 volume percent of the cholesterol-rich bovine fraction prepared as described above. Both fermenters were then incubated at 37° C. for 44 hours under the above anaerobic atmosphere. The pH was controlled at 6.5 by periodic additions of 5N sodium hydroxide.
At the conclusion of the above incubation, appropriate samples were taken from each fermenter, and the fermenter contents were then treated with 0.15 volume percent formalin to inactivate the cells. The cell samples were examined microscopically, the total cell count was measured in a Petroff-Hauser counting chamber, and the viable cell count was determined by serial dilution on freshly poured 5 percent bovine blood agar plates. The blood agar plates were incubated at 37° C. under an anaerobic atmosphere of 50 volume percent hydrogen and 50 volume percent carbon dioxide for 4 days. The T.hyodysenteriae colonies were observed as individual zones of hemolysis. The results of these examinations are listed below in Table 1.
TABLE 1______________________________________Growth of T. hyodysenteriae ATCC 31212 in MediaWith and Without Cholesterol-Rich Bovine Fraction Total Viable Microscopic Cell CellMedia Examination Count Count______________________________________Without Loosely coiled; 1.3 × 10.sup.9 /ml 3.7 × 10.sup.7 /mlCholesterol relatively longFraction thin walled cells; generally inactiveWith Tightly coiled; 2.6 × 10.sup.9 /ml 1.4 × 10.sup.9 /mlCholesterol shorter, thickerFraction walled cells; active______________________________________
It can be seen from the above data that the presence of the cholesterol-rich bovine fraction doubled the total cell count, increased viable cell count 100-fold, and had a positive effect on cell morphology.
EXAMPLE 2
Seed cultures of T.hyodysenteriae ATCC No. 31212 prepared as described in Example 1 above were then used to inoculate at a 3 volume percent level the contents of three 500 ml. bottles each containing 200 ml. of Tryptic Soy Broth mixed with 1 percent yeast extract, 3 percent lamb serum, 1 percent dextrose, 0.05 percent 1-cysteine HCl and 0.25 mcg/ml. vitamin B-12. The percents were on a weight/volume basis. One of the bottles (Control) contained 2.5 volume percent of the cholesterol-rich bovine fraction prepared as described in Example 1. A second bottle contained 2.5 volume percent of Cholesterol Concentrate Code 82-010 from Miles Laboratories, Inc. A third bottle contained 2.5 volume percent Bovine Cholesterol Concentrate List 3200 from Biocell Laboratories. These inoculated bottles were then incubated under an anaerobic atmosphere of 10 volume percent hydrogen, 80 volume percent nitrogen and 10 volume percent carbon dioxide at 37° C. for 38 hours. The bottle contents were adjusted to pH 7.0 at 24 and 31 hours by addition of 2N sodium hydroxide. The total cell count from each bottle was measured in a Petroff-Hauser counting chamber. The results are shown below in Table 2.
TABLE 2______________________________________Growth of T. hyodysenteriae ATCC No. 31212 in MediaContaining Various Cholesterol-RichBovine FractionsMedia Supplement Total Cell Count______________________________________Preferred cholesterol 2.5 × 10.sup.9 /mlfraction (Control)Cholesterol Concentrate 2.7 × 10.sup.9 /mlCode 82-010Bovine Cholesterol Con- 3.0 × 10.sup.9 /mlcentrate List 3200______________________________________
It can be seen from the above data that cholesterol-rich bovine fractions from various sources can be employed to produce a desirably high cell count of T.hyodysenteriae.
EXAMPLE 3
The procedure of Example 1 was generally repeated using T.hyodysenteriae strain ATCC No. 31287 with media supplemented with the preferred cholesterol-rich fraction to produce a high concentration of cells.
EXAMPLE 4
A vaccine or bacterin was prepared by mixing the killed T.hyodysenteriae cells prepared in the manner described in Example 1 using the preferred cholesterol-rich fraction in the growth media with 10 volume percent HAVLOGEN adjuvant described in U.S. Pat. Nos. 3,919,411 and 1:10,000 merthiolate. The vaccine contained 2×10 9 cells/ml. This vaccine was then used in five separate challenge studies to determine the effectiveness of the vaccine against swine dysentery. In each of the vaccination/challenge studies the swine were obtained from a herd with no history of swine dysentery and were of mixed sex and generally Yorkshire, Hampshire or Cross breeds. At the time of first vaccination, the swine were at least 3 weeks post weaning and in the range of 35 to 40 lbs.
All vaccination/challenge studies were run in an isolation facility permitting segregation of vaccinated and control swine. The pigs were fed a protein grower ration containing no antibiotics. Prior to challenge, the swine were rectal swabbed and shown to be free of T.hyodysenteriae and Salmonella spp. following testing on appropriate isolation media.
The swine were challenged intragastrically with T.hyodysenteriae strains ATCC No. 31212 or 31287 which had been grown by a procedure similar to Example 1 except that the final cells were not killed. The challenge dose consisted of 100 ml. of active culture diluted to contain 10 8 to 10 9 organisms which was administered to individual pigs via stomach tube, following a 48 hour starvation period.
Each challenged pig was observed on a daily basis over a 28 day post challenge observation period. Following onset of clinical disease, dysenteric pigs were rectal swabbed to isolate the causative agent. Confirmation of T.hyodysenteriae infection was made by subculturing swabs onto Spectinomycin blood agar plates, incubating at 42° C. for 4 to 6 days, and microscopically examining hemolytic agar plaques for presence of spirochetes. A necropsy was performed on each pig which died during the five studies. Macroscopic lesions were recorded, and rectal swabs were taken of colonic mucosa to be subcultured as above.
Clinical response of individual swine to challenge was measured using the following Clinical Index:
______________________________________CLINICAL INDEXGeneral Feces FecesCondition Composition Consistency______________________________________0 - Normal 0 - Normal 0 - Normal1 - Diarrhea 1 - Mucus 1 - Soft2 - Dysentery 2 - Blood & Mucus 1.5 - Loose3 - Gaunt 3 - Blood 2 - Runny4 - Moribund 3 - Watery5 - Dead______________________________________
Various methods of analysis were used to evaluate clinical index data and are defined below:
(a) Daily Clinical Index (DCI)--A daily clinical index for each challenged pig was calculated using the three above described parameters:
DCI=General condition+Feces Composition+Feces Consistency
(b) Daily Group Clinical Index (DGCI)--A daily group clinical index for vaccinate and control groups was calculated using the following formula: ##EQU1## (c) Individual Cumulative Clinical Index (ICCI)--A cumulative clinical index for each pig over the entire 28 day post-challenge period was calculated as follows: ##EQU2## (d) Group Cumulative Clinical Index (GCCI)--A group cumulative clinical index for vaccinates and controls was obtained by averaging the ICCI's within a particular group of pigs: ##EQU3## Study No. 1: Ten (10) pigs were divided equally into two rooms. Five vaccinates received two 5 ml. intramuscular doses of the above described vaccine at three week intervals. Five unvaccinated control pigs were held in a separate room. Two weeks post booster, all pigs were challenged with virulent T.hyodysenteriae ATCC No. 31212.
Study No. 2: Twenty-nine (29) pigs were divided into 5 rooms of 23 vaccinates and two rooms of 6 controls. Vaccinates received two 5 ml. intramuscular doses of the above described bacterin at three week intervals. Challenge was the same as in Study No. 1.
Study No. 3: Ten (10) pigs were divided equally into two rooms. Five vaccinates received two 5 ml. intramuscular doses of the above-described bacterin at three week intervals. Five pigs were held as unvaccinated controls. Two weeks post booster all pigs were challenged with virulent T.hyodysenteriae ATCC No. 31287.
Study No. 4: Forty-six (46) pigs were divided into nine rooms of 36 vaccinates and two rooms of 10 unvaccinated controls. Vaccinated swine received two 4 ml. doses of the above described bacterin at three week intervals. Challenge was the same as in Study No. 3.
Study No. 5: Forty-six (46) pigs were divided into nine rooms of 36 vaccinates and two rooms of 10 unvaccinated controls. Vaccinated swine received two 5 ml. doses of the above described bacterin at three week intervals. Challenge was the same as in Study No. 1.
The five studies included a total of 105 vaccinates and 36 controls. Results of the five studies are summarized in Tables 3 and 4.
TABLE 3__________________________________________________________________________CLINICAL RESPONSE OF PIGS CHALLENGED INTRAGASTRICALLYWITH T. HYODYSENTERIAE ATCC NO. 31212 Clinical Dysentery Gaunt Death GroupNo. of No. of Mean Mean Days No. of No. of Days ClinicalPigs Cases Percent Day Onset Duration Cases Percent Cases Percent Anorexia Index__________________________________________________________________________VACCINATESStudy 1 5 1 20 10 5 0 0 0 0 0 8.8Study 223 8 34.7 12.6 3.5 1 4.3 0 0 1 23.3Study 536 2 5.5 15.5 3.5 0 0 0 0 0 2.3TOTAL64 11 17.2 12.9 3.6 1 1.6 0 0 1 10.4CONTROLSStudy 1 5 5 100 10.8 12.9 0 0 3 60 9 159.0Study 2 6 4 66.7 7.0 8.4 0 0 1 16.7 4 82.3Study 510 6 60 10.3 6.6 1 10 1 10 2 45.9TOTAL21 15 71.4 9.6 10.3 1 4.8 5 23.8 15 83.2__________________________________________________________________________
Following intragastric challenge with strain ATCC 31212, clinical dysentery was observed in 17.2% of vaccinated pigs (11 of 64) and in 71.4% of control pigs (15 of 21). This represents a 75.9% reduction in actual cases of clinical dysentery among vaccinated pigs. The cumulative clinical index (GCCI) calculated for the entire 28 day post-challenge observation period was 10.4 for vaccinated pigs as compared to 83.2 for unvaccinated controls. This represents an 87.5% reduction in total clinical signs (diarrhea, dysentery, gauntness, death) as measured by the clinical index. No deaths were seen among vaccinated pigs whereas 5 of 21 control pigs dies post challenge (23.8%). Onset of clinical dysentery was delayed in vaccinated pigs and duration of clinical disease reduced. Anorexia was appreciably reduced in vaccinated swine.
TABLE 4__________________________________________________________________________CLINICAL RESPONSE OF PIGS CHALLENGED INTRAGASTRICALLYWITH T. HYODYSENTERIAE ATCC No. 31287 Clinical Dysentery Gaunt Death GroupNo. of No. of Mean Mean Days No. of No. of Days ClinicalPigs Cases Percent Day Onset Duration Cases Percent Cases Percent Anorexia Index__________________________________________________________________________VACCINATESStudy 3 5 2 40 11.5 3.0 0 0 0 0 0 21.2Study 436 12.5 34.7 13.6 2.5 0 0 0 0 0 18.2TOTAL41 14.5 35.4 13.3 2.6 0 0 0 0 0 18.6CONTROLSStudy 3 5 3 60 6.3 15.3 1 20 1 20 4 93.2Study 410 7.5 75 6.6 6.4 1 10 1 10 0 63.6TOTAL15 10.5 70 6.6 8.9 2 13.3 2 13.3 4 73.5__________________________________________________________________________
Following intragastric challenge with strain ATCC 31287 clinical dysentery was observed in 35.4% of vaccinated pigs (14 of 41, one pig ±) and in 70.0% of control pigs (10 of 15, one pig ±). This represents a 49.4% reduction in actual cases of dysentery among vaccinated swine. The group cumulative clinical index for vaccinated pigs was 18.6 as compared with 73.5 for unvaccinated controls. This represents a 74.7% reduction in total clinical signs among vaccinates. No deaths were seen among vaccinates whereas 2 of 15 control pigs died post-challenge (13.3%). Onset of clinical dysentery was significantly delayed and duration of clinical disease reduced in vaccinated swine.
Confirmation of T.hyodysenteriae as the causative agent of clinical dysentery was achieved in all cases following plating of rectal swabs on spectinomycin blood agar plates. Simultaneous plating on selective media for Salmonella spp. gave negative results.
Colonic contents of dead pigs were bloody and watery, and the colons themselves were grossly inflamed and devoid of villi. Rectal swabs taken from intestinal walls at time of necropsy were positive for T.hyodysenteriae and negative for Salmonella spp. Rectal swabs taken from protected vaccinates at 28 days post challenge were negative in all cases following subculture on spectinomycin blood agar plates at 42° C.
Taking all 141 vaccinated and control pigs into account, one can construct Table 5 summarizing clinical response through five challenge studies. Of 105 vaccinates, 25.5 developed clinical dysentery (24.3%) whereas 25.5 of 36 unvaccinated controls developed clinical dysentery (70.8%). This represents a 65.7% reduction in clinical dysentery among all vaccinated swine. Seven of 36 control pigs died post challenge (19.4%) whereas no vaccinated swine died post challenge. The Group Cumulative Clinical Index for all 105 vaccinated pigs is 13.6; the G.C.C.I. for 36 unvaccinated controls is 79.2. This translates into an 82.8% reduction in total clinical signs (diarrhea, dysentery, gauntness, death) among all vaccinated pigs.
Taking Vaccination/Challenge results from the five individual studies into consideration, one can conclude that the T.hyodysenteriae bacterin will show a definite degree of efficacy when used under field conditions as an aid in prevention of Swine Dysentery.
TABLE 5__________________________________________________________________________VACCINATION CHALLENGE STUDIES 1, 2, 3, 4, 5CLINICAL RESPONSE OF PIGS CHALLENGED INTRAGASTRICALLY WITHTREPONEMA HYODYSENTERIAE STRAINS ATCC No. 31212 and 31287 Clinical Dysentery Gaunt Death GroupNo. of No. of Mean Mean Days No. of No. of Days ClinicalPigs Cases Percent Day Onset Duration Cases Percent Cases Percent Anorexia Index__________________________________________________________________________Vaccinates 105 25.5 24.3 13.1 2.8 1 1.0 0 0 1 13.6Controls 36 25.5 70.8 8.2 9.1 3 8.3 7 19.4 21 79.2__________________________________________________________________________
The preferred cholesterol-rich fraction can be prepared by an alternate process described in the following example.
EXAMPLE 5
Fresh bovine serum was brought to a temperature of 20°-25° C. and 14.7 g/l of sodium citrate (serum ionic strength of 0.5) was added. The resulting solution was agitated for at least 30 minutes, and the pH was adjusted to 6.9-7.1 by addition of appropriate amount of 1N sodium hydroxide or 1N hydrochloric acid. Finely-divided silica was added in an amount of 10 g/l, and the resulting slurry was agitated for 3-4 hours at room temperature. Polyethylene glycol having nominal molecular weight of 3350 daltons was added in an amount of 10 g/l, and the resulting mixture was agitated for 1 hour at room temperature. The silica containing adsorbed material was then separated from the liquid phase by centrifugation, and the liquid was discarded. The silica paste was then frozen at -20° C. and stored at that temperature for at least 2 weeks. The frozen paste was then thawed at room temperature for 24-48 hours until no visible ice crystals were present. The expressed liquid was discarded. The silica paste was then suspended in 2 liters of 0.85 percent (weight/volume basis) aqueous sodium chloride solution (0.146M NaCl) for each kilogram of silica paste. It was mixed gently for 15 minutes and allowed to settle for at least 3 hours for adequate sedimentation. The supernatant liquid was siphoned off and discarded. This washing step was repeated at least two times. The washed paste was then suspended in 2 liters deionized water per kilogram of silica paste with agitation at room temperature. The resulting suspension was then carefully warmed to 20°-25° C. The pH was adjusted to 10.5 with addition of 1N sodium hydroxide. The resulting suspension was stirred at room temperature for 2 hours while constantly maintaining pH at 10.4-10.6 by addition of 1N sodium hydroxide or hydrochloric acid. The stirring was stopped, and the suspension was allowed to settle for at least 12 hours. The supernatant was removed by siphon and clarified by filtration and centrifugation. The silica was discarded. The liquid was then frozen at -20° C. and stored at that temperature for 48-72 hours. The frozen material was then thawed at room temperature for 48-72 hours until no visible ice crystals were present. The resulting liquid product was clarified by centrifugation and any solid material was discarded. The pH of the clarified solution was adjusted to 11.9-12.1 by addition of 1N sodium hydroxide. The solution was then concentrated to about 20-25 percent of its initial volume by ultrafiltration using hollow fiber or spiral wound molecular filters having a nominal molecular weight cut-off of 5,000-30,000 daltons. The concentrated material was then dialyzed against 7 volumes of 0.3 M sodium carbonate and against 7 volumes of deionized water. The solution was then concentrated by ultrafiltration to its volume prior to dialysis. The pH was then adjusted to 8.6 by addition of 1N hydrochloric acid, and the resulting solution was heated at 80° C. for at least 30 minutes. The solution was then cooled to about 30° C. The cholesterol level of the product was analyzed by known techniques and diluted to a concentration of 10 mg./ml with deionized water. Sodium chloride in an amount of 8.5 g/l was then added and the pH was adjusted to 7.7-7.9 by addition of 1N sodium hydroxide or hydrochloric acid. The resulting product was then sterile filtered using 0.45 and 0.2 micron microporous filtration media. The filtered materials was then recovered as a purified cholesterol-rich fraction.
This product material can be used in the same manner as that described above in Examples 1-4. | A process is provided for increasing the yield of active cells of Treponema hyodysenteriae by growing such cells in a nutrient medium containing a cholesterol-rich bovine fraction. Killed cells grown in this manner can be used to produce a bacterin which is effective against swine dysentery. | 2 |
FIELD OF THE INVENTION
[0001] The present invention relates generally to landscaping and more particularly to an expandable bag for protecting a live tree during vehicular transport.
BACKGROUND
[0002] Different styles of tree bags have been used primarily for transporting evergreen types of cut Christmas trees. U.S. Pat. No. D469,609 S to Hoffman, which is herein incorporated by reference, teaches the use of a zippered-style gusset bag that is fastened with a zipper when positioned around the tree. U.S. Pat. No. 5,291,999 to Phair, which is incorporated by reference, teaches the use of a tree bag having a conical shape: that is wrapped around the tree and secured with an elongated side fastener. Finally, U.S. Pat. No. 4,054,166 to Burke teaches a Christmas tree cover that is secured using snap fasteners and a belt.
[0003] One problem associated with these types of Christmas tree bags is they cannot be expanded for use with trees having a substantially large circumference. Moreover, they can only be used with conifer trees and cannot be reversed. The shape and closing techniques used by bags in the prior art do not operate to protect leafy deciduous trees during transport. For example, the style as shown in U.S. Pat. No. D469,609S will not work with deciduous trees, since it offers no place for tall deciduous branches to extend from the top. The style in U.S. Pat. No. 5,291,999 will not work well with deciduous trees since deciduous trees have small trunks and are often bulky at the top of the tree. Thus, if the tree bag described in this patent were reversed, there is no way for the bulky top portion of the deciduous tree to be completely wrapped. Similarly, the style of bag described in U.S. Pat. No. 4,054,166 is wider at the bottom for a conifer tree but could not be reversed to work with deciduous tree since the belt at the bottom of the bag would not operate to extend around the deciduous tree with tall leafy branches.
[0004] Hence, the need exists to provide a tree bag that is expandable and can operate to protect both live conifer and deciduous trees from wind stress during transport.
BRIEF DESCRIPTION OF THE FIGURES
[0005] The accompanying figures, where like reference numerals refer to identical or functionally similar elements throughout the separate views and which together with the detailed description below are incorporated in and form part of the specification, serve to further illustrate various embodiments and to explain various principles and advantages all in accordance with the present invention.
[0006] FIGS. 1-2 are side perspective views of an expandable tree bag in accordance with the invention shown in open and closed positions, respectively.
[0007] FIG. 3 is a side perspective of a panel extension for the expandable tree bag in accordance with the invention.
[0008] Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of embodiments of the present invention.
DETAILED DESCRIPTION
[0009] Before describing in detail embodiments that are in accordance with the present invention, it should be observed that the embodiments reside primarily in combinations of method steps and apparatus components related to a reversible tree bag. Accordingly, the apparatus components and method steps have been represented where appropriate by conventional symbols in the drawings, showing only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having the benefit of the description herein.
[0010] In this document, relational terms such as first and second, top and bottom, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. The terms “comprises,” “comprising,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element preceded by “comprises . . . a” does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element.
[0011] FIG. 1 and FIG. 2 illustrate a side perspective view of the expandable tree bag for both conifer and deciduous trees 100 in accordance with the invention. FIG. 1 illustrates the bag in an open position and FIG. 2 illustrates the bag in a closed position. The tree bag 100 is formed using 60 percent nylon shade cloth material into a face 1101 that is substantially oblong or an extended ovular shape. The shade cloth material is porous to light and selected such that its density will permit 60 percent of the light to be blocked. This leaves approximately 40 percent of the light present on the outside of the material to penetrate inside the bag to reach the tree. Those skilled in the art will recognize that although 60 percent nylon shade cloth material is described herein, any percentage of shade cloth material may be selected depending on environmental factors.
[0012] The elongated oval shape of the tree bag 100 is configured so that a long curved edge 103 and short curved edge 105 are positioned on either end of the bag depending on whether a conifer or deciduous tree is covered. The long curved edge 103 includes a plurality of grommets 104 that extend around the perimeter of the long curved edge 103 . A rope 106 is threaded through apertures 104 for controlling the size of the curved edge 103 . Similarly a first side edge 107 includes a half zipper 109 while the second side edge 111 includes the other half zipper 113 that includes a fastener 115 , A series of hook and loop fasteners 110 , 112 are used along both edges of the bag allowing the bag to be easily closed by merely meshing the hook and loop fasteners together. Those skilled in the art will recognize that hook and loop fasteners may initially be used to seal the bag which enables the zipper to be more easily closed. With the zipper in a closed position, this allows trees to be protected from high wind forces that are present when transporting a tree at highway speeds.
[0013] FIG. 3 illustrates a side perspective view of an expansion panel 201 that is used to increase the circumference of the tree bag 100 in order to accommodate conifer and/or deciduous trees having a larger diameter. Like the tree bag 100 , the expansion panel 201 includes a first curved edge 203 and second curved edge 205 . A first side edge 27 includes a half zipper 209 and a second side edge 211 has a half zipper 213 . An integrated pouch or pocket 210 is included within the expansion panel for carrying rope, bungee cords, tools or other accessories needed for transport. In operation, the expansion panel 201 can be zipped into the tree bag to increase the overall circumference of the bag. Typically, this is accomplished by meshing the half zipper 209 with the half zipper 113 and then zipping the half zipper 213 with the half zipper 109 to form an enclosed tree bag.
[0014] The tree bag 100 also offers an advantage in that it may be positioned in either direction depending on whether it is to be fitted around either a confer tree or deciduous tree. When used with a conifer tree, the tree bag 100 is used with the long curved edge 103 down around the base of the conifer tree and the short curved edge 105 positioned around the top of the tree. If a deciduous tree is used, then the bag configuration is reversed with the short curved edge 105 positioned at the lower trunk of the tree and the long curved edge 105 positioned about the top leafy section of the tree. The invention offers a greater amount of utility over tree bags used in the prior art since one bag can be used with either type of tree in order to prevent wind damage during high-speed vehicular transport.
[0015] Thus, the invention offer advantages over tree bags described in the prior art since it is easily expansible and maybe be easily oriented in order to cover both conifer and deciduous trees during vehicular transport. The invention includes a pocket expansion panel and apertures positioned about the bag face for allowing a tree carrier to be easily used when the tree bag is used with conifer trees.
[0016] In the foregoing specification, specific embodiments of the present invention have been described. However, one of ordinary skill in the art will appreciate that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of present invention. The benefits, advantages, solutions to problems, and any element(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential features or elements of any or all the claims. The invention is defined solely by the appended claims including any amendments made during the pendency of this application and all equivalents of those claims as issued. | An expandable tree bag assembly ( 100 ) for use with both conifer and deciduous trees includes an extended ovular shaped face ( 101 ) having a long curved edge ( 103 ) and short curved edge ( 105 ). Side edges ( 109, 113 ) operate using a zippered closing mechanism allowing an expansion panel ( 201 ) to be attached for increasing the circumference of the ovular shaped face ( 101 ). The face includes a carrier aperture positioned alone the long curved edge ( 103 ) for allowing the tree carrier to extend therethrough. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based on, claims the benefit of, and incorporates herein by reference in their entirety, PCT International Application PCT/US2009/065750 filed on Nov. 24, 2009, which claims benefit of U.S. Provisional Patent Application Ser. No. 61/117,705, filed on Nov. 25, 2008, entitled “System and Method for Analyzing the Carpal Tunnel Using Ultrasound.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with government support under grant number AR049823, awarded by the National Institutes of Health. The government has certain rights in the invention.
FIELD OF THE INVENTION
The present invention relates to systems and methods ultrasonic imaging and, more particularly, to systems and methods for analyzing the health of structures within a subject's carpal tunnel using ultrasonic imaging methods.
BACKGROUND OF THE INVENTION
Carpal tunnel syndrome (CTS), which is a pressure induced neuropathy of the median nerve at the wrist, is a common clinical problem. The carpal tunnel is a sheath of tough connective tissue that protects and encloses a variety of structures, including the flexor tendons and the median nerve. Also within the carpal tunnel is the subsynovial connective tissue (SSCT), a specially adapted paratendon that mediates movement between the flexor tendons and the median nerve. The mechanical significance of the SSCT relates to its effect on the kinematics within the carpal tunnel and, as a framework for blood and lymph vessels, the SSCT plays a fundamental role in the nutrition of the structures embedded in it.
Studies have shown that SSCT motion characteristics and thickness differ between subjects with CTS and unaffected subjects. It is believed that an increased volume of the SSCT, especially if combined with altered transmission of tendon forces through the SSCT in the carpal tunnel, affects carpal tunnel pressure and therefore increases the likelihood of CTS.
Diagnostic ultrasonography has previously been used in confirming the diagnosis of CTS and in excluding other pathologies. Specifically, ultrasonography has been used to diagnose CTS, based on static images of nerve morphology. Static ultrasound imaging for CTS diagnosis can detect thickening and echogenicity alteration of the flexor tendons and flexor retinaculum, restricted median nerve sliding in the carpal tunnel, synovial proliferation, and flattening of the median nerve. However, static ultrasound imaging cannot assess dynamic features within the carpal tunnel, for example, tendon mechanics and pathomechanics. Thus, dynamic observations of the SSCT have traditionally required surgical exposure of the carpal tunnel and are not useful for the assessment of early changes in the SSCT in individuals affected by, or at risk for, CTS.
There are a number of modes in which ultrasound can be used to produce images of objects. For example in static, “B-scan,” ultrasound imaging, the transducer transmits a series of ultrasonic pulses as it is scanned across the object along a single axis of motion. The resulting echo signals are recorded and their amplitude is used to modulate the brightness of pixels on a display. The location of the transducer and the time delay of the received echo signals locates the pixels to be illuminated. With this static method, enough data are acquired from which a two-dimensional image of the refractors can be reconstructed. Rather than physically moving the transducer over the subject to perform a scan it is more common to employ an array of transducer elements and electronically move an ultrasonic beam over a region in the subject.
Another example is Doppler ultrasound imaging. Doppler systems employ an ultrasonic beam to measure the velocity of moving reflectors, such as flowing blood cells. Blood velocity is detected by measuring the Doppler shifts in frequency imparted to ultrasound by reflection from moving red blood cells. Accuracy in detecting the Doppler shift at a particular point in the bloodstream depends on defining a small sample volume at the required location and then processing the echoes to extract the Doppler shifted frequencies.
A Doppler system is incorporated in a real time scanning imaging system. The system provides electronic steering and focusing of a single acoustic beam and enables small volumes to be illuminated anywhere in the field of view of the instrument, whose locations can be visually identified on a two-dimensional B-scan image. A Fourier transform processor faithfully computes the Doppler spectrum backscattered from the sampled volumes, and by averaging the spectral components the mean frequency shift can be obtained. Typically the calculated blood velocity is used to color code pixels in the B-scan image.
Doppler imaging has been attempted to be used for assessing tendon velocity and excursion for hand and wrist motions. However, tissue Doppler imaging is a one-dimensional method that can only quantify the axial component of motion in an angle dependent manner. Doppler measurements lose its validity when the angle between the ultrasonic beam and the tissue exceeds a certain range. As a result, static ultrasonography and tissue Doppler imaging cannot adequately assess the condition of the SSCT and a subject's risk of developing CTS.
It would therefore be desirable to develop a system and method for non-invasively analyzing the carpal tunnel, and the SSCT in particular, that could be used to generate risk factors indicative of a subject's risk of developing carpel tunnel syndrome or SSCT damage.
SUMMARY OF THE INVENTION
The present invention overcomes the aforementioned drawbacks by providing a system and method for analyzing the health of a subject's carpal tunnel without invasive analysis. Specifically, the present invention provides a system and method for performing ultrasound analysis of a subject's carpal tunnel by arranging a subject within an examination apparatus, acquiring a plurality of time series of ultrasound images of the subject's carpal tunnel as the subject performs a series of tasks controlled by the examination apparatus and performing speckle tracking on the time series of ultrasound images. The speckle tracking is then analyzed to determine a plurality of functional parameters of the subject and statistical analysis is performed to compare the functional parameters of the subject to a priori functional parameters from normal subjects and subjects having carpal tunnel syndrome. Thereby, risk factors indicative of the subject's risk of developing carpal tunnel syndrome or subsynovial connective tissue damage are generated.
In accordance with one aspect of the invention, a system is provided for generating a report indicating a subject's risk for developing a disorder of a carpal tunnel. The system includes an examination apparatus configured to control motion of the subject through a predetermined set of motions, an ultrasound transducer arranged proximate to the subject's carpel tunnel to acquire a time series of medical imaging data of a region of interest including at least a portion of the subject's carpel tunnel, and a processor configured to receive the time series of medial imaging data. The processor includes instructions configured to cause the processor to carry out the steps of generating a time series of images from the time series of medial imaging data and receiving an indication of anatomical features within the time series of medical images. The processor also carries out the steps of analyzing the time series of medical images to determine indicia of acoustic signals arising from coherent reflection of ultrasound waves generated by the transducer from predetermined features within the region of interest and track the determined indicia across the time series of medical images. Also, the processor carries out the steps of determining a pattern of motion of the determined indicia across the time series of medical images, generating a series of functional parameters characterizing pattern of motion of the determined indicia across the time series of medical images, and, using the series of functional parameters, generating a report indicating the subject's risk of developing at least one of carpel tunnel syndrome (CTS) and subsynovial connective tissue (SSCT) damage.
Various other features of the present invention will be made apparent from the following detailed description and the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of an ultrasonic imaging system configured to employs the present invention;
FIG. 2 is a block diagram of a transmitter that forms part of the system of FIG. 1 ;
FIG. 3 is a block diagram of a receiver that forms part of the system of FIG. 1 ;
FIG. 4 is a flowchart setting forth the steps of a method for generating risk factors indicative of a subject's risk of developing CTS or SSCT damage using an ultrasonic imaging system in accordance with the present invention;
FIG. 5 is a perspective view of an examination apparatus for use with the ultrasonic imaging system of FIG. 1 in accordance with the present invention; and
FIG. 6 is an exemplary image showing the tracking of features within the carpal tunnel using methods in accordance with the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 , an ultrasonic imaging system includes a transducer array 11 comprised of a plurality of separately driven elements 12 which each produce a burst of ultrasonic energy when energized by a pulse produced by a transmitter 13 . The ultrasonic energy reflected back to the transducer array 11 from the subject under study is converted to an electrical signal by each transducer element 12 and applied separately to a receiver 14 through a set of switches 15 . The transmitter 13 , receiver 14 and the switches 15 are operated under the control of a digital controller 16 responsive to the commands input by the human operator. A complete scan is performed by acquiring a series of echoes in which the switches 15 are set to their transmit position, the transmitter 13 is gated on momentarily to energize each transducer element 12 , the switches 15 are then set to their receive position, and the subsequent echo signals produced by each transducer element 12 are applied to the receiver 14 . The separate echo signals from each transducer element 12 are combined in the receiver 14 to produce a single echo signal which is employed to produce a line in an image on a display system 17 .
The display system 17 receives the series of data points produced by the receiver 14 and converts the data to a form producing the desired image. For example, if an A-scan is desired, the magnitude of the series of data points is merely graphed as a function of time. If a B-scan is desired, each data point in the series is used to control the brightness of a pixel in the image, and a scan comprised of a series of measurements at successive locations along the length of the transducer 11 (linear array mode) or steering angles (PASS mode) is performed to provide the data necessary for display.
Referring particularly to FIG. 2 , the transmitter 13 includes a set of channel pulse code memories which are indicated collectively at 50 . Each pulse code memory 50 stores a bit pattern 51 that determines the frequency of the ultrasonic pulse 52 that is to be produced. This bit pattern is read out of each pulse code memory 50 by a master clock and applied to a driver 53 which amplifies the signal to a power level suitable for driving the transducer 11 . In the example shown in FIG. 2 , the bit pattern is a sequence of four “1” bits alternated with four “0” bits to produce a 5 MHz ultrasonic pulse 52 . The transducer elements 11 to which these ultrasonic pulses 52 are applied respond by producing ultrasonic energy.
As indicated above, to steer the transmitted beam of the ultrasonic energy in the desired manner, the pulses 52 for each of the N channels must be produced and delayed by the proper amount. These delays are provided by a transmit control 54 which receives control signals from the digital controller 16 of FIG. 1 . When the control signal is received, the transmit control 54 gates a clock signal through to the first transmit channel 50 . At each successive delay time interval thereafter, the clock signal is gated through to the next channel pulse code memory 50 until all the channels to be energized are producing their ultrasonic pulses 52 . Each transmit channel 50 is reset after its entire bit pattern 51 has been transmitted and the transmitter 13 then waits for the next control signal from the digital controller 16 .
Referring particularly to FIG. 3 , the receiver 14 is includes three primary sections including a time-gain control section 100 , a beam forming section 101 , and a mid processor 102 . The time-gain control section 100 includes an amplifier 105 for each of the N receiver channels and a time-gain control circuit 106 . The input of each amplifier 105 is connected to a respective one of the transducer elements 12 to receive and amplify the echo signal which it receives. The amount of amplification provided by the amplifiers 105 is controlled through a control line 107 that is driven by the time-gain control circuit 106 . As is well known in the art, as the range of the echo signal increases, its amplitude is diminished. As a result, unless the echo signal emanating from more distant reflectors is amplified more than the echo signal from nearby reflectors, the brightness of the image diminishes rapidly as a function of range (R). This amplification is controlled by the operator who manually sets TGC linear potentiometers 108 to values which provide a relatively uniform brightness over the entire range of the scan. The time interval over which the echo signal is acquired determines the range from which it emanates, and this time interval is divided into segments by the TGC control circuit 106 . The settings of the potentiometers are employed to set the gain of the amplifiers 105 during each of the respective time intervals so that the echo signal is amplified in ever increasing amounts over the acquisition time interval.
The beam forming section 101 of the receiver 14 includes N separate receiver channels 110 . Each receiver channel 110 receives the analog echo signal from one of the TGC amplifiers 105 at an input 111 , and it produces a stream of digitized output values on an I bus 112 and a Q bus 113 . Each of these I and Q values represents a sample of the echo signal envelope at a specific range (R). These samples have been delayed in the manner described above such that when they are summed at summing points 114 and 115 with the I and Q samples from each of the other receiver channels 110 , they indicate the magnitude and phase of the echo signal reflected from a point P located at range R on the ultrasonic beam.
Referring still to FIG. 3 , the mid processor section 102 receives the beam samples from the summing points 114 and 115 . The I and Q values of each beam sample is a digital number which represents the in-phase and quadrature components of the magnitude of the reflected sound from a point P. The mid processor 102 can perform a variety of calculations on these beam samples, where choice is determined by the type of image to be reconstructed. For example, if a conventional magnitude image is to be produced, a detection process indicated at 120 is implemented in which a digital magnitude M is calculated from each beam sample and output at 121 .
M =√{square root over ( I 2 +Q 2 )}
The detection process 120 may also implement correction methods, for example, such as that disclosed in U.S. Pat. No. 4,835,689. Such correction methods examine the received beam samples and calculate corrective values that can be used in subsequent measurements by the transmitter 13 and receiver 14 to improve beam focusing and steering. Such corrections are desirable, for example, to account for the non-homogeneity of the media through which the sound from each transducer element travels during a scan.
The mid processor may also include a Doppler processor 122 . Such Doppler processors often employ the phase information (φ) contained in each beam sample to determine the velocity of reflecting objects along the direction of the beam (i.e. direction from the transducer 11 ), where φ=tan −1 (I/Q).
The mid processor may also include a correlation flow processor 123 , such as that described in U.S. Pat. No. 4,587,973, issued May 13, 1986 and entitled “Ultrasonic Method Can Means For Measuring Blood Flow And The Like Using Autocorrelation”. Such methods measure the motion of reflectors by following the shift in their position between successive ultrasonic pulse measurements.
As appreciated by one of ordinary skill, the above-described system can be used to perform a number of imaging studies. In accordance with the present invention, the system may be designated to analyze the tissues of the carpal tunnel and generate risk factors indicative of a subject's risk of developing CTS or SSCT damage.
Referring to FIGS. 4 and 5 , a general method for ultrasound analysis of CTS risk factors starts and, at process block 500 , a subject 600 is prepared for scanning. Specifically, the forearm of the subject is fasted to an examination apparatus, indicated generally at 602 , and the transducer head of an ultrasound probe 604 is placed just proximal to the subject's wrist flexion crease and its position is maintained by an ultrasound holding mechanism 606 that is included in the examination apparatus 600 . The examination apparatus 600 further includes objects, for example, a gripping devices 608 , which may, as illustrated, be a series of acrylic tubes having varying diameters, that a subject manipulates to perform a task, for example, flexing and extending the wrist to grip and release the varying tubes. The examination apparatus 602 is designed to permit desired motion of the subject but restrict undesired motion. It is contemplated that the subject may be trained to perform these tasks repeatedly and consistently, such as using a metronome marking a beat, for example, 0.80 Hz, for flexion and extension.
Referring still to FIG. 4 , at process block 502 , a time series of ultrasound images is acquired at a specified acquisition rate as the subject performs a task. For example, an ultrasound image may be acquired seventy times each second, providing a 70 Hz image acquisition rate. The tasks generally involve manipulating an object so as to cause flexion and extension of the structures within the carpal tunnel. To improve results and account for any abnormal subject motion, it is contemplated that the subject may repeat the task at least three times while a time series of ultrasound images is acquired. It is further contemplated that imaging is performed using an ultrasound scanner equipped with a 15L8 linear array transducer set to a depth of 20 mm with a 14 MHz image acquisition frequency. At process block 506 , the examination apparatus, and the subject's position within the apparatus, are changed so the subject may perform additional tasks. For example, if the subject is flexing and extending their wrist around an acrylic tube, the acrylic tube may be removed from the examination apparatus and replaced with an acrylic tube having a different diameter. This step may further include repositioning the subject within the examination apparatus to allow ultrasound imaging to be performed on the other forearm. At process block 502 , the subject performs the new task while a time series of ultrasound images is acquired. The steps in process block 502 and 506 are repeated until, at decision block 504 , it is decided that an appropriate number of tasks and ultrasound scans have been performed.
At process block 508 , the acquired ultrasound data is preprocessed. Processing includes image compression, truncating the time series of ultrasound images so that only relevant time frames remain, and altering the frame rate of the time series as it is recorded to a computer system. For example, the image acquisition frame rate may be at 70 Hz. However, when operating the ultrasound machine in ‘cine’ function, where the frames for the previous few seconds are stored in cine memory, regularly, the play speed is slowed down to 37 percent of its original speed. This is because, if the cine images were saved without reduction of the play speed, some of the frames will be truncated during the image saving process. To minimize the flame reduction, the play speed is, thus, slowed down to 37 percent of its original speed.
Referring to FIGS. 4 and 6 , speckle tracking is performed on the processed time series of ultrasound images at process block 510 . Speckle tracking is an angle-independent, two-dimensional dynamic ultrasonic imaging technique that analyzes the motion of a tissue by tracking speckles, which are acoustic signals that arise from the coherent reflection of ultrasound waves off small features, for example, very small cells, in a subject. Speckles are tracked from frame to frame in a time series of ultrasound images with an optimized pattern-matching algorithm, allowing the analysis of dynamic features, for example, the motion of fluid and tissues, by reconstructing the deformation and motion of the speckles.
Anatomical features within the carpel tunnel are tracked by placing tracking markers 700 on speckles within portions of the image containing structures of interest, for example, the flexor digitorum superficialis (FDS) and the SSCT. It is contemplated that three markers may be placed on the FDS tendon tissue speckles, perpendicular to the direction of tendon motion, with a distance between the two furthest markers of one millimeter. The SSCT, a highly echogenic layer at the border of the tendon, is normally thinner than 1 mm and may be tracked by placing markers at the following locations: one at the border between the tendon and the highly echogenic layer; one within the highly echogenic layer; and one at the outer border of the highly echogenic layer. These markers define what is considered a representative segment of the SSCT. Following placement of the markers, speckle tracking software implements a desired optimized pattern-matching algorithm to track the areas bounded by the applied markers. For example, the paths 702 show the motion of the tracking markers 700 through the course of a time series of ultrasound images.
At process block 512 , the results of speckle tracking are analyzed and a series of functional parameters characterizing the motion of the tracked structures are generated. Speckle tracking should show a clear difference in the direction of motion of structures within the carpal tunnel between periods of flexion and periods of extension. Therefore, tracking points that most strongly display this difference are selected and analyzed to generate a series of functional parameters characterizing the motion of the tracked structures. For example, velocity and strain time series, may be calculated for the FDS and SSCT. From these time series, the maximum velocities and excursions of the FDS and SSCT may be calculated. Additional functional parameters, such as the maximum velocity ratio, which is the ratio of the SSCT maximum velocity relative to the FDS maximum velocity, and the shear index may be generated. The shear index, which represent SSCT displacement relative to FDS displacement, may be calculated by the following equation:
Shear index=[(Excursion FDS −Excursion SSCT )/(Excursion FDS )]*100 percent
Still referring to FIG. 4 , following the generation of the functional parameters statistical analysis is performed at process block 514 . The statistical analysis compares the functional parameters acquired from a subject to a priori functional parameters obtained from normal subjects and subjects having CTS. At process block 516 , the results of the statistical analysis are used to generate risk factors indicative of a subject's risk of developing CTS or SSCT damage. The motion patterns of the SSCT relative to the flexor tendon are known to be different in CTS patient compared to normal subject. This suggests shear condition of the SSCT may be different between CTS patients and normal subjects. By analyzing the difference in the relative motion of SSCT, subjects with a predisposition for CTS, for example, subjects having a normal median nerve but a structurally abnormal SSCT can be identified.
The present invention has been described in terms of one or more preferred embodiments, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention. | A system and method is provided for using dynamic ultrasonic imaging to analyze a subject's carpal tunnel and generate risk factors indicative of the health of the subject's subsynovial connective tissue and the subject's risk of developing carpal tunnel syndrome. The system and method uses speckle imaging techniques to track dynamic structures within the carpal tunnel and statistical analysis techniques to compare the properties of these dynamic structures of the subject to those of normal subjects and subjects having carpal tunnel syndrome. | 0 |
RELATED APPLICATIONS
The present application is a continuation, and claims the priority under 35 U.S.C. §120, of previous U.S. patent application Ser. No. 10/343,535, filed Oct. 17, 2003, which claims the priority of previous international application PCT/US00/42246, filed Nov. 20, 2000, which claimed the priority of U.S. patent application Ser. No. 09/668,867, filed Sep. 25, 2000, now U.S. Pat. No. 6,347,839. Applicant claims the priority of all and each of these previous applications, which are hereby incorporated by reference in their respective entireties.
BACKGROUND
Traditionally, wheel rims have been constructed utilizing very old stamping processes from metal, typically steel or aluminum, and while such rims are in common use, they possess several undesirable characteristics. Steel metal wheel rims corrode, and aluminum wheel rims are prone to dent and deform, and both types of rims generally offer only silver color as a finish option. Further, such stamping processes on aluminum require rolling, bending, stamping, and piercing metal that often creates micro-fractures and weakened areas of the metal that, in turn, must be heavily reinforced to create sufficient strength to endure over a predictable rim life-span. For a steel rim, while the stamping processes create little damage to the metal, such stamping processes are very capital intensive, requiring heavy forming equipment with significant maintenance requirements. In practice, the industry recognized that a steel rim, with its excessive weight, unattractive appearance and tendency to corrosion, is not a popular item with consumers. For example, in North America and Western Europe, manufactures of steel rims are forced to operate at very low profit margins.
Presently, wheel rims constructed from a glass, carbon and graphite fibers that are attractive to consumers have generally been prohibitively expense for an average bicycle enthusiast. An example of a high quality composite rim whose construction is labor intensive and thus must be sold at a high price is shown in a U.S. Patent Application entitled “A Two Component Composite Bicycle Rim”, Ser. No. 09/548,068, filed Apr. 12, 2000, by one of the present inventors.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings illustrate various examples of the principles described herein and are a part of the specification. The illustrated examples are merely examples and do not limit the scope of the claims.
FIG. 1 is an elevation perspective view from the front and side of a bicycle having wheels that include the rims of the invention;
FIG. 2 is an enlarged end sectional view taken along the line 2 - 2 of FIG. 1 , showing a section of the rim of the invention wherefrom the spoke ends have been removed, and showing, in broken lines, a section of a solid spin cast urethane tire fitted to the rim;
FIG. 3A shows a group of four plys of resin impregnate fiber mats that overlay one another at crossing angles of a first or bottom layer of fibers at angle B to vertical axis A, followed by a second layer whose fibers are at angle C to vertical axis A, followed by a third layer whose fibers are at angle D to vertical axis A, with a fourth, or top layer, having fibers are at angle E to vertical axis A;
FIG. 3B shows the identicals groups of layers of FIG. 3A laid up, one over the other;
FIG. 4 shows the preferred twenty four (24) plys laid up in repeating groups of four (4) plys each aligned for placement against a mandrel forming a laminate having the shape of the rim open area between the rim side walls, with the top group to be laid up first, followed be the next group down, and so on, with the side edges of each group of plys to be bent over the mandrel edges, forming a hook bead type rim hook ends, and showing the laminate coated mandrel aligned for fitting in the cavity of a mold to receive a mold cap thereover;
FIG. 5 shows an enlarged end sectional view of the groups of plys laid up on the mandrel of FIG. 4 , and fitted into the mold that includes the cap, and showing the mandrel as having a removable center section; and
FIG. 6 shows the mandrel, groups of fiber plys and mold of FIG. 5 exploded apart, and shows the center of the mandrel as having been removed, allowing half sections of the mandrel to be tilted towards one another and pass between the rim side wall hook ends.
Throughout the drawings, identical reference numbers designate similar, but not necessarily identical, elements.
DETAILED DESCRIPTION
The present disclosure provides a composite rim that is formed as a more universal and less expensive bicycle rim, from inexpensive materials, for example carbon plys or glass fibers, and utilizes apparatus and method for its manufacture that are more efficient and labor saving. A rim made according to the principles disclosed herein is therefore as strong as a steel rim and is as light in weight as a comparable aluminum rim, can be attractively finished, and is less expensive and accordingly has a broader sales appeal in the market place that steel or aluminum rims. Heretofore, within the knowledge of the inventors, a composite rim like that of the invention for mounting tires formed with continuous side wall mounting grooves has not been known.
The present specification relates to composite bicycle wheel rims and other like wheel rims where multiple resin impregnated layers or “plys” of fibers are applied at selected crossing angles onto a mandrel to form a laminate, with heat and pressure applied thereto in a molding process to cure the laminate into a composite hook bead type rim that has inwardly pointing hook ends for fitting into locking grooves formed around a tire side walls.
A composite bicycle rim, or like rim has heretofore usually been constructed in sections from layers or plys of unidirectional fiber layers that are laid up, one layer over another, on a mandrel, forming a laminate that is then cured under heat and pressure, with the rim sections then finished, assembled and secured together along section junctions, forming a continuous rim. The present disclosure provides, in a single operation, forming a continuous unwarped composite hook bead type rim having side walls whose upper ends are formed as inwardly pointing hooks that are for fitting into side wall grooves of a molded tire, for mounting the tire onto the rim. The rim is preferably a laminate constructed by laying up, one over the other, mats or plys of resin coated or impregnated fiber glass onto a circular mandrel whose width can be reduced to pass between the rim side hook ends. The mandrel, as shown, includes movable or removable center sections that, when removed, shorten the distance across the mandrel so as to allow it, after laminate rim curing, to be conveniently removed from between the rim side wall hook ends. The hook ends are then shaped, as with a turning router blade, or the like, to extend inwardly a required distance from the rim inner side wall ends to hook into the tire side wall grooves.
To form the rim of the invention, mats or plys of resin epoxy impregnated or coated directional glass fibers are sequentially laid up, one over the another, forming a laminate, with the fiber direction of each mat or ply laid over a prior mat or ply such that the fibers are at a different crossing angles, providing a stack of fiber glass mats or plys where the crossing angles of the fibers of each mat or ply are at a selected angle to adjacent mats. So arranged, a laminate is formed having an architecture that is balanced and interlocking, providing a finished rim that is free from residual stress, without stress risers and is dimensionally stable and unwarped.
In one example, a stack of mats containing twenty four (24) discrete resin impregnated mats or plys of fiber glass, each of a thickness of from twenty eight (28) to thirty four (4) thousands (1000) of an inch, are laid up as a laminate on a mandrel for curing to form the rim. The twenty (24) plys are grouped in six (6) identical groups of four (4) plys each that are arranged to cross at the design crossing angles, and repeat in each of the six (6) identical groups. The first ply in a group is preferably parallel to the mold circumference, and the last ply in the group, is preferably, perpendicular to a tangent to the mold circumference, with the fibers of the center two (2) plys at crossing angles of less than ninety (90) and greater than forty five (45) degrees to one another. So arranged, after curing the laminate is removed off of the mandrel by a reduction of the mandrel cross section to allow the mandrel or mandrel sections to be slid past the inwardly pointing rim hook ends. So arranged, the rim shape will remain undeformed and faithful to the cavity of the mold.
After curing and removal from the mold, the rim hook ends as have been formed by bending the edges of the plys over the mandrel edges, are finished, as with a router. This finishing provides a required hook end distance from the rim interior side wall surfaces, and a desired spacing distance between the hook ends to allow a tire side walls to be fitted into the rim to with the hook ends passing into the tire side wall continuous grooves, mounting the tire mounting onto the rim. Prior to which tire mounting, the rim is drilled to receive spokes that radiate inwardly therefrom to fit to a hub, forming a wheel. The rim, with the drilled spoke holes, preferably receives a urethane polymer coating applied thereover that enhances the overall rim strength and finish quality, creating a smooth, colorful appearance that is unaffected by ultra-violet rays, moisture, salt-water, most chemicals, and most cleaners.
The present disclosure provides a continuous composite rim that is preferably formed as a laminate from inexpensive glass fiber mats or plys coated with an epoxy resin that are laid up in groups of mats or plys, with crossing angles between the plys selected to provide, a balanced laminate where the laminate, after curing, is free of stress risers and is dimensionally stable.
The present disclosure also provides a composite rim that is conveniently and economically formed by laying up epoxy risen impregnated fiber mats or plys over a mandrel where upper ends of rim walls are formed as inwardly pointing hook ends by bending mat or ply along the mandrel parallel edges with, after curing in a mold, the mandrel wall to collapse, shortening its width, so as to allow the mandrel to pass between the hook ends that are each then machined to a desired distance from the surfaces of the rim interior walls to accommodate and mount to mounting grooves in a tire side walls.
The present disclosure also provides a composite rim that is easy and economical to manufacture to provide a rim that is of like weight to a comparable aluminum rim and is as strong as a steel rim at lower weight than such comparable steel rim, and can be painted or otherwise colored to present an attractive appearance.
The present disclosure also provides a composite rim that, after fabrication, can be easily drilled to accommodate radially mounted spokes thereto that connect to a hub, forming a bicycle wheel.
The present disclosure also provides a rim that receives a urethane polymer coating after curing to enhance overall rim strength and finish quality, creating a smooth, colorful appearance that is unaffected by ultra-violet rays, moisture, salt-water and most chemicals and cleaners.
The invention, as is hereinafter described, relates to a composite bicycle rims, and other vehicle rims, that are formed as a full rims. The composite rim of the invention is formed by laying-up successive layers of fiber mat or plys, as a laminate, that are, for example, fiber glass mats or plys, but may be carbon, graphite, boron, or other appropriate fiber mats or plys, within the scope of this disclosure. The mats or plys are coated or impregnated with an epoxy thermoset resin, or a nylon thermo plastic resin, or the like, and fitted onto a mandrel. The mats or plys are preferably laid up on the mandrel in groups of four plys each, and the mandrel whereon they are laid up is then fitted into a mold cavity that is closed with heat and pressure are applied to the laminate, curing the laminate that emerges as a full rim.
As shown in FIG. 1 , a rim formed by the principles disclosed herein is fitted with spokes and a hub as a wheel 11 mounting a bicycle tire 12 . Though, of course, a rim for another appropriate vehicle could be formed like that of the rim 10 , within the scope of this disclosure. In FIG. 2 , the rim 10 is shown as an enlarged section and includes a section of tire 12 fitted thereto, as shown in broken lines. The rim 10 , as shown in FIGS. 2 , 3 B, 4 , 5 and 6 , is preferably formed from groups 14 of four (4) plys 13 a , 13 b , 13 c and 13 d , for each group 14 that are laid up upon a mandrel 15 . The groups 14 , as shown best in FIG. 4 , are positioned over one another, for curing in a mold 16 , as shown in FIGS. 4 , 5 and 6 . Shown in FIG. 3A , the individual plys 13 a , 13 b , 13 c and 13 d , of the four (4) plys that make up each group 14 are formed from fibrous mats or plys, preferably fiber glass mats or plys, forming a rim 10 that is as light as a comparable aluminum rim, but is less expensive than an aluminum rim, and which rim 10 , when cured, is as strong as a comparable steel rim. Through, it should be understood, mats or plys of other fibers such as carbon, graphite, boron, or the like, could be so used within the scope of this disclosure.
The fibers of each ply are directional and are laid up in groups 14 on mandrel 15 , as shown in FIG. 4 . The groups 14 , as set out above, are identical to one another and are formed, as shown in FIG. 3A , by laying up the four (4) plys that make up a group 14 onto mandrel 15 . Starting from the bottom ply of FIG. 3A , ply 13 a has its fibers are at zero degrees to Axis A and parallel to the mandrel circumference, and is first positioned on mandrel 15 , followed by plys 13 b , 13 c , with ply 13 d then positioned thereover with its fibers perpendicular to axis A and perpendicular to a tangent to the mandrel circumference.
To provide a strong, stable and balanced laminate that does not have residual stresses and so is dimensionally stable upon removal from the mold 16 . The plys 13 a , 13 b , 13 c and 13 d are arranged at selected crossing angles. Such a balanced laminate, in practice, is not easily achieved, with proper fiber direction and selected laminate thickness required to achieve this optimal condition. If such balanced laminate is not achieved the casting will include stress risers and be dimensionally deformed.
In one example, for a rim 10 , that is shown as a broad rim and is appropriate for use as part of a mountain bike wheel, the required laminate architecture requires that the fibers of the ply 13 a be laid down at a zero angle to a vertical axis A, parallel to the circumference of the mold 16 , with a next ply 13 b laid thereon at, preferably, a plus thirty eight (38) degrees to the vertical axis A, followed by a next ply 13 c laid thereover that, preferably, is at a minus thirty eight (38) degrees to the vertical axis A, with, finally, the ply 13 d laid thereover, is, preferably, at ninety (90) degrees to vertical axis A, and is perpendicular to a tangent to the mold circumference, forming a group having a thickness of from between twenty eight (28) and thirty four (34) thousands (1000) of an inch. Accordingly, in practice, ply 13 a is placed against the mandrel 15 surface, ply 13 b is positioned over ply 13 a , followed a placement of ply 13 c over the ply 13 b , and, finally, ply 13 d is placed over ply 13 c . So arranged, the bottom and top plys, 13 a and 13 d , respectively, are, respectively, aligned with, and are perpendicular to, the mold circumference, with the inner plys 13 b and 13 c , respectively, at design crossing angles to one another. For the single group 14 , the plys crossing angles are therefore from zero (0) degrees to ninety (90) degrees, with the groups each crossing one another at their contact plys at ninety (90) degrees or at right angles. In practice, the center plys 13 b and 13 c crossing angles, as are preferred, are at, respectively, plus thirty eight (38) and minus (38) degrees, to axis A. Which crossing angles, however, can, in practice, be plus or minus five (5) degrees to the preferred plus thirty eight (38) and minus thirty eight (38) degrees and still maintain a desired ply bonding, as a balanced laminate. The balanced laminate will retain the mold cavity shape, without stress risers and dimensional deformation or warping or going out of round, after removal from mold 16 , as set out below.
In laying up the groups 14 of plys 13 a , 13 b , 13 c and 13 d , and with the groups 14 stacked upon one another, the order of stacking is that the top ply 13 d in a group 14 is in contact with the bottom ply 13 a of the group stacked thereon, and with the individual plys 13 a and 13 d of each group are in contact with ply 13 a and 13 d of the adjacent stacked groups. So arranged, the ply fibers at the junctions of which groups are at ninety (90) degrees to one another. To form the rim 10 , as a balanced laminate, preferably six (6) groups 14 are laid up upon one another on mandrel 15 , though, it should be understood other numbers of plys in multiples of fours can constitute a group, such as eight (8), and therefore other number of groups than six (6) can be laid up as the laminate, within the scope of this disclosure. Accordingly, it should be understood that, for another rim configuration such as a different bicycle rim than a mountain bike rim, or for a scooter rim, or for an even a larger vehicle rim, the number of groups 14 and plys within the group, can be varied for the type of vehicle the rim 10 is being formed for.
The mandrel 15 , as shown in FIGS. 4 , 5 and 6 , is shaped around the sides 15 a and across the bottom 15 b thereof, to essentially have, the profile of the bottom area 12 a of tire 12 , that is shown in broken lines in FIG. 2 . Shown in FIG. 2 , the mandrel is split longitudinally at 17 , dividing the mandrel into mirror image half sections 18 and 19 that include slot sections 18 a and 19 a , respectively, formed in the abutting surfaces, along split 17 . Which slot sections 18 a and 19 a are each shown as stepped above the mandrel bottom 15 b to form a slot that is to receive a bar 20 fitted therein. In practice, the mandrel half sections 18 and 19 are preferably formed as arcuate sections that are fitted together, each to form a continuous ring, and the half sections are, in turn, fitted together to form the mandrel 15 . With the mandrel sections 18 and 19 held together as by fastener means, not shown, to form the continuous ring shaped mandrel 15 . Which mandrel receives the ply groups 14 laid thereover, extending around the mandrel, and with the groups 14 sides bent over the mandrel top edges, forming the rim hook ends 31 a and 31 b , as shown in FIGS. 2 , 5 and 6 . After curing, as set out below, the bar 20 sections are removed, as shown in FIG. 6 , allowing the mandrel arcuate sections 18 and 19 to collapse towards one another and allow them to individually be removed from the rim 10 , passing between the rim hook ends 31 a and 31 b , as shown in FIG. 6 , and as discussed hereinbelow.
To lay up the groups 14 of plys 13 a , 13 b , 13 c and 13 d , the groups, as shown in FIG. 3A , are cut to be long enough to fit around the mandrel 15 inner circumference, covering the mandrel bottom 15 b and extending over the mandrel sides 15 a , to lap over the mandrel sides 15 a top edges, or the groups 14 edges are fitted into grooves 18 b and 19 b , respectively, that are formed along which top edges, as shown in FIG. 5 . The over lapped portions of groups 14 of plys as are laid up over the mandrel top edges or as are fitted into grooves 18 b and 19 b , form the inwardly pointing hook ends 31 a and 31 b of the rim 10 side walls of the finished rim.
With the groups 14 laid up over mandrel 15 that is formed in sections that are joined into a continuous ring and the assembly is fitted into mold 16 that includes a mold base 21 . The mold base 21 has a cavity 22 formed therein that duplicates the rim 10 outer surface. A cap 23 is included that is joined in sections to be continuous for fitting over the mold open end and has a center groove 24 and side grooves 25 a and 25 b that individually receive and press against, respectively, the center bar 20 and in-turned top sections of the groups 14 of plys as have been fitted into the mandrel grooves 18 b and 19 b . So arranged, the mandrel 15 applies pressured onto the inner surface of the laid up groups 14 , in the mold cavity 22 , compacting the laid up groups 14 between the mold and mandrel surfaces. Heat is added through mold 16 such that the groups 14 of plys that have been coated or impregnated with an epoxy resin are cured, with the resin flowing through and binding the fibers together, forming the composite rim 10 . Whereafter, the rim 10 containing the mandrel 15 is removed, as shown in FIG. 6 , and the center bar 20 sections are pulled out from the mandrel sections 18 and 19 groove segments 18 a and 19 a . The mandrel sections 18 and 19 are thereby freed to individually pass out from between the rim 10 side walls 30 a and 30 b hook ends 31 a and 31 b.
The composite rim 10 can then be smoothed as by sanding, sand blasting, or other process or procedure for smoothing a surface and, as needed, the ends of hook ends 31 a and 31 b can be finished, as by passing a router therebetween to provide a desired spacing distance so that the hook ends snugly fit into mounting grooves 12 b of tire 12 , as shown in broken lines in FIG. 2 , locking the tire 12 onto the rim 10 .
The rim 10 can be drilled, forming holes 33 through a rim bottom web 32 that are to receive spoke ends fitted through and secured to the rim web. The spokes are connected, on their opposite ends, to a hub, and the rim 10 , spokes and hub form the wheel 11 , as shown in FIG. 1 . The rim 10 laminate surface is then finished by an application of a urethane polymer coating 35 , as shown in FIG. 2 , that can itself be colored, can include colored chips, mica chips, or the like, and can serve as a base coat to be painted, or the like. The polymer coating 35 provides an enhancement to the overall rim strength, and, in addition, provides a finish to the glass fiber surface that creates a smooth, colorful appearance that in unaffected by ultra-violet rays, moisture, salt water, most chemicals, and most cleaners. The urethane polymer enhances rim strength and may be applied to both the rim 10 outer and inner surfaces, with the smooth finish on the rim inner surface to facilitate fitting tire 12 therein.
It should be understood that the invention in rim 10 is not limited to any particular arrangement of mandrel 15 , so long as that arrangement allows the mandrel to be removed and pass between the inwardly facing rim side wall hook ends 31 a and 31 b . Accordingly, a mandrel to receive the individual groups 14 of individual plys 13 a , 13 b , 13 c and 13 d , can be any mandrel arrangement where the mandrel cross section can be reduced to allow the mandrel to pass out from within the finished rim 10 , passing between the rim hook ends. For example, the mandrel, rather than being formed by expanding sections, can be a tubular shaped bladder that, when inflated with air, provides a surface to receive the groups 14 of fiber glass plys laid up thereover, and that, when deflated, will collapse sufficiently to be pulled out from between the rim side wall hook ends 31 a and 31 b . Such bladder may or may not including slots 18 b and 19 b formed around the side top edges, that the plys are fitted into to form the hook ends. With, if slots 18 b and 19 b are not provided, the hook ends 31 a and 31 b can then be formed by bending the edges of the groups of plys over the mandrel edges. For either procedure, the formed hook ends 31 a and 31 b need to be finished after mandrel removal, as with a router, or like tool, to where each hook end extends a desired distance inwardly from the rim side wall inner surface and is smooth so as to fit into the tire mounting rim groove.
Hereinabove has been set out a description of a preferred composite rim of the invention shown herein as a bicycle rim though, it should be understood the invention can be applied to rims additional to bicycle rims. Accordingly, it should be understood that the present invention can be varied within the scope of this disclosure without departing from the subject matter coming within the scope of the following claims, and a reasonable equivalency thereof, which claims we regard as our invention.
The preceding description has been presented only to illustrate and describe embodiments and examples of the principles described. This description is not intended to be exhaustive or to limit these principles to any precise form disclosed. Many modifications and variations are possible in light of the above teaching. | A method of manufacturing a rim for a bicycle wheel includes wrapping plys of fibers in a resin matrix around a mandrel; curing the plys to form the rim; and reducing a size of the mandrel to allow the mandrel to be removed from the rim. | 1 |
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No. 10/856,632, filed May 28, 2004, which claims the benefit under 35 USC 119(e) of the provisional patent application Ser. No. 60/474,843, filed Jun. 2, 2003. All prior applications above are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] A. Area of Invention
[0003] The present invention relates to electromedicine and, more particularly, to the application of a magnetic field to tissue and the subsequent measurement of electron spin and paramagnetic resonance properties of the tissue to ascertain and treat abnormalities associated therewith and with specific disease states.
[0004] B. Prior Art
[0005] The value and application of electron magnetic resonance (EMR) in biomedicine has been recognized, given its similarity, at least in principle, to proton magnetic resonance (often termed nuclear magnetic resonance or NMR). However, the field and frequency conditions under which an EMR signal is seen are different. In proton MRI, one of most common forms of NMR, the DC field may be on the order of 20,000 gauss (2 Tesla) at a radio frequency of about 85 MHz. In new high resolution NMR, the field strength may be increased to 12 Tesla at a microwave frequency of about 500 MHz. In distinction, the field associated with an EMR field may be as low as a fraction of a Tesla and under 1 GHz. These conditions, which historically related to different instrumentation, more importantly have lead to the realization that EMR techniques can be several orders of magnitude more sensitive than NMR, given that the electron magnetic moment is approximately 650 times stronger than that of the proton, even though the mass of the electron is far less than that of a proton, as above noted, is obtainable at field strengths and frequencies that are far less intrusive and, thereby, less hazardous than those associated with NMR. Because of these actors, the primary historic use of the NMR has been in association with analysis, imaging, and diagnosis of a wide variety of tissue related traditions, while NMR found little application in the treatment of tissue abnormalities or disorders.
[0006] EMR was discovered in 1925 by Goudsmit and Uhlenbeck. Thereafter its practical application was primarily in EMR spectrometers and, through the present, is used primarily in such applications. See for example U.S. Pat. No. 6,335,625 (2002) to Bryant et al.
[0007] EMR, sometimes termed electron paramagnetic resonance (EPR), has become a generic name given to the magnetic behavior of the electron when immersed in an external magnetic field. In EMR, the electron exhibits two key properties, namely, its magnetic field and a gyroscopic behavior. Therein, its electric field plays no part. Its magnetic field is often termed its dipole moment while its gyroscopic behavior is called its gyroscopic moment.
[0008] The greater the time domain differences between the magnetic components of an electromagnetic wave of a tissue, the greater will be the phase differences between the components and, thereby, the greater the energy loss or gain. As such, measurement of differences in phase between both magnetic moments of the electron have developed as a means of recognizing differences of properties between respective materials subject to an EM wave of typically of dipole and gyroscopic moment inducing strength. This phase change and energy loss or gain relates exponentially to cellular and tissue function.
[0009] From the perspective of quantum mechanics, the electron, while shifting positions within a permissible set of patterns relative to the atomic nucleus, generates specific energy emissions or spectra, i.e., EMR by body tissues and physiological structures. Such patterns have been found to comprise unique tissue signatures and, as such, a product of the individual atomic, molecular and cellular quantum movements which characterize the given tissue, organ or physiological structure of interest. Thereby, from my perspective of biophysics, the initial step in pathology emanating from a dysfunctional, damaged or diseased tissue is considered a misfunction of the EMR of the normal electron cloud associated with such tissue. EMR disorders thereby predispose biochemical and bioelectrical alterations reflected in each unique EMR signature of the tissue or structure of interest. When a disorder of measurable EMR occurs, the resonance and configuration of the normal electron cloud at the atomic level exhibit phase shifts which break and disturbs the otherwise orderly pathways of communication from atom to molecule, molecule to cell, cell to tissue, and tissue to organ. This results in breakdown in molecular and cellular communication one end result for example being a reduction in tissue conductivity.
[0010] For the inventive electron magnetic resonance analyzer and treatment system to function, the system sends or receives information to and from the body, the body's cellular network or in some cases, the central nervous system, that is, its pain processing center. This pathway allows the EMR of the inventive system to record and analyze any phase-shifted EMR patterns emanating by and from the body's tissues and structures.
[0011] In case of assessing and treating pain, the inventive system also employs inductors and applicators at the site of pain, tissue abnormality and/or upon selected nervous system trigger or motor points (which can also comprise of acupuncture or pressure points). A synthesized EMR pattern is transmitted into the tissue which encounters the inherent resonance pattern produced by the tissue or subject matter under study. The information generated by this initial step of the analysis process is returned to the system where, after removal of impedance static in the signal it is analyzed, digitized and, if desired, compared to predetermined EMR patterns associated with such normal tissue. Thereby, the recorded data is assessed and evaluated for irregulates or abnormalities. The inherent EMR signatures of normal atoms, molecules, tissues and structures may thereby be employed as “standards” in the digitizing of values based on recorded and peak resonance emissions of healthy, non-diseased, non-damaged tissues. When such a first phase of the EMR pattern measurement and assessment is complete, the system has detected any disorder or shifting of EMR peaks at the pain site under study, if a phase shifts exists.
[0012] A second aspect of operation of the inventive system is that of its therapeutic action. If an EMR phase shift of the targeted tissue or organ is detected in the first aspect of analysis, the shift can be corrected through the application of a counter or neutralizing EMR which, as set forth below, is calculated and computed by the system, thereby resulting in a neurotransmitter function which is regulated by administration of a counter EMR pattern. It has been found that upon realignment of the phase shifted EMR pattern, reduction and alleviation of pain occur instantaneously, healing time is reduced and, upon suitable repetition of therapy, result in long term improvement of the abnormality of interest.
[0013] Pain is reduced or eliminated by means of effect on nociceptive afferent neurons which are sensitive to magnetic as well as a variety of noxious stimuli including thermal, mechanical, and chemical. Excitation of nociceptive neurons induce a field gradient into magnetic sensitive ion channels, particularly sodium, calcium and potassium channels. Nerve terminal membranes are magnetically encoded through the activation of inward depolarizing membrane currents or activation of outward currents. The main channels responsible for inward membrane currents are the voltage activated sodium and calcium channels.
[0014] It is known that an ionic gradient exists across the plasma membrane of virtually all human and animal cells. In particular, the concentration of potassium ions inside the cell is about ten times that in the extracellular fluid. Also sodium ions are present in much higher concentrations outside a cell than inside. As such, the potassium and sodium channels play an important role in membrane excitation and, thereby, in determining the intensity of pain. Sodium channels are now considered a destabilizing membrane in the pain process. These channels, which can open rapidly and transiently when the membrane is depolarized beyond about minus 40 mV, are essential for action of most neurons, potential generation, and conduction. These open channels are also believed to be responsible for the neuron action leading to pain. Sodium is also an alkali element (with an atomic number of 11) and is paramagnetic. That is, when placed in a magnetic field, a paramagnetic substance becomes magnetized parallel to the field. It is believed that a magnetic interaction thereby occurs between sodium channels and the EMR patterns and peaks discussed above. EMR affects sodium which in turn affects the excitability of nociceptive neurons which are chemically distinct from most other neurons
[0015] It has been found that EMR fields which consist of an EM carrier of a range of about 1 Hz to about 1 GHz, when modulated by EMR patterns in a range of about 0.1 gauss to about 4 Tesla, provide a regulating effect upon sodium channels, this leading to pain reduction.
[0016] Tests have also indicated that EMR fields alter the pH level of water, which relates to another theory of the pain reduction associated with the present system. That is, it has been shown that the pH of extra-cellular fluid is associated with a number of patho-physiological conditions such as hypoxia/anoxia and inflammation. It has been reported that the pH of synovial fluid from enflamed joints is significantly more acid than is that of normal joints. As such, low pH solutions evoke a prolonged activation of sensory nerves and produce a sharp stinging pain. Consequently, when pH of tissue is changed, pain reduction is often achieved.
[0017] Successful treatment of arthritis, fibromyalgia, neuralgia, neuropathy, categories of joint and tissue injury, wound healing, calcific tendonitis, and various types of migraine headaches has been demonstrated.
SUMMARY OF THE INVENTION
[0018] A patient treatment unit for analyzing and treating abnormality of human or animal tissues, includes a display; a pulse generator circuit that outputs a sequence of electrical pulses at a pulse frequency, the electrical pulses having a pulse width, the pulse generator controlling the pulse frequency and the pulse width of the electrical pulses; a pair of probes for contacting a body of a patient and electrically coupled to the pulse generator; and a voltage and current sensing circuit that senses a voltage or a current via the probes when contacting the body of the patient.
[0019] It is an object of the present invention to employ principles of electron magnetic resonance (EMR) for the analysis and relief of pain and correction of abnormalities of human tissue.
[0020] It is another object to provide a system to analyze and digitize normal EMR patterns of specific tissues.
[0021] It is further object of the invention to correct abnormal EMR patterns by applying a countervailing or neutralizing EMR field spectra utilizing inductive sensors and applicators to apply EMR patterns of an intensity from about 0.1 gauss to about 4 Tesla.
[0022] It is further object to measure and analyze EMR out-of-phase peak resonances associated with abnormal tissue function, chronic pain, and traumatic injuries of soft tissue.
[0023] It is further object to provide a system of the above type in which useful EMR pattern information is measured at a trigger point, at or near a tissue dysfunction or pain site, and a counter resonance pattern is applied to said site to realign phase shifted resonance patterns associated with the electron of cells affection by an abnormal or pain condition.
[0024] It is further object to provide a system of the above type which can be readily interfaced with existing electromedical technologies including, without limitation, CT Scan, MRI, stereotactic imaging, and PET scanning. The advantage of this interface is the ability to visually “light up” an anatomical area with phase shift activity. By using an algorithm to monitor the amplitude of the signal and the degree of electromagnetic flux variation, various colors can be assigned to this phenomenon indicating antiphase or phase shifted areas. i.e., red being a reactive area and blue being a normal area. This information can then overlay a two or three dimensional diagnostic image, visually pinpointing an antiphase or phase shifted anatomical area. The advantage of this is being able to visualize functional variations and abnormalities as well as gross anatomical abnormalities. Another iteration of the technology is the attachment of an LCD screen to the back of a hand held wireless induction coil. Anatomical areas of the body can be scanned while watching for color changes on the attached LCD when a phase shift area is detected.
[0025] The above and other objects in advantage of the present invention will become apparent from the hereinafter set forth. Brief Description of the Drawings, Detailed Description of the Invention and Claims appended herewith.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 is a block diagram showing the basic hardware and software functions of the inventive system.
[0027] FIG. 2 is a schematic view of a patient treatment unit (“PTU”) and associated diagnostic unit.
[0028] FIG. 3 is a block diagram view of a functional management unit (“FMU”).
[0029] FIG. 4 is a block diagram view of the local controller and system custom software operating upon a PC platform to control the PTU and manage a patientlist. Also shown is a radio interface unit between the PC and the PTU.
[0030] FIG. 5 is a block diagram view of a tissue measurement module.
[0031] FIGS. 5A-5D show impedance, power and frequency relationships for the PTU.
[0032] FIG. 6 is a block diagram view of a communication module.
[0033] FIG. 7 is a block diagram view of the PTU inclusive of the PC radio interface and local controls of the PTU.
[0034] FIG. 8 is a block diagram view of the stimuli module.
[0035] FIGS. 9 and 10 are a respective signal and resonance peak waveforms of a healthy tissue.
[0036] FIGS. 11 and 12 are respective signal and spectrum waveforms of an abnormal tissue.
[0037] FIGS. 13 and 14 are respective signal and EMR peak for spectra diagrams showing the treatment wave superimposed upon the waveform to be treated.
DETAILED DESCRIPTION OF THE INVENTION
[0038] With reference to the general block diagram view of FIG. 1 , my inventive system for analyzing and treating abnormality of human and animal tissues may be seen to include a functional management unit (“FMU”) 100 which supervises functions of a communication module 102 , a stimuli module 104 , and a measurement module 106 .
[0039] As may be noted in FIG. 2 , the primary hardware of the inventive system is associated with a patient treatment unit (“PTU”) 108 which includes said measurement module 106 and stimuli module 104 . The stimuli module functions through probes or induction coils 110 / 111 thru which the initial data required by measurement module 106 is captured. In FIG. 2 may also been seen the physical relationship between a PC 112 and a diagnostic unit 114 which includes said communication module 102 . Diagnostic unit 114 and PC 112 comprise integral components of said FMU 100 . Further shown in FIG. 2 are pads 116 which facilitate treatment of patient 118 by an operator 120 . Line 122 represents a human and animal interface between patient 118 and operator 120 while line 124 represents a radio interface means between the PC and diagnostic unit, 114 on the one hand, and the PTU 108 on the other. Structural and parametric heuristic control of diagnostic unit 114 and PTU 108 are indicated by line 126 of FIG. 2 .
[0040] The electrical output specifications of PTU 108 are as follows:
[0000]
Power Supply
115 VAC, 60 Hz
Maximum Power Consumption
21 W
Output voltage
Range of normal use: 50-60 V
Peak pulse amplitude: 120 V
Pulse Rate
1-490 Pulses/second, ±6%
Pulse Duration
0.34-0.74 millisecond
Output Current (maximum)
8.9 milliamps
Maximum charge per pulse
7 micro coulombs
Wave Form
Complex pulse trains: variable frequen-
cy, variable pulse width, AC-coupled
rectangular pulse
[0041] In FIG. 3 is shown FMU 100 , inclusive of stimuli-measurement timing control means 128 , radio interface control 130 , local handle treatment control inputs 132 which are associated with said pads 116 , a PTU display management facility 134 associated with said diagnostic unit 114 , and a battery status monitor 136 .
[0042] In FIG. 4 is schematically shown the use of custom software running upon said PC 112 to control the PTU 108 and manage a patient list. Said PC is connected to a PTU 108 through said radio interface 124 .
[0043] In FIG. 5 is shown measurement module 106 which includes means 138 for measurements of the surface impedance of a treated tissue and means 140 for measurement of the impedance of the tissue to be treated.
[0044] Output waveforms of PTU 108 , showing various impedance, power, and frequency relationships are shown in FIGS. 5A-5D . More particularly, FIG. 5A indicates a 1 M-Ohm maximum impedance, in which the output waveform varies depending on the load as shown in FIGS. 5B-5D . That is, FIG. 5B shows voltage versus time at 500 ohms. FIG. 5C shows voltage versus time at 5000 ohms, and FIG. 5D shows voltage versus time at 10,000 ohms. Therein, changes in load affect both pulse duration and maximum pulse frequency. Maximum pulse frequency lies in a range of 490±6% from 500 ohms to 1,000,000 ohms. Lower impedances have lower maximum pulse rates. Pulse width is fixed at a given impedance, and declines from 0.74 milliseconds at 500 ohms to 0.34 milliseconds at 1,000,000 ohms.
[0045] In FIG. 6 is shown communication module 102 and its important internal functions which include subsystem 142 which indicates the receipt and resending of error check stimuli information from a local controller (LC) which includes battery status information 144 and electrode or induction coil status information 146 . Communication module 102 also includes subsystem 148 which sends, receives and error checks measurements of both surface and tissue as above described with reference to FIG. 5 . Therein the skin-electrode or induction coil and tissue electrode or induction coil impedance is continually monitored at the LC in visual and/or audio terms to thereby enable the medical technician to adjust the pressure of the electrodes or the medium (such as electro-jelly) used between the electrode and the treated tissue.
[0046] In FIG. 7 are shown the primary constituent subsystems of the PTU 108 , these including a microcontroller 149 having a said local treatment controls 132 , said display 134 , status LEDs 135 , a memory 150 used for purposes of recording data, and a DC to DC converter 152 . As may be noted, the output of converter 152 feeds into pulse generator and level shifting means 154 which include current and voltage limiting means. The output of said means 154 is provided to means 156 for the simultaneous sensing of voltage and current associated with skin and tissue measurements. The output thereof is provided to said microcontroller 149 which operates with PC 112 through radio interface unit 124 . The PTU 108 also includes a battery pack 158 and its charger 160 .
[0047] Inputs to probes or induction coils 110 and 111 are provided through said dual voltage and current sensing means 156 . It is noted that there are two areas in which magnetic resonance fluxuation is measured. The first is through an induction coil and the second is through the treatment measurement probes. The more phase shift (disorder or electrons loss of energy etc) the lower the measured amplitude and the greater the electromagnetic fluxuation.
[0048] In FIG. 8 is shown stimuli module 104 and, more particularly, over voltage and over-current software monitoring means 162 , associated electrode or induction coil monitoring means 164 , and associated RI means 166 for processing data received from radio interface unit 124 , and means 168 for processing data from local treatment controls 132 .
[0049] It is to be appreciated that electrodes associated with probes 110 / 111 and pad 116 , that is two electrodes connected via wire, one of which electrodes is provide with a linear potentiometer are used to adjust or select the intensity of the energy provided to the treated tissue. A number of safety features are incorporated into the instant system including visual and/or audio warning means, amplitude limit means (per block 156 ), amplitude override means, amplitude ramp back means, and patient control means. Therein data transmitted from functional management unit 100 to the PTU 108 includes stimuli frequency, stimuli duty cycle, and patient pain threshold information (based upon patient history) to thereby optimize PTU-side intensity settings. Data transmitted between the PTU and FMU include skin voltage, electromagnetic fluxuation and current (see FIG. 5 ), phase between skin and voltage current, tissue voltage and current, phase between tissue voltage, electromagnetic fluxuation and current, and stimulus on/off status (see FIG. 3 ).
[0050] Importantly, the local controller (see FIG. 4 ) of the present EMR system employs various algorithms.
[0051] Perhaps most importantly, the LC of the EMR system employs various algorithms, starting with a so called inverse wave form of the injury tissue as a first order basis of treatment, this to be followed by robust stochastic models to generate appropriate stimuli profiles to enable the FMU 100 to provide a sophisticated treatment or correction signal. Therein at least three models or algorithms are contemplated, these including the following:
sequential, adaptive self-learning method and implementation (for a single electrode pair); block adaptive self-learning method and implementation (for an electrode array); one and multi dimensional neural network-based controller algorithms; sequential data autoregressive method and implementation (for a single electrode pair); and block data autoregressive method and implementation (for an electrode array)
[0057] In addition, the filtering of the measurement module of the FMU eliminates error signals which typically appear as waveform ripples, to thereby enable generation of a correction or treatment signal from a self-learning multi-electrode PTU, thereby having enhanced efficacy in the cancellation of pain and, ultimately, long term treatment of the condition of interest.
[0058] Combinations of algorithms may be employed to generate interchannel waveform correlations to ensure convergence of the model analysis and promotion of its learning curve for the modeling of the tissue injury, treatment profiles and peak resonances associated therewith.
[0059] In summary, the technology employ a frequency of 1 Hertz to 1 G hertz, and low gauss (0.1 to 4 Tesla) in treatment signals to increase, decrease, flatten or nullify out of phase resonance peaks of a measured waveform of the tissue to be treated. Similarly, the correction or treatment signal which is applied to treat the abnormal tissue signal obtained by the measurement module is intelligently developed by a self-learning multi-electrode PTU in which various heuristic algorithms are used to ensure convergence and efficient development of models necessary to optimize tissue profile, peak resonance codes, and the use of this information for effective therapy in an array of medical conditions.
[0060] This technology also enables treatment of conditions such as arthritis, post surgical pain, post surgical reduction of swelling inflammation and bruising, Osgood Schlater Disease, treatment of organ transplant patients for the purpose of reducing organ rejection, adhesive capsilitus, MS, ALS, motor neuron disease, reduction of keloid scaring treatment of skin graft sites for better vasculasation and better chance of successful graft improvement of circulation and oxygen saturation in compromised tissue and limbs, limb and digit reattachment for better chance of successful graft, improvement and normalization of conductivity in infarcted cardiac tissue, joint inflammation and injuries, fibromyglia, reflex sympathetic dystrophy, neuralgia, peripheral neuropathy, macular degeneration, wounds and sclerdemia. However, a library of tissue profiles and peak resonance codes may be employed in the system in the development of a separate library of profiles and EMR resonance codes for each patient and, also, as a baseline/or electromagnetic structures, of healthy tissue of many types, which might be employed in the generation of an inverse waveform (see discussion in FIGS. 13-14 below) or treatment purposes. Accordingly, my historic library of tissue profiles and peak resonance codes may be intergraded into the stochastic models, as set forth above, to generate appropriate stimuli profiles to enable a sophisticated treatment or correction signal. Therein a simple low-order low pass filtering process, to eliminate signal ripples, constitutes a starting point.
[0061] The next step is typically the generation of the inverse waveform or inverse EMR spectra which is a generation of an opposite magnetic single pattern from that shown in FIGS. 11 and 12 . The application of this inverse pattern, has a pulse width modulation (PWM) process imposed upon a “sick” signal of the abnormal tissue is shown in FIG. 13 . Thereby the system generates and applies to such tissue, a waveform of EMR peak spectra substantially inverse to that of out-of-phase resonances of said tissue signal to thereby increase or nullify EMR peaks of the signal associated with abnormalities. See FIG. 14 .
[0062] While there has been shown and described the preferred embodiment of the instant invention it is to be appreciated that the invention may be embodied otherwise than is herein specifically shown and described and that, within said embodiment, certain changes may be made in the form and arrangement of the parts without departing from the underlying ideas or principles of this invention as set forth in the Claims appended herewith. | A patient treatment unit for analyzing and treating abnormality of human or animal tissues, includes a display; a pulse generator circuit that outputs a sequence of electrical pulses at a pulse frequency, the electrical pulses having a pulse width, the pulse generator controlling the pulse frequency and the pulse width of the electrical pulses; a pair of probes for contacting a body of a patient and electrically coupled to the pulse generator; and a voltage and current sensing circuit that senses a voltage or a current via the probes when contacting the body of the patient. | 0 |
BACKGROUND OF THE INVENTION
The most varied constructions of high frequency therapy apparatus are known. It is common to all the said apparatus that they generate a high frequency field by means of suitable transmitters and said field penetrates the patient's body and brings about an endogenous thermal action therein. Due to limited resorption in the adipose tissue and at the same time a good energy conversion in the perfused tissue microwave therapy has become more widely used than the previously preferred short wave equipment.
However, when using microwave equipment the power limit is very rapidly reached, because there is a natural limit of the power rise in the excellently resorbing skin layer. An increase in the apparatus power can admittedly be attained by larger electrodes. However, this only has an effect on large treatment surfaces. In order to increase the penetration depth, the radiation energy per cm 2 must be increased, but the aforementioned strong resorption in the skin layer is prejudicial to this.
The previously preferred short waves used in such therapy apparatus have been supplemented by microwaves and ultra-high frequency wave equipment. The individual therapy forms differ only in their electrode application and only then to an insignificant extent. In each case, there is a movable sheet steel casing, where the radiation source electrode is carried on one or, in the case of short wave, generally two supporting arms. The radiation source is generally connected to the apparatus by a high frequency cable. The known high frequency therapy apparatus require a large amount of space due to the arranging and directing of the radiation source and the supporting arm or arms.
It has been found that it is in connection with the accessories such as radiation source arms, high frequency cables, etc. that the main problems linked with expensive repairs are encountered.
With the known high frequency therapy apparatus, it is impossible to avoid scorched connecting cables and sockets, damaged radiation sources and loose or broken-off supporting arm joints. In addition, the swivel hinge connected to the hinged bracket for the radiation source used on known high frequency therapy apparatus is difficult of access, access being necessary so that the radiation source can be kept in the particular desired position. To adjust the radiation source, the latter is often used as a lever arm, but this can in turn damage the radiation source. Furthermore, considerable forces are required for swinging the radiation source, unless mechanical or electromotive auxiliary pivoting means are used, which considerably increases the cost of such high frequency therapy apparatus. It is also impossible with the known high frequency therapy apparatus to house the magnetron, i.e. the high frequency generator in the radiation source, because otherwise the weight of the radiation source at the free end of the hinged bracket would be even greater, so that single swivel hinges would be inadequate.
BRIEF SUMMARY OF THE INVENTION
The problem of the present invention is to provide a high frequency radiation therapy apparatus which can be operated extremely easily and rationally, which has no fault-prone components and which by adjusting to different treatment areas is suitable for use both on the entire body and for individual parts of the body.
According to the invention, this problem is solved by a high frequency radiation therapy apparatus, wherein it comprises the combination of the following features:
(a) in a couch frame of a couch with a lying surface a slide is arranged so as to be movable in the longitudinal direction of the couch beneath the lying surface and which carries a high frequency generator with a waveguide and a control section;
(b) the waveguide having a box-like casing has a length approximately corresponding to the width of the lying surface and in order to obtain a lateral power distribution is subdivided into two or more, separately operable groups of slot-shaped openings formed in the front panel of the casing and in the wall current area of the waveguide;
(c) the slot-shaped openings of each group can be closed independently of one another by means of closing devices using knobs on the control section.
A high frequency radiation therapy apparatus constructed in this way permits therapy to be carried out on lying patients, which permits the treatment of patients who cannot assume a sitting or standing position. Furthermore, the therapy apparatus constructed in couch-like manner permits space-saving in the generally constricted treatment cubicles. As the radiation source or waveguide is displaceable in the longitudinal direction of the couch, below the lying surface of the therapy apparatus it is possible to reach any part of the patient's body which is to be treated. The wave-guide can be moved up to any part of the body without exerting any noteworthy force.
This therapy apparatus also has no fault-prone components, because the high frequency generator and the waveguide, together with the associated electrical components and control mechanism are housed in the slide displaceable below the lying surface and which is constructed in a casing-like manner. This obviates high frequency cables, plug connections and the pivotable supporting arm otherwise used in the known apparatus for supporting the radiation source. In addition, the couch-like therapy apparatus requires no additional space in practice rooms or surgeries, because the latter in any case contain couches for treatment purposes, for taking electrocardiograms, for resting, etc. Thus, the therapy apparatus can be used in place of the couches otherwise employed in the surgeries.
As a result of the lying treatment position made possible by the therapy apparatus particularly favourable static conditions are obtained, because with a sitting patient muscular stresses are an undesired attendant phenomenon. Unlike in the case of a sitting patient, when using the therapy apparatus it is possible to maintain the position assumed through the radiation period. This applies for example to lumbago treatment. A painless position can easily be found and therefore maintained.
Due to the fact that the waveguide is constructed in such a way that different treatment fields can be set and applied at any point in the longitudinal direction of the couch, the possibility is provided by switching in or off individual treatment fields to treat the right, central or left parts of a patient's body. The proven high frequency pulse therapy ensures a maximum penetration depth and therefore optimum endogenous heating with minimum surface loading.
According to the invention, the waveguide is developed in such a way that on the high frequency radiation input side the waveguide has two slot-shaped openings combined into a group, followed by three slot-shaped openings, combined into a group and then four slot-shaped openings combined into a group in the front panel, the slot-shaped openings of each group being closable by means of a closing device constructed as a slide plate and which is provided with a number of equally large openings which corresponds to the number of slot-shaped openings in the waveguide casing and are spaced from one another in such a way that each is somewhat larger than the width of each slot-shaped opening in the waveguide casing.
Due to this advantageous construction of the waveguide, the possibility is provided on one side of switching on, off or in different treatment fields and on the other side it is ensured by freeing all the slot-shaped openings in the waveguide casing that equal radiation intensities are achieved in all sections of the waveguide.
Further advantageous developments of the invention can be gathered from the subclaims.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described in greater detail hereinafter relative to non-limitative embodiments and the attached drawings, wherein show:
FIG. 1 a high frequency radiation therapy apparatus constructed as a couch with a slide movable beneath the lying surface and with a high frequency generator and waveguide located therein, in a diagrammatic view.
FIG. 2 the high frequency radiation therapy apparatus with the lying surface removed in a view from above onto the couch frame.
FIG. 3 a diagrammatic view of the therapy apparatus waveguide.
FIG. 4 the waveguide in a view from above.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The high frequency radiation therapy apparatus comprises a couch 10, its couch frame 11 and the frame legs 12, 13, 14, 15. The couch frame 11 has a preferably cushioned lying surface 16, which can also comprise a number of parts (FIG. 1).
Below lying surface 16, couch frame 11 has parallel, spaced guide rails 20, 21 running in the longitudinal direction of the couch along which is displaceable a slide 30 or along which can be moved the couch 30 by means of runners 31 provided thereon (FIG. 2).
The slide 30 is constructed in box-like manner and receives a high frequency generator 40, a waveguide 50 and a control section 60. The high frequency generator 40 with waveguide 50 and control section 60 are displaceable in the direction of arrow X1 with the slide 30. The two guide rails 20, 21 can be replaced by a single, centrally arranged guide rail, which then receives the slide 30. For this purpose, the guide rail is provided with a cross-sectional profile, whilst the slide 30 has a corresponding mating profile, so that the slide 30 is guided and held in the said guide rail.
Control section 60 has the necessary electric components, time switches, knobs, etc. for operating the therapy apparatus. A handle indicated on slide 30 at 35 in FIGS. 1 and 2 is used for the effortless movement of slide 30 below the lying surface 16. In the embodiment shown in FIGS. 1 and 2, the slide 30 has a length corresponding to the width of couch 10, part of the slide being formed by waveguide 50.
Waveguide 50 arranged in slide 30 comprises a box-like casing 51 made from metallic materials, whose front panel 52 facing the lying surface 16 has a plurality of slot-shaped openings 70, 71, 80, 81, 82, 90, 91, 92 and 93. These slot-shaped openings are at right angles to the longitudinal direction of the waveguide casing 51. The high frequency rays from the high frequency generator 40 enter in the direction of arrow Y.
In order to achieve a lateral power distribution the entire width or length of waveguide 50 is divided into three separate and separable groups A, B and C, each of which has a plurality of slot-shaped openings. Group A has two slot-shaped openings 70, 71, group B three openings 80, 81, 82 and group C four openings, 90, 91, 92 and 93. Group A with two slot-shaped openings 70, 71 is provided in the waveguide casing 51 on the high frequency radiation input side. Groups B and C with the slot-shaped openings 80 to 82 and 90 to 93 are at the other end of waveguide casing 51. The different number of slot-shaped openings in the three groups A, B and C permits a uniform power distribution if all the openings of groups A, B and C are open. The slot-shaped openings 70, 71, 80 to 82 and 90 to 93 are all of the same size and shape (FIGS. 3 and 4).
The slot-shaped openings 70, 71, 80 to 82 and 90 to 93 of each of the groups A, B and C are closable by means of slide plates 75, 85, 95. The slide plates can be U-shaped or can embrace the waveguide casing 51 in an annular manner. It is important that the plates 75, 85, 95 can be displaced on the waveguide casing 51 and specifically in the longitudinal direction thereof. It is obviously necessary for there to be a good contact between the metallic slide plates 75, 85, 95 and the box-shaped waveguide casing 51.
Each of the slide plates 75, 85, 95 is provided with a plurality of slot-shaped openings in accordance with its association with the individual groups A, B and C and this corresponds to the plurality of slot-shaped openings 70, 71, 80 to 82 and 90 to 93 in groups A, B and C. Thus, slide plate 75 has two slots 170, 171 for the slot-shaped openings 70, 71 of group A, whilst slide plate 85 has three slots 180, 181, 182 for the slot-shaped openings 80 to 82 of group B and slide plate 95 has four slots 190, 191, 192, 193 corresponding to the four slot-shaped openings 90 to 93 of group C. The shape and size of slots 170, 171, 180 to 182 and 190 to 193 correspond to the slot-shaped openings 70, 71, 80 to 82 and 90 to 93, so that when slide plates 75, 85 and 95 are in an appropriate position slots 170, 171, 180 to 182 and 190 to 193 coincide with the slot-shaped openings 70, 71, 80 to 82 and 90 to 93 in waveguide casing 51 (FIG. 3).
The reciprocal spacing of slots 170, 171, 180 to 182 and 190 to 193 approximately corresponds to the width of the slot-shaped openings 70, 71, 80 to 82 and 90 to 93, so that on displacing the slide plates 75, 85, 95 in the direction of arrows Y1, Y2, Y3 the slot-shaped openings of the individual groups A, B and C are closed or, if desired, can be opened again. This provides the possibility of setting seven different treatment fields, which in the longitudinal direction of couch 10 can be applied to any pint. Irradiation takes place from below through the cushions of lying surface 16 of couch 10.
In order to operate the slide plates 75, 85 95 each of them is connected to an operating rod 76, 86, 96. The free ends of these operating rods 76, 86, 96 are guided into the control section 60 and carry knobs 77, 87, 97, so that from control section 60 it is possible to bring about the closing or opening of the slot-shaped openings 70, 71 and/or 80 to 82 and/or 90 to 93 by corresponding displacement of slide plates 85, 75, 95. However, other operating mechanisms can also be provided with slide plates 75, 85, 95. The important point is that the displacement of the slide plates can take place in a completely satisfactory manner. Thus, it is possible to displace each individual slide plate 75 or 85 or 95 with two operating rods positioned laterally of the slide plate and the waveguide casing 51, whose free ends located in control section 60 are interconnected and in this case the said connecting portions carry the knobs 77, 87 or 97 (FIG. 4).
In this embodiment, shown in FIG. 4, the slide plates 75 or 85 or 95 are operated by the connected operating rods 76, 76a or 86, 86a or 96, 96a.
Other closing means can be used in place of slide plates 75 or 85 or 95.
There can be a random number of slot-shaped openings in waveguide casing 51. There can also be a random number of slot-shaped openings combined into the individual groups, but the arrangement of the slot-shaped openings must be such that if all the said openings in waveguide casing 51 are open, the rays can pass out of them with the same intensity and this can also be achieved in that the slot-shaped openings in wave-guide casing 51 are given different dimensions. | The invention relates to a high frequency radiation therapy apparatus permitting therapy on the lying patient and which is constructed in such a way that a high frequency generator with a waveguide is displaced in the vicinity of the lying surface of a patient on a couch. The waveguide used is subdivided into a plurality of separately operable groups to obtain a lateral power distribution. Each group has slot-like openings in the wall current area of the waveguide and the openings of each group can be closed independently of one another. | 0 |
This application is a continuation of Ser. No. 08/367,242, filed Feb. 27, 1995, now U.S. Pat. No. 5,604,235, which is a 371 of PCT/US93/04096, filed May 6, 1993, which is a continuation-in-part of U.S. patent application Ser. No. 07/823,845, filed Jan. 22, 1992, now U.S. Pat. No. 5,243,049.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain pyrroloquinolinones which selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing alertness. The interaction of pyrroloquinolinones of the invention with a GABA binding site, the benzodiazepines (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.
2. Description of the Related Art
γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. In most regions of the brain, GABA is associated with local inhibitory neurons and only in two regions is GABA associated with longer projections. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Recent investigations have indicated that the complex of proteins associated with postsynaplic GABA responses is a major site of action for a number of structurally unrelated compounds capable of modifying postsynaptic responses to GABA. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).
1,4-Benzodiazepines continue to be among the most widely used drugs in the world. Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam, flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. The benzodiazepines were capable of enhancing presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb. Exptl. Pharmacol. 3: 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general consensus among electrophysiologists that the benzodiazepines could enhance the actions of GABA.
With the discovery of the "receptor" for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior.
Studies on the mechanistic nature of these interactions depended on the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the boney fishes (Squires & Braestrup 1977, Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiated diazepam, and a variety of other compounds, it has been demonstrated that these benzodiazepine binding sites fulfill many of the criteria of pharmacological receptors; binding to these sites in vitro is rapid, reversible, stereospecific, and saturable. More importantly, highly significant correlations have been shown between the ability of benzodiazepines to displace diazepam from its binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler & Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in man also correlate with receptor potency (Tallman et al. 1980, Science 207: 274-281).
In 1978, it became clear that GABA and related analogs could interact at the low affinity (1 mM) GABA binding site to enhance the binding of benzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978, Nature, 274: 383-85). This enhancement was caused by an increase in the affinity of the benzodiazepine binding site due to occupancy of the GABA site. The data were interpreted to mean that both GABA and benzodiazepine sites were allosterically linked in the membrane as part of a complex of proteins. For a number of GABA analogs, the ability to enhance diazepam binding by 50% of maximum and the ability to inhibit the binding of GABA to brain membranes by 50% could be directly correlated. Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA receptor antagonist (+) bicuculline; the stereoisomer (-) bicuculline is much less active (Tallman et al., 1978, Nature, 274: 383-85).
Soon after the discovery of high affinity binding sites for the benzodiazepines, it was discovered that a triazolopyridazine could interact with benzodiazepine receptors in a number of regions of the brain in a manner consistent with receptor heterogeneity or negative cooperativity. In these studies, Hill coefficients significantly less than one were observed in a number of brain regions, including cortex, hippocampus, and striatum. In cerebellum, triazolopyridazine interacted with benzodiazepine sites with a Hill coefficient of 1 (Squires et al., 1979, Pharma. Biochem. Behav. 10: 825-30. Klepner et al. 1979, Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepine receptors were predicted in the cortex, hippocampus, striatum, but not in the cerebellum.
Based on these studies, extensive receptor autoradiographic localization studies were carried out at a light microscopic level. Although receptor heterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol. Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216: 425-430. Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), no simple correlation between localization of receptor subtypes and the behaviors associated with the region has emerged from the early studies. In addition, in the cerebellum, where one receptor was predicted from binding studies, autoradiography revealed heterogeneity of receptors (Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).
A physical basis for the differences in drug specificity for the two apparent subtypes of benzodiazepine sites has been demonstrated by Sieghart & Karobath, (1980, Nature 286: 285-87). Using gel electrophoresis in the presence of sodium dodecyl sulfate, the presence of several molecular weight receptors for the benzodiazepines has been reported. The receptors were identified by the covalent incorporation of radioactive flunitrazepam, a benzodiazepine which can covalently label all receptor types. The major labeled bands have moelcular weights of 50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibit labeling of the slightly higher molecular weight forms (53,000, 55,000, 57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).
At that time, the possibility was raised that the multiple forms of the receptor represent "isoreceptors" or multiple allelic forms of the receptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44). Although common for enzymes, genetically distinct forms of receptors have not generally been described. As we begin to study receptors using specific radioactive probes and electrophoretic techniques, it is almost certain that isoreceptors will emerge as important in investigations of the etiology of psychiatric disorders in people.
The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into μ, β, g, d, (E, and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The γ subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA. For example, the beta-carbolines were first isolated based upon their ability to inhibit competitively the binding of diazepam to its binding site (Nielsen et al., 1979, Life Sci. 25: 679-86). The receptor binding assay is not totally predictive about the biological activity of such compounds; agonists, partial agonists, inverse agonists, and antagonists can inhibit binding. When the beta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviorally. It was immediately realized that the beta-carbolines could antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288; 609-10). In addition to this antagonism, beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines; they become known as inverse agonists.
In addition, a number of other specific antagonists of the benzodiazepine receptor were developed based on their ability to inhibit the binding of benzodiazepines. The best studied of these compounds is an imidazodiazepine, (Hunkeler et al., 1981, Nature 290: 514-516). This compound is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and is capable of blocking the pharmacological actions of both these classes of compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur. J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of this compound was studied (Mohler & Richards, 1981, Nature 294: 763-65). it was demonstrated that this compound would interact with the same number of sites as the benzodiazepines and beta-carbolines, and that, the interactions of these compounds were purely competitive. This compound is the ligand of choice for binding to GABAa receptors because it does not possess receptor subtype specificity and measures each state of the receptor.
The study of the interactions of a wide variety of compounds similar to the above has led to the categorizing of these compounds. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists. This categorization has been developed to emphasize the fact that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same receptor to produce opposite effects, and to indicate that beta-carbolines and antagonists with intrinsic anxiogenic effects are not synonymous. A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor continues to emphasize the interaction with the GABAergic system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81), compounds with antagonist properties show little GABA shift (i.e., change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature 24: 763-65), and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup & Nielson 1981, Nature 294: 472-474). Thus, the GABA shift predicts generally the expected behavioral properties of the compounds.
Various compounds have been prepared as benzodiazepine agonists and antagonists. For example, U.S. Pat. Nos. 4,312,870 and 4,713,383, and European Patent Application EP 181,282 disclose assorted compounds useful in treating anxiety or depression. U.S. Pat. No. 4,713,383 teaches compounds of the formula: ##STR1## wherein R 1 =(un)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl, (dihydro)thienyl, tetrahydrothienyl, pyranyl, ribofuranosyl, all C-attached; R 2 =H, alkyl; X=O, S, R 3 N; R 3 =H, alkenyl, alkynyl, C 3-20 cycloalkyl, (un)substituted alkyl, aryl, aralkyl, where aryl is Ph, pyridinyl, thienyl, furanyl; ring A may be substituted by alkyl, alkoxy, halo, amino, alkylthio, etc.
European Patent Application EP 181,282 discloses compounds of the formula: ##STR2## wherein R 1 =(substituted) Ph or heterocycle; R 2 =H, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl; R 3 =H, alkyl, alkoxy, HO, halo, F 3 C, O 3 N, H 2 N, alkylthio, alkylsulfinyl, alkylsulfonyl, aralkoxy; X=O, S, NR 4 ; and R 4 =H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl, (substituted) aminoalkyl, hydroxyalkyl.
U.S. Pat. No. 4,312,870 teaches compounds of formulas: ##STR3## where Ph is 1,2-phenylene, unsubstituted or substituted by up to 3 identical or different members selected from lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogeno, trifluoromethyl, nitro, amino, mono- or di-lower alkylamino, cyano, carbamoyl and carboxy; R is unsubstituted or substituted phenyl as defined by H-Ph, pyridyl, lower alkylpyridyl, or halogenopyridyl; R 1 is hydrogen, lower alkyl or lower (hydroxy, dialkylamino or H-Ph)-alkyl; and R 2 is hydrogen or lower alkyl; their 3-hydroxy-tautomers; lower alkanoyl, carbamoyl, mono- or di-lower alkylcarbamoyl derivatives of said (hydroxy or amino)-(phenyl or phenylene) compounds;
and ##STR4## where R" is hydrogen, alkyl or alkoxy with up to 4 carbon atoms each, hydroxy, fluoro, chloro, bromo, or trifluoromethyl; and R' is hydrogen, o- or m-fluoro; or it is p-fluoro when R" is chloro.
The compounds of the present invention differ from these compounds. These compounds are not oxazoloquinolinones and/or lack the various ring substituents of the compounds of the present invention.
J. Chem. Soc. (C): 1886-1891 (Roy et al., 1969) discloses 1,2-Dihydro-1-methyl-2-oxoquinoline-N-phenyl-3,4-dicarboximide, which has the following structural formula: ##STR5## This compound contains an N-methyl group and thus is different than the compounds of the present invention.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in enhancing alertness, treatment of seizure, anxiety, and sleep disorders, and treatment of benzodiazepine overdoses. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: ##STR6## and the pharmaceutically acceptable non-toxic salts thereof wherein: R 1 and R 4 are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
X and Y are the same or different and represent oxygen or H 2 with the proviso that not both X and Y are H 2 ;
W is
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono- or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; and
R 2 and R 3 are the same or different and represent
hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, mono or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--R 5 , --OR 5 , --COR 5 , --CO 2 R 5 , or --OCOR 5 , where R 5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, R 6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, and R 7 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, and NR 6 R 7 forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--NR 8 CO 2 R 9 where R 8 and R 9 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms, or
C(OH)R 10 R 11 where R 10 and R 11 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms.
These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory.
BRIEF DESCRIPTION OF THE DRAWING
FIGS. 1A-D show representative pyrroloquinolinones of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by the following general formula I: ##STR7## and the pharmaceutically acceptable non-toxic salts thereof wherein: R 1 and R 4 are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
X and Y are the same or different and represent oxygen or H 2 with the proviso that not both X and Y are H 2 ;
W is
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono- or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; and
R 2 and R 3 are the same or different and represent
hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, mono or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--R 5 , --OR 5 , --COR 5 , --CO 2 R 5 , or --OCOR 5 , where R 5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, R 6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, and R 7 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, and NR 6 R 7 forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--NR 8 CO 2 R 9 where R 8 and R 9 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms, or
--C(OH)R 10 R 11 where R 10 and R 11 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms.
In addition, the present invention encompasses compounds of Formula II. ##STR8## wherein: R 1 and R 4 are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
W is
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono- or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; and
R 2 and R 3 are the same or different and represent
hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, mono or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--R 5 , --OR 5 , --COR 5 , --CO 2 R 5 , or --OCOR 5 , where R 5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, R 6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, and R 7 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, and NR 6 R 7 forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--NR 8 CO 2 R 9 where R 8 and R 9 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms.
The present invention also encompases compounds of Formula III: ##STR9## wherein: R 1 and R 4 are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
W is
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono- or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; and
R 2 and R 3 are the same or different and represent
hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, mono or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms, or
--R 5 , --OR 5 , --COR 5 , --CO 2 R 5 , or --OCOR 5 , where R 5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, R 6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, and R 7 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, and NR 6 R 7 forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--NR 8 CO 2 R 9 where R 8 and R 9 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic, hydroiodic, acetic and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in FIG. 1 and their pharmaceutically acceptable salts. The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
By lower alkyl in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl,
By lower alkoxy in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy,
By halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
By N-alkylpiperazyl in the invention is meant radicals of the formula: ##STR10## where R is a straight or branched chain lower alkyl as defined above.
The pharmaceutical utility of compounds of this invention are indicated by the following assay for GABAa receptor activity.
Assays are carried out as described in Thomas and Tallman (J. Bio. Chem. 156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer (pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4° C.) at 20.000×g for 20 minutes. The supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000×g. The supernatant is decanted and the pellet is frozen at -20° C. overnight. The pellet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice. The pellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris HCl buffer (pH 7.4 at 40° C.).
Incubations contain 100 ml of tissue homogenate. 100 ml of radioligand 0.5 nM ( 3 H-RO15-1788 3 H-Flumazenil! specific activity 80 Ci/mmol). drug or blocker and buffer to a total volume of 500 ml. Incubations are carried for 30 min at 4° C. then are rapidly filtered through GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05M Tris HCl buffer (pH 7.4 at 40° C.) and counted in a liquid scintillation counter. 1.0 mM diazepam is added to some tubes to determine nonspecific binding. Data are collected in triplicate determinations, averaged and % inhibition of total specific binding is calculated. Total Specific Binding=Total Nonspecific. In some cases, the amounts of unlabeled drugs is varied and total displacement curves of binding are carried out. Data are converted to a form for the calculation of IC 50 and Hill Coefficient (nH). Data for the compounds of this invention are listed in Table I. Compounds having IC 50 s greater than 1 μM are considered inactive in the assay.
TABLE I______________________________________Compound Number.sup.1 IC.sub.50 (μM)______________________________________1 0.0362 0.4004 0.70016 0.602______________________________________ .sup.1 Compound numbers relate to compounds shown in FIG. 1.
1,2-Dihydro-1-methyl-2-oxoquinoline-N-phenyl-3,4-dicarboximide, an N-methyl compound disclosed in J. Chem. Soc. (C): 1886-1891 (Roy et al., 1969), was tested in the above assay and showed an inhibition of binding at 1 μM of 40% and, therefore, had an IC 50 of considerably greater than 1 μM in the assay.
The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known lo the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents, for example, corn starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example 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 monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethyicellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleale, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitor or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of 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 sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. 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 are conventionally 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 find use in the preparation of injectables.
The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Illustrations of the preparation of compounds of the present invention are given in Scheme 1. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. ##STR11## wherein:
R 1 and R 4 are the same or different and represent
hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms or straight or branched chain lower alkoxy having 1-6 carbon atoms;
W is
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or
phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl each of which is mono or disubstituted with halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono- or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; and
R 2 and R 3 are the same or different and represent
hydrogen, halogen, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, mono or dialkylamino where each alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--R 5 , --OR 5 , --COR 5 , --CO 2 R 5 , or --OCOR 5 , where R 5 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, R 6 is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, and R 7 is hydrogen, straight or- branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--CONR 6 R 7 or --(CH 2 ) n NR 6 R 7 , where n is 0, 1, or 2, and NR 6 R 7 forms a heterocyclic group which is morpholyl, piperidyl, pyrrolidyl, or N-alkylpiperazyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms; or
--NR 8 CO 2 R 9 where R 8 and R 9 are the same or different and represent hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms, or
--C(OH)R 10 R 11 where R 10 and R 11 are the same or different and represent straight or branched chain lower alkyl having 1-6 carbon atoms, phenylalkyl where the alkyl portion is straight or branched chain lower alkyl having 1-6 carbon atoms.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.
Example I ##STR12##
To a solution of 2-Nitrophenylacetonitrile (18 g) in 300 mL of dry tetrahydrofuran cooled to -70° C. was added potassium t-butoxide (12.4 g) in one portion and the reaction was gradually warmed to 0° C. To this mixture was added diethyloxomalonate (19.3 g) and the mixture was stirred at 0° C. for 30 min. The reaction was quenched with acetic acid and the solvent was removed in vacuo. The residue was diluted with water and the product was extracted with ethyl acetate. After drying over magnesium sulfate the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 3% methanol in methylene chloride as the eluent to afford Ethyl-α-carboethoxy-β-cyano-2-nitro cinnamate as a yellow solid.
Example II ##STR13##
To a solution of Ethyl-α-carboethoxy-β-cyano-2-nitro cinnamate (6 g) in 100 mL of acetic acid is added iron powder (5 g) and the mixture was refluxed with stirring for 40 min. The reaction mixture was cooled to room temperature, filtered through celite and the solvent was removed in vacuo. The residue was subjected to flash chromatography on silica gel with 5% methanol in methylene chloride as the eluent to afford 3-Carboethoxy-4-cyano-1H-quinolin-2-one as a yellow solid.
Example III ##STR14##
A mixture of 3-Carboethoxy-4-cyano-1H-quinolin-2-one (3 g), acetic acid (24 mL), sulfuric acid (4 mL) and water (50 mL) was heated at reflux with vigorous stirring for 90 min. The reaction mixture was cooled to 0° C. and the product was collected to afford 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid as a solid.
Example IV ##STR15##
A mixture of 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid (2 g), phosphorous oxychloride (4 g) and dry chloroform (30 mL) was heated at reflux for 2 h. The solvent and excess reagents are removed in vacuo and the residue was treated with ice water to afford Furo 3,4-c!quinoline-1,3,4(5H)-trione as a yellow solid.
Example IV ##STR16##
A mixture of Furo 3,4-c!quinoline-1,3,4(5H)-trione (215 mg) and aniline (93 mg) in dry dimethylformamide (3 mL) was heated at 100° C. for 5 min. After coolong to room temperature 1,1'-Carbonyidiimidazole (200 mg) was added. The reaction mixture was then heated again to 100° C.. for an additional 5 min. After cooling the reaction mixture was poured onto water to afford 2-Phenyl-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 1) as yellow crystals melting at >390° C.
Example V
The following compounds were prepared essentially according to the procedures set forth in Examples I-IV:
(a) 2-(4-Methoxyphenyl)-pyrrolo 3,4-c!quinoline 1,3,4(5H)-trione (Compound 2), m.p. 350-352° C.
(b) 2-(4-Chlorophenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 3), m.p. 380-381° C.
(c) 2-(2-Fluorophenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 4), m.p. 355-358° C.
(d) 2-(2-Methylphenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 5), m.p. 320-323° C.
(e) 2-(2-Pyridyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 6), m.p. 325-326° C.
(f) 2-(3-Pyridyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 7), m.p. 380-383° C.
(g) 2-(4-Pyridyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 8), m.p. 405-406° C.
(h) 2-(3-Methylphenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 9), m.p. 325-328° C.
(i) 2-(3-Fluorophenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 10), m.p. >390° C.
(j) 2-(4-Fluorophenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 11), m.p. >390° C.
(k) 2-(2-Thienyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 12).
(l) 2-(3-Thienyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 13).
(m) 2-(3-Methoxyphenyl)-pyrrolo (3,4-c!quinoline-1,3,4(5H)-trione (Compound 14).
(n) 8-Bromo-2-(3-methoxyphenyl)-pyrrolo 3,4-c!quinoline-1,3,4(5H)-trione (Compound 15).
Example VI ##STR17##
A mixture of 2(1H)-Oxo-quinoline-3,4-dicarboxylic acid (2.0 g), phosphorous oxychloride (10 mL) and 8 drops of dimethyl formamide was refluxed with stirring for 20 min. The reaction mixture was concentrated in vacuo and the residue treated with ice water to afford 4-Chloro-furo 3,4-c!quinoline-1,3-dione as a tan solid.
Example VII ##STR18##
To a well stirred mixture of 4-Chloro-furo 3,4-c!quinoline-1,3-dione (1.9 g) in tetrahydrofuran (10 mL) was added sodium borohydride (400 mg) at 0° C. and stirring was continued for 2 h. The reaction was then quenched with excess 6N HCl and water, and concentrated in vacuo to afford 4-Chlorofuro 3,4-c!quinolin-3(1H)-one as a pink solid along with a small quantity of 4-Chloro-furo 3,4-c!quinolin-1(3H)-one which could be isolated by column chromatography on silica gel.
Example VIII ##STR19##
A mixture of 4-Chloro-furo 3,4-c!quinolin-3(1H)-one (500 mg), 10% Palladium on carbon (100 mg) and sodium acetate (500 mg) in 20 mL of acetic acid was hydrogenated at atmospheric pressure for 2 h. After filtration through celite, the solvent was removed in vacuo, and the residue was taken up in methylene chloride. After filtration the solvent was removed in vacuo to afford Furo 3,4-c!quinolin-3(1H)-one as a solid.
Example IX ##STR20##
A mixture Furo 3,4-c!quinolin-3(1H)-one (100 mg) and aniline (2 mL) was heated at 180° C. for 5 min. After cooling to room temperature the mixture was slowly diluted with hexane and the resulting product was collected and washed with hexane to afford 2-Phenyl-pyrrolo 3,4-c!quinolin-3(1H)-one.
Example X ##STR21##
A mixture of 2-Phenyl-pyrrolo 3,4-c!quinolin-3(1H)-one (60 mg), and m-chloroperbenzoic acid (105 mg) in 3 mL of methylene chloride was kept at room temperature for 24 h. The mixture was diluted with methylene chloride and washed with sodium carbonate solution. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was heated at 50° C. for 3 h with 1 mL of acetic anhydride. The reaction was quenched with methanol and made basic with ammonium hydroxide. The reaction mixture was concentrated in vacuo, and the resulting aqueous solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 2-Phenyl-pyrrolo 3,4-c!quinoline-3(1H),4(5H)-dione (Compound 16) as a white solid.
Example V
The following compounds were prepared essentially according to the procedures set forth in Examples VI-X:
(a) 2-(4-Methoxyphenyl)-pyrrolo 3,4-c!quinoline-3(1H),4(5H)-dione (Compound 17).
(b) 2-(3-Methoxyphenyl)-pyrrolo 3,4-c!quinoline-3(1H),4(5H)-dione (Compound 18).
(c) 2-(4-Methoxyphenyl)-pyrrolo 3,4-c!quinoline-1(3H),4(5H)-dione (Compound 19).
(d) 2-(3-Methoxyphenyl)-pyrrolo 3,4-c!quinoline-1(3H),4(5H)-dione (Compound 20).
(e) 2-Phenyl-pyrrolo 3,4-c!quinoline-1(3H),4(5H)-dione (Compound 21).
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. | This invention encompasses compounds of formula (I), and pharmaceutically acceptable non-toxic salts thereof wherein X and Y are the same or different and represent oxygen or H 2 with the proviso that not both X and Y are H 2 ; W represents phenyl, thienyl, or pyridyl, each of which may be unsubstituted or mono or disubstituted with organic or inorganic substituents; and R 1 , R 2 , R 3 , and R 4 are variables representing organic and inorganic substituents. These compounds are highly selective agonists, antagonists or inverse agonists for GABAs brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine drugs, and enhancement of memory. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. patent application Ser. No. 11/970,936 filed on Jan. 8, 2008.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] This invention relates to an image recording apparatus, and more particularly to a contiguous microlens array, a method of fabricating the same and a photomask for defining the same, which can be applied to any image recording apparatus that requires focusing light on photosensing devices.
[0004] 2. Description of Related Art
[0005] In a semiconductor-type image recording apparatus like a charge-coupled device (CCD) or CMOS image recording apparatus, a microlens array is often disposed over the array of photosensing devices to enhance the sensitivity of the same, wherein one microlens focuses light on one photosensing device.
[0006] FIG. 1A is a local contour plot of a conventional microlens array, and FIG. 1B shows the height variations of one microlens in two vertical cross-sectional views at different angles. Because a microlens 110 is formed by reflowing a square photoresist pattern formed on a based layer 10 , the shapes of the lower contours thereof are close to squares, as shown in FIG. 1A , so that the microlens 110 has different curvatures in vertical cross-sectional views at different angles. For example, the curvature of the 45° cross section (B-B′) is relatively smaller than that of the 0° cross section (A-A′), as shown in FIG. 1B , so that the microlens 110 is insufficient in the focusing effect. Moreover, because neighboring microlenses 110 are not connected with each other and there are planar sections without a focusing effect between them, the incident light are not fully collected so that the light focusing is not quite effective.
[0007] There is also an issue on the integration of the conventional microlens array with other elements in a image recording apparatus, which is described below with a CMOS image recording apparatus having photodiodes as photosensing devices as an example. Referring to FIG. 2 schematically showing a part of a CMOS image recording apparatus in the prior art, the microlens array 100 is formed on a transparent base layer 10 , which includes a color filter array 12 and other functional layers on a multi-level interconnect structure 20 including a first-level interconnect layer 22 and a second-level interconnect layer 24 over a photodiode array 30 . The eyepiece 40 of the CMOS image recording apparatus is disposed above the microlens array 100 , apart from it by a certain distance.
[0008] Because the incident angle of the light incident to a microlens 110 in a peripheral portion of the microlens array 100 overly deviates from 90° (the direction of 90° means the normal line direction of the image sensor chip, hereinafter) so that the focus of light is not directly under the microlens 110 , the microlens 110 is laterally shifted relative to the corresponding photodiode 30 to make the light focus on the latter, as shown in FIG. 2 . However, this makes the exit light 50 a from the microlens 110 partially blocked by the second-level interconnect layer 24 and thus lowers the recording accuracy of the image. This problem can be solved by laterally shifting portions of the 2 nd -level interconnect layer 24 under the peripheral part of the microlens array 100 , but the interconnect circuit design would become more complicated by doing so.
SUMMARY OF THE INVENTION
[0009] In one embodiment, a contiguous microlens array is provided. The contiguous microlens array consists of a plurality of touching microlenses, wherein the adjacent microlenses are connected to each other to form a contiguous microlens array and curvatures of every angle cross section of each microlens are the same.
[0010] In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, a preferred embodiment accompanied with figures is described in detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1A is a local contour plot of a conventional microlens array, and FIG. 1B shows the height variations of each microlens in two vertical cross-sectional views at different angles.
[0012] FIG. 2 schematically shows a part of a CMOS image recording apparatus in the prior art.
[0013] FIG. 3A is a local contour plot of a contiguous microlens array of an example in a first embodiment of this invention, and FIG. 3B shows the height variations of one microlens in two vertical cross-sectional views at different angles.
[0014] FIGS. 3C and 3D are local contour plots of the contiguous microlens arrays of two other examples in the first embodiment of this invention.
[0015] FIG. 4A and FIG. 4B respectively illustrate, according to the first embodiment of this invention, two examples of a contiguous microlens array wherein neighboring microlenses are entirely connected with each other without a gap between them ( 4 A) or are connected with each other just at their edges ( 4 B).
[0016] FIGS. 5A-1 to 5 A- 3 and FIGS. 5B-1 to 5 B- 3 respectively illustrate, according to the first embodiment of this invention, two examples of a method of fabricating a contiguous microlens array shown in FIGS. 4A and 4B , respectively.
[0017] FIG. 5 C/ 5 D illustrates exemplary polygonal photoresist patterns that can be converted to microlenses similar to those shown in FIG. 3 C/ 3 D.
[0018] FIG. 6 A/ 6 B shows exemplary photomask patterns that can define the photoresist patterns of FIG. 5 A- 1 / 5 B- 1 according to the first embodiment of this invention.
[0019] FIG. 6 C/ 6 D shows exemplary photomask patterns that can define the photoresist patterns of FIG. 5 C/ 5 D according to the first embodiment of this invention.
[0020] FIG. 7 schematically illustrates a part of an example of a CMOS image recording apparatus including a contiguous microlens array of a second embodiment of this invention.
[0021] FIG. 8A shows a local contour plot in a contiguous microlens array according to the second embodiment.
[0022] FIG. 8B shows a cross-sectional view of some contiguous asymmetric microlenses shown in FIG. 8A .
[0023] FIG. 9A shows a top view of some photoresist patterns formed as the precursors of some asymmetric microlenses in a method of fabricating a contiguous microlens array according to the second embodiment of this invention.
[0024] FIG. 9B shows a cross-sectional view of some photoresist patterns formed as the precursors of some asymmetric microlenses shown in FIG. 9A .
[0025] FIG. 10 illustrates exemplary photomask patterns that can define the photoresist patterns of FIG. 9A according to the second embodiment of this invention.
DESCRIPTION OF EMBODIMENTS
First Embodiment
[0026] In the 1 st embodiment of the invention, each microlens is substantially symmetric in any vertical cross-sectional view. A microlens in the central part of the microlens array is aligned with the corresponding photosensing device, and a microlens in the at least one peripheral part of the same is laterally shifted relative to the corresponding photosensing device so that light is focused on the latter. Since FIG. 2 has illustrated such a design, the latter figures relating to the first embodiment do not show again the arrangements of the microlenses in different parts of the microlens array relative to the photosensing devices.
[0027] Moreover, since a microlens in the central part of the array is aligned with the corresponding photosensing device, the photoresist pattern as a precursor of a microlens in the central part and the photomask pattern for defining a microlens in the central part both are aligned with the corresponding photosensing device. Since a microlens in the peripheral part is laterally shifted relative to the corresponding photosensing device, both the photoresist pattern as a precursor of a microlens in the peripheral part and the photomask pattern for defining a microlens in the peripheral part are laterally shifted relative to the corresponding photosensing device. The alignment/shift of a photoresist pattern or a photomask pattern relative to the corresponding photosensing device is not illustrated here because it is easily understandable to one of ordinary skill in the art.
[0028] FIG. 3A is a local contour plot of a contiguous microlens array in one example of the first embodiment of this invention. The microlens array includes a plurality of contiguous microlenses 310 a disposed on a base layer 10 . Each microlens 310 a has substantially circular contours at the heights higher than the connection sections of the same with neighboring microlenses 310 a, and has substantially partially circular contours at the heights on the connection sections adjacent to the neighboring microlenses 310 a. As indicated by the contours in FIG. 3A , each microlens 310 a is substantially symmetric in any vertical cross-sectional view, and has substantially the same curvature in the vertical cross-sectional views at all angles. As shown in FIG. 3B , the curvature of the 45° cross section (B-B′) is substantially the same as that of the 0° cross section (A-A′). In this example, neighboring microlenses 310 a are not entirely connected with teach other, and small gaps are formed between them exposing small portions of the base layer 10 .
[0029] FIGS. 3C and 3D are local contour plots of two contiguous microlens arrays respectively in two other examples of the first embodiment of this invention.
[0030] Referring to FIG. 3C , the structure of the contiguous microlens array of this example is similar to that shown in FIG. 3A except that neighboring microlenses 310 c are entirely connected with each other without a gap exposing the base layer 10 between them. Because neighboring microlenses 310 c are contiguous in any direction, the incident light can be fully collected to achieve more effective light focusing.
[0031] Referring to FIG. 3D , the structure of the contiguous microlens array of this example is similar to that shown in FIG. 3A except that the connection section of any two neighboring microlenses 310 d has a thickness of zero, i.e., any two neighboring microlenses 310 d just contact with each other at their edges. However, because variations are inevitable in a real fabricating process, it is impossible to make any two neighboring microlenses 310 d just contact with each other at their edges. Accordingly, it is more accurate to state that each connection section has a thickness “close to” zero in consideration of the real fabricating process. The light collection efficiency of such a microlens can be up to about 78%, which is still notably higher than that (−65%) of a conventional microlens with a square-like bottom and a round top as shown in FIG. 1A .
[0032] FIG. 4A and FIG. 4B respectively illustrate, according to the first embodiment of this invention, two examples of a contiguous microlens array wherein neighboring microlenses are entirely connected with each other without a gap between them ( 4 A) or are connected with each other just at their edges ( 4 B). FIGS. 5A-1 to 5 A- 3 and FIGS. 5B-1 to 5 B- 3 respectively illustrate, according to the first embodiment of this invention, two examples of a method of fabricating a contiguous microlens array according to the first embodiment shown in FIGS. 4A and 4B , respectively.
[0033] Referring to FIGS. 4 A/ 4 B and 5 A- 1 / 5 B- 1 , a plurality of photoresist patterns 302 / 312 are formed, as an array of photoresist patterns, respectively in a plurality of regions 60 predetermined for forming microlenses. Each photoresist pattern 302 / 312 has a substantially circular shape in the top view, and neighboring photoresist patterns as formed are connected with each other ( 302 ) or are close to each other ( 312 ), so that neighboring photoresist patterns are connected with each other after the reflow step. Each photoresist pattern 302 / 312 includes a pillar part 302 a/ 312 a having a substantially circular shape in the top view and a number of annular segments 302 b ( c )/ 312 b around the pillar part 302 a/ 312 a each having a substantially circular shape in the top view and having a height smaller than that of the pillar part 302 a/ 312 a. The annular segments 302 b ( c )/ 312 b are different in the height and the height thereof decreases from inner to outer.
[0034] It is particularly noted that the annular segments of a photoresist pattern 302 in FIG. 4A include the intact annular segments 302 b and partial annular segments 302 c therearound, both of which are generally called “annular segments” in the specification and claims of this invention. The partial annular segments 302 c of a photoresist patter 302 are connected with those of the neighboring photoresist patterns 302 . For a partial annular segment 302 c, the center thereof is defined as the center of an imaginary intact annular segment including the partial annular segments 302 c itself. Moreover, as shown in FIG. 4 A/ 4 B, in each photoresist pattern 302 / 312 , the center of the pillar part 302 a/ 312 a substantially coincides with that of each annular segment 302 b ( c )/ 312 b and also with that of the corresponding region 60 predetermined for forming the microlens.
[0035] Referring to FIG. 4A , the outmost annular segments 302 c of four neighboring photoresist patterns 302 enclose a small gap that exposes a small portion of the base layer 10 . Moreover, the shape of each of the pillar part 302 a and the annular segments 302 b ( c ) can be changed to a polygonal shape, as indicated by the reference characters 302 ′, 302 a ′, 302 b ′ and 302 c ′ in FIG. 5 . Since the corners of polygonal photoresist patterns will be rounded in the later reflow step, the microlenses formed therefrom are similar to those formed from circular photoresist patterns.
[0036] Differently, the annular segments of a photoresist pattern 312 in FIG. 5B-1 include intact annular segments 312 b only, wherein the outmost intact annular segments 312 b of neighboring photoresist patterns 312 are sufficiently close to each other so that the neighboring photoresist patterns 312 are connected with each other after the reflow step. The shape of each of the pillar part 312 a and the annular segments 312 b can also be changed to a polygonal shape in the example, as indicated by the reference characters 312 ′, 312 a ′ and 312 b ′ in FIG. 5D . Since the corners of the polygonal photoresist patterns will be rounded in the later reflow step, the microlenses formed therefrom are similar to those formed from circular photoresist patterns.
[0037] Referring to FIG. 5 A- 2 / 5 B- 2 , a reflow step 304 is performed, including heating the above photoresist patterns 302 / 312 to round their surfaces and thereby form surface-rounded photoresist patterns 306 / 316 . The reflow step 304 may be conducted at a temperature of about 120-140° C. for about 10-15 minutes. When the surface of each photoresist pattern 302 / 312 has a proper height distribution, the surface of each surface-rounded photoresist pattern 306 / 316 can be close to a part of a spherical surface 307 / 317 that is namely a partial spherical surface.
[0038] Moreover, for the photoresist pattern array in FIG. 4A and FIG. 5A-1 , the photoresist material of the outmost annular segments 302 c of four neighboring photoresist patters 302 flows into the small gap between them in the reflow step so that each microlens has a curved surface covering all the corresponding region 60 predetermined for its formation. For the photoresist pattern array in FIG. 4B and FIG. 5B-1 , the photoresist material of the outmost annular segment 312 b of each photoresist pattern 312 flows outward in the reflow step so that neighboring photoresist patterns 312 which are not connected with each other as formed are connected with each other.
[0039] Referring to FIG. 5 A- 3 / 5 B- 3 , a fixing step 308 is then performed to remove the residual solvent in each surface-rounded photoresist patterns 306 / 316 and thereby fix the shape of the same to form a microlens 310 c/ 310 d. In an embodiment, the fixing step 308 uses UV-light to irradiate the photoresist patterns 306 / 316 , wherein the wavelength of the UV-light used may be about 365 angstroms, the intensity of the UV-light may be about 300 mJ/cm 2 and the processing time may be about 10-15 minutes. In another embodiment, the fixing step 308 includes further heating the surface-rounded photoresist patterns 306 / 316 at a temperature higher than that set in the reflow step 304 , such as a temperature within the range of 180-200° C. The processing time may be about 10-15 minutes.
[0040] Exemplary photomask patterns that can define the photoresist patterns in FIG. 4 A/ 4 B are illustrated in FIG. 6 A/ 6 B. The photomask includes a transparent substrate 500 / 530 , and a plurality of photomask patterns 510 / 540 thereon that are disposed in the regions 502 / 532 corresponding to the regions 60 predetermined for the microlenses and constitute a photomask pattern array corresponding to the microlens array to be defined.
[0041] In the example of FIG. 6A , each photomask pattern 510 is typically a square unit pattern apart from the neighboring photomask patterns 510 and has therein a number of annular partition lines 520 that expose portions of the transparent substrate 500 and are for defining the annular segments of the photoresist pattern. In a photomask pattern 510 , one of any two neighboring annular partition lines 520 is surrounded by the other of the two neighboring annular partition lines 520 . The annular partition lines 520 include intact annular partition lines 520 a and partial annular partition lines 520 b therearound, both of which are generally called “annular partition lines” in the specification and claims of this invention.
[0042] Moreover, the distance between neighboring photomask patterns 510 is small enough so that the neighboring photoresist patterns defined thereby are not disconnected. Each annular partition line 520 is sufficiently narrow such that no annular trench pattern is formed in the photoresist layer but the irradiation on the region around the portion of the photoresist corresponding to the partition line 520 is raised, so that the photoresist layer in the region is partially removed to form an annular segment of a photoresist pattern. Accordingly, when there are two or more annular partition lines 520 , the photoresist pattern defined by the photomask pattern 510 has a number of annular segments that descend stepwise in the height from inner to outer, as shown in FIG. 5A-1 . Moreover, because there are two straight partition lines crossing in the region between four neighboring photomask patterns 510 , the photoresist material in the region is entirely removed to form the small gap between the corresponding four neighboring photoresist patterns, as shown in FIG. 4A .
[0043] In the example of FIG. 6B , the photomask patterns 540 are circular patterns, each of which includes a number of annular partition lines 550 exposing portions of the transparent substrate 530 that are all intact annular partition lines, wherein any two neighboring annular partition lines 550 are in the relationship of inner and outer rings. Neighboring photomask patterns 540 are properly spaced from each other such that the neighboring photoresist patterns defined thereby are not connected with each other until the reflow step is conducted. The effect of the annular partition lines 550 is the same as that of the annular partition lines 520 in FIG. 6A , so that the photoresist pattern defined by such a photomask pattern 540 also has a number of annular segments that descend stepwise in the height from inner to outer, as shown in FIG. 5B-1 .
[0044] Exemplary photomask patterns that can define the photoresist patterns in FIG. 5 C/ 5 D are illustrated in FIG. 6 A/ 6 D. The photomask patterns can be derived from FIG. 6 A/ 6 B by changing the above circular annular partition lines 520 ( a/b ), circular photomask patterns 540 and circular annular partition lines 550 to polygonal annular partition lines 520 ′ (including 520 a ′ and 520 b ′), polygonal photomask patterns 540 ′ and polygonal annular partition lines 550 ′. In addition, the transparent substrate is labeled with 500 ′/ 530 ′, the region corresponding to a region 60 predetermined for forming a microlens is labeled with 502 ′/ 532 ′, and the square unit pattern corresponding to a microlens to be defined is labeled with 510 ′.
[0045] Moreover, by properly adjusting at least one of the thickness and the absorption coefficient of the photoresist layer as well as the number and the width of the partition line(s), the envelop of the disk-like portions of a photoresist pattern can be close to a partial spherical surface with a required curvature so that the microlens formed from the photoresist pattern through the reflow step has a surface close to the partial spherical surface with the required curvature.
[0046] In this embodiment, since each microlens has substantially circular or regular-polygonal contours at the heights higher than the connection sections of the microlens with neighboring microlenses, has substantially partially circular contours at heights on the connection sections adjacent to the neighboring microlenses and is substantially symmetric in any vertical cross-sectional view, the curvature variation over the cross sections of all angles in the microlens is smaller than that in a conventional microlens with a squire-like bottom and a circular top so that the microlens provides better focusing than the conventional one. Moreover, in a case where no gap is present between neighboring microlenses, the incident light can be fully collected to increase the light collection efficiency because there is no planar section in the contiguous microlens array.
Second Embodiment
[0047] In the second embodiment of this invention, each microlens is aligned with the corresponding photosensing device, a microlens in a central part of the microlens array is substantially symmetric in any vertical cross-sectional view, and a microlens in the peripheral part of the microlens array has an asymmetric vertical cross section.
[0048] A CMOS image recording apparatus including photodiodes as the photosensing devices is taken as an example again in the second embodiment. FIG. 7 schematically shows a part of an example of such a CMOS image recording apparatus. The structure of the CMOS image recording apparatus is similar to that shown in FIG. 2 except the shapes and positions of microlenses 610 a/b/c in the microlens array 600 . Specifically, the microlens array 600 is formed on a transparent base layer 10 , which includes a color filter array 12 and other functional layers and is disposed on a multi-level interconnect structure 20 including a first-level interconnect layer 22 and a second-level interconnect layer 24 over the array of photodiodes 30 . The eyepiece 40 of the image recording apparatus is disposed above the microlens array 600 , apart from it by a certain distance.
[0049] A microlens 610 a in the central part of the microlens array 600 is substantially symmetric in any vertical cross-sectional view, and a microlens 610 b/c in the peripheral part of the array 600 has an asymmetric vertical cross section. It is noted that the center-shift direction of an asymmetric microlens 610 b/c is set according to the incident angle of light, such that the incident light 50 overly deviating from 90° is converted to exit light 51 having an average exit angle close to 90° that focuses on the photodiode 30 directly under the microlens 610 b/c. For example, the center of the left asymmetric microlens 610 b is shifted left as being subjected to incident light inclining toward the right side, while the center of the right asymmetric microlens 610 c is shifted right as being subjected to incident light inclining toward the left side.
[0050] FIG. 8A shows a local contour plot and a cross-sectional view of some contiguous asymmetric microlenses 610 b and FIG. 8B shows a cross-sectional view of FIG. 8A , while the structures of the asymmetric microlenses 610 c and those in other portions of the peripheral part can be known based on FIGS. 8A and 8B . As shown in FIGS. 8A and 8B , each microlens 610 b also has substantially circular contours at heights above the connection sections of the same with neighboring microlenses 610 b. As in the cases of FIG. 3D , it is also possible that the thickness of each connection section is alternatively close to zero.
[0051] FIG. 9A depicts a top view and FIG. 9B depicts a cross-sectional view of exemplary photoresist patterns that can serve as the precursors of the asymmetric microlenses 610 b, wherein each photoresist pattern 602 includes a pillar part 602 a having a substantially circular shape in the top view and a number of annular segments 602 b/c therearound that are lower than the pillar part 602 a and different in the heights, wherein the heights thereof decreases from inner to outer. It is particularly noted that the intact annular segments 602 b and the partial annular segments 602 c therearound both are generally called “annular segments” in the specification and claims of this invention. Meanwhile, the center of a partial annular segment 602 c is defined as the center of an imaginary intact annular segment that includes the partial annular segment 602 c itself.
[0052] In the top view of a photoresist patter 602 , the center of the pillar part 602 a and that of the annular partition line 602 b/c both are shifted relative to the center of the region 60 in which the photoresist patter 602 is located. Moreover, it is also possible to form a photoresist pattern including a polygonal pillar part and at least one polygonal annular segment therearound, which can be easily understood based on the above mentioned and are not illustrated in the drawings.
[0053] FIG. 10 illustrates exemplary photomask patterns that can define the photoresist patterns in FIG. 8 according to the second embodiment. The photomask patterns 910 are formed on a transparent substrate 900 in the areas 902 corresponding to the regions 60 predetermined for forming the microlenses 610 b, along with the photomask patterns for defining the microlenses 610 a, 610 c and so forth.
[0054] Each photomask pattern 910 is substantially a square unit pattern and has therein annular partition lines 920 that expose portions of the transparent substrate 900 and are for defining the annular segments of a photoresist pattern. The annular partition lines 920 include intact annular partition lines 920 a and partial annular partition lines 920 b therearound. Moreover, the distance between neighboring photomask patterns 910 is sufficiently small so that the neighboring photoresist patterns defined thereby are not disconnected from each other. It is particularly noted that the intact annular partition lines 920 a and the partial annular partition lines 920 b both are generally called “annular partition lines” in the specification and claims of this invention, while the center of a partial annular partition line 920 b is defined as the center of an imaginary intact annular partition line that includes the partial annular partition line 920 b itself.
[0055] Moreover, in a photomask pattern 910 , the center of each annular partition line 920 a/b is laterally shifted relative to that of the region 902 in which the photomask pattern 910 is located. In addition, each annular partition line 920 a/b is sufficiently narrow so that the photoresist pattern defined by a photomask pattern 910 has a number of annular surfaces that descend stepwise in the height from inner to outer, as mentioned in the descriptions of FIG. 6A-6D . Moreover, if a photoresist pattern including a polygonal pillar part and at least one polygonal annular segment therearound is to be formed, the shape of each partition line 920 a/b must be made polygonal. This is easily understood based on the above mentioned and is therefore not illustrated in the drawings.
[0056] As mentioned above, in the second embodiment, a microlens in the peripheral portion with incident angles of light overly deviating from 90° has an asymmetric vertical cross section to make the exit angle of light from the microlens close to 90°. Hence, each microlens in the central part and the peripheral part are allowed to align with the corresponding photodiode without a lateral shift relative thereto. Thereby, the interconnect structures under the peripheral part of the microlens array are not necessary to shift, so that no modification is required for the interconnect circuit design.
[0057] This invention has been disclosed above in the preferred embodiments, but is not limited to those. It is known to persons skilled in the art that some modifications and innovations may be made without departing from the spirit and scope of this invention. Hence, the scope of this invention should be defined by the following claims. | The present disclosure provides a contiguous microlens array, which consists of a plurality of touching microlenses, wherein the adjacent microlenses are connected to each other to form a contiguous microlens array and curvatures of every angle cross section of each microlens are the same. The shape of the curved surface of a microlens in the microlens array is selectively adjusted according to its position in the array and the incident angle of light incident thereto. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to Korean Patent Application No. 10-2010-0025874, filed on Mar. 23, 2010, and all the benefits accruing therefrom under 35 U.S.C. §119, the content of which in its entirety is herein incorporated by reference.
BACKGROUND
1. Field
The present disclosure relates to microarray package devices and methods of manufacturing the same.
2. Description of the Related Art
A method of analyzing a target biomaterial using a microarray has been used in various fields, for example, in studying functions of human genes, genetic analysis for diagnosing various diseases including cancer, and pharmacogenomics. A microarray is a device which includes biomaterial probes that are capable of being complementarily coupled, e.g., hybridized, to a target biomaterial, and plays a significant role in detecting and analyzing the target biomaterials. A microarray package device has been suggested for effectively analyzing a reaction of a microarray. In order to effectively perform an analysis process on a microarray, it is beneficial to ensure the structural stability of the microarray and the reliability of results obtained therefrom. Generally, a microarray is fixed in a microarray package, and a microarray analysis process is performed using an analyzing device such as an optical scanner. Thus, research has been conducted into use of a microarray package that provides structural stability for the microarray and increases a reliability of results obtained therefrom.
SUMMARY
Provided are microarray package devices that may provide structural stability and reliable experimental results.
Provided are methods of manufacturing microarray package devices that may provide structural stability and reliable experimental results.
Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description, or may be learned by practice of the presented embodiments.
According to an embodiment of the present disclosure, a microarray package device includes; a microarray substrate including a front surface on which a biomaterial probe is disposed, a package substrate comprising a microarray accommodation unit, wherein the microarray accommodation unit comprises a bottom, at least one concave portion disposed in the bottom, and a sidewall connected to the bottom, wherein when a bottom surface of the microarray substrate is attached to the bottom, the bottom surface of the microarray substrate is aligned with the at least one concave portion, and the sidewall faces a side surface of the microarray substrate, and an adhesive disposed in a space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit which adheres the microarray substrate and the package substrate to each other, wherein the adhesive fills and covers the at least one concave portion.
In one embodiment, the microarray package device may include a microarray substrate on which a biomaterial probe is disposed.
In one embodiment, the microarray package device is manufactured so that a microarray substrate is fixed to an external structure thereof, for example, a package substrate, and analysis of the microarray substrate is performed using a microarray analyzing device. Thus, the microarray package device may be installed to the microarray analyzing device, or alternatively, a sample including a target material may be introduced and analyzed by the microarray analyzing device, in order to perform analysis using the microarray substrate. In one embodiment, the microarray analyzing device may be, for example, a hybridization station. In one embodiment, the analysis of the target material may be performed by dying the target with a fluorescent material and analyzing the target material using an optical scanner.
In one embodiment, the microarray substrate includes a biomaterial probe that is fixed thereto and is capable of being coupled to a target material. For example, the biomaterial probe may be disposed on a front surface of the microarray substrate. The target material includes any biomaterial to be detected. Examples of the biomaterial include nucleic acids, proteins, sugars, viruses, cells, cell organelles and other similar materials. The nucleic acids may be DNA, RNA, PNA, oligonucleotides or other similar materials. The biomaterial may be derived from living organisms, or synthesized or semi-synthesized. The biomaterial may include at least one biomaterial monomer. Examples of the biomaterial may include DNA, RNA, nucleotide, nucleoside, protein, polypeptide, peptide, amino acid, carbohydrate, enzyme, an antibody, an antigen, a receptor, virus, stroma, ligand, membrane, and combinations thereof, but are not limited thereto. The microarray substrate may be used in various reactions such as a biological or biochemical reaction. For example, in an embodiment wherein a target nucleic acid is detected, the reaction may include providing a microarray substrate to which a nucleic acid probe having a complementary sequence to a known target nucleic acid is fixed, introducing a sample including a target nucleic acid labeled with a label (e.g., a fluorescent material) that is detected by the microarray substrate, and performing hybridization of the nucleic acid probe and the target nucleic acid. The reaction may include performing washing after the hybridization and removing a material not affected by the hybridization, and irradiating excited light to the fluorescent material of the hybridized result to detect fluorescent light emitted from the fluorescent material by using a microarray scan system. The microarray substrate may include a material, for example, quartz, silicon, glass, metal, plastic, ceramic or other material with similar characteristics, for coupling the biomaterial probe thereto, that is, a material that is capable of being coupled to the target material. For example, in one embodiment, the microarray substrate may be formed of silicon, quartz or glass. In addition, when the microarray substrate is formed of silicon, the microarray substrate may be processed to form an oxide layer (SiO 2 ) thereon. A surface of the microarray substrate may be processed with various materials in order to couple the biomaterial probe and the oxide layer to each other. For example, the processed material may include a material selected from the group consisting of various kinds of linkers, an amine group, a carboxyl group, an epoxy group, a sulfur group, an aldehyde group, activated ester, and maleimide. In one embodiment, the microarray substrate may have a flat, bead, or spherical shape, but is not limited thereto. For example, in one embodiment the microarray substrate may have a flat shape. In addition, the microarray substrate includes a predetermined region where the biomaterial probe is disposed. The region may be variously determined according to the use and type of the microarray.
In one embodiment, the microarray package device may include a package substrate comprising a microarray accommodation unit comprising a bottom and a sidewall, wherein a bottom surface of the microarray substrate is attached to the bottom, at least one concave portion is disposed on the bottom in a region corresponding to an attached lower portion of the microarray substrate, and the sidewall is connected to the bottom and faces a side surface of the microarray substrate.
In one embodiment, the package substrate may be formed of a material, for example, plastic, that is capable of being coupled to a bottom surface of the microarray substrate, but is not limited thereto. The package substrate may be formed to be flush with the microarray substrate. Generally, since the microarray package device is used with a fluorescent image detection system using an optical scanner, a portion of the package substrate for fixing the microarray substrate may be flush with the microarray substrate because, when a package substrate having a bottom including a protrusion is used, a surface of the microarray or a lens of the optical scanner may be damaged during the analysis of the optical scanner.
In one embodiment, the package substrate includes a microarray accommodation unit to which the microarray substrate is fixed. The microarray accommodation unit may have a space to which the microarray substrate is fixed. The space may have a length, area, or volume that varies with a type of the microarray substrate. The microarray accommodation unit includes a bottom and a sidewall that define a space to which the microarray substrate is fixed.
In one embodiment, the bottom is a portion to which a bottom surface of the microarray substrate is attached. The bottom may include an opening formed through the package substrate. The opening may define a fixation point for fixing the microarray substrate on the bottom surface of the microarray substrate during measurements, e.g., focusing and leveling, which are performed by the microarray analyzing device. Thus, compared to a package substrate having no opening, the package substrate having the opening may reduce an area of the microarray substrate when the two package substrates have the same biomaterial probe region. In addition, when the two package substrates have the same area as the microarray substrate, the integrity of the biomaterial probe may be increased.
In one embodiment, the bottom may include at least one concave portion disposed in a region to which the bottom surface is attached. A cross section of the concave portion may have a triangular shape, rectangular shape, semicircular shape, elliptical shape or other similar shape. At least two concave portions may be used. By disposing the concave portion on the bottom, a surface area of the bottom is greater than a surface area of the bottom surface. Therefore, when adhesives are disposed in a space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit in order to adhere the microarray substrate and the package substrate to each other, the adhesives fill and cover the concave portion.
In one embodiment, the sidewall is connected to the bottom, and faces a side surface of the microarray substrate. A height of the sidewall may vary, but in one embodiment may be substantially equal to a height of the microarray substrate. Generally, since the microarray package device is used with a fluorescent image detection system using an optical scanner, the microarray package device including the microarray substrate may be compatible with the optical scanner in terms of the field of view and depth of focus. When the microarray package device deviates from a photographing region, or is inclined in a vertical direction, or when the microarray substrate is deformed due to physical external stress, an obtained image may be incorrect, e.g., warped or obfuscated, thus, a reliable analysis result may not be obtained. In order to prevent the deviation from an image acquisition region of the optical scanner, the microarray substrate may be fixed to the bottom and side wall. When the microarray substrate is fixed to the microarray accommodation unit, the microarray substrate is fixed to the bottom and the sidewall, a location of the microarray substrate may not deviate from the a permissible range of an image acquisition region of the optical scanner.
In one embodiment, the sidewall may include at least one protrusion that protrudes towards a side surface of the microarray substrate. In one embodiment, the protrusion may protrude from the sidewall to the side surface of the microarray substrate. In another embodiment, the protrusion may extend from the bottom. Thus, the side surface of the microarray substrate may be fixed to the microarray accommodation unit by the protrusion, and a portion of the sidewall which excludes the protrusion maintains a predetermined distance from the side surface of the microarray substrate. Thus, a space is formed between the sidewall and the side surface of the microarray substrate.
In one embodiment, the microarray package device may include an adhesive disposed in a space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit so that the microarray substrate and the package substrate are adhered to each other, wherein the adhesives fill and cover the concave portion. In one embodiment, the adhesive may be an ultraviolet (UV) curable adhesive.
When the microarray substrate and the package substrate are adhered to each other by the adhesive, the adhesive may contract at an adhesion surface between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit since the adhesive are hardened, thereby causing deformation of the microarray substrate and/or the package substrate. When the microarray substrate formed of silicon and the package substrate formed of plastic are adhered to each other by the UV curable adhesives, the adhesive may contract due to the hardening of the adhesive, and thus a volume of the adhesive may be reduced, thereby causing deformation of the microarray substrate and/or the package substrate. Due to the deformation, flatness of the microarray package device may deteriorate, and thus it may be difficult to obtain reliable analyzing results of the optical scanner. However, in the embodiment of a microarray package device according to the present disclosure, the adhesive is disposed in the space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit, and fills and covers the concave portion, thereby reducing the contraction of the adhesive and the deformation of the microarray substrate and/or the package substrate due to the hardening of the adhesive. When the adhesive fills and covers the concave portion, the adhesive contacts a greater area of the bottom of the package substrate than that of the bottom surface of the microarray substrate. Thus, a contraction of the adhesive due to the hardening thereof may be reduced, thereby reducing the deformation of the microarray substrate and/or the package substrate.
In one embodiment, when the microarray substrate and the package substrate are adhered to each other by the adhesive, since the adhesive is disposed between the adhesion surface between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit in a fluid state, the adhesive may be distributed in a narrow space between the side surface of the microarray substrate and the sidewall of the package substrate according to a capillary phenomenon. Thus, the adhesive may contract due to the hardening thereof between the side surface of the microarray substrate and the sidewall of the package substrate, and deformation of the microarray substrate and/or the package substrate may be caused. Due to the deformation, flatness of the microarray package device may deteriorate, and thus it may be difficult to obtain reliable analyzing result of the optical scanner. However, in another embodiment of a microarray package device according to the present disclosure, since at least one protrusion protruding towards the side surface of the microarray substrate is disposed on the sidewall of the microarray accommodation unit, the microarray substrate is fixed by the protrusion and does not deviate from a permission range of an image acquisition region of the optical scanner. In addition, since the space between the sidewall, excluding the protrusion, and the side surface of the microarray substrate and the sidewall is sufficiently wide, the distribution of the adhesives due to a capillary phenomenon may not occur. Thus, the contraction of the adhesive due to the hardening of the adhesive may be reduced between the side surface of the microarray substrate and the sidewall, thereby reducing the deformation of the microarray substrate and/or the package substrate.
According to another embodiment of the present disclosure, a method of manufacturing a microarray package device includes providing a microarray substrate including a front surface on which a biomaterial probe is disposed, providing a package substrate comprising a microarray accommodation unit comprising; a bottom corresponding to a bottom surface of the microarray substrate and comprising at least one concave portion disposed in a region to which a bottom surface is attached, and a sidewall connected to the bottom and corresponding to a side surface of the microarray substrate, and adhering the microarray substrate and the package substrate to each other with an adhesive which fills and covers the at least one concave portion.
In one embodiment, the method may include providing a microarray substrate on which a biomaterial probe is disposed to a front surface of the microarray substrate.
In one embodiment, the microarray package device is manufactured so that a microarray substrate is fixed to an external structure thereof, for example, a package substrate, and analysis is performed by a microarray analyzing device. Thus, the microarray package device may be installed to the microarray analyzing device, or alternatively, a sample including a target material is introduced, and is analyzed by the microarray analyzing device, in order to perform analysis using the microarray substrate. In one embodiment, the microarray analyzing device may be, for example, a hybridization station. In one embodiment, the analysis of the target material may be performed by dying the target with a fluorescent material and analyzing the target material by using an optical scanner.
In one embodiment, the microarray substrate includes a biomaterial probe that is fixed thereto and is capable of being coupled to a target material. For example, in one embodiment, the biomaterial probe may be disposed on a front surface of the microarray substrate. The target material includes any biomaterial to be detected. Examples of the biomaterial include nucleic acids, proteins, sugars, viruses, cells, and cell organelles and other similar materials as discussed above. The nucleic acids may be DNA, RNA, PNA, oligonucleotide and other similar materials as discussed above. The biomaterial may be derived from living organisms, or synthesized or semi-synthesized. The biomaterial may include at last one biomaterial monomer. Examples of the biomaterial may include DNA, RNA, nucleotide, nucleoside, protein, polypeptide, peptide, amino acid, carbohydrate, enzyme, an antibody, an antigen, a receptor, virus, stroma, ligand, membrane, and combinations thereof, but are not limited thereto. The microarray substrate may be used in various reactions such as a biological or biochemical reaction.
In one embodiment, the method may include providing a package substrate comprising a microarray accommodation unit comprising a bottom corresponding to a bottom surface of the microarray substrate and comprising at least one concave portion disposed in a region to which a bottom surface is attached, and a sidewall connected to the bottom and corresponding to a side surface of the microarray substrate.
In one embodiment, the package substrate may be formed of a material, for example, plastic, that is capable of being coupled to a bottom surface of the microarray substrate, but is not limited thereto. The package substrate may be flush with the microarray substrate. Generally, since the microarray package device is used with a fluorescent image detection system using an optical scanner, a portion of the package substrate for fixing the microarray substrate may be flush with the microarray substrate because, when a package substrate having a bottom including a protrusion is used, a surface of the microarray or a lens of the optical scanner may be damaged during the analysis of the optical scanner.
In one embodiment, the package substrate includes a microarray accommodation unit to which the microarray substrate is fixed. In one embodiment, the microarray accommodation unit may have a space to which the microarray substrate is fixed. In one embodiment, the space may have a length, area or volume that varies with a type of the microarray substrate. In one embodiment, the microarray accommodation unit includes a bottom and a sidewall that constitute a space to which the microarray substrate is fixed.
In one embodiment, the bottom is a portion to which a bottom surface of the microarray substrate is attached. The bottom may include an opening formed through the package substrate. The backside of the microarray substrate exposed by the opening may provide a fixation point for mounting the microarray substrate onto a microarray analyzing device for the measurement of focusing and leveling. While a package substrate without opening uses additional points for focusing and leveling on the front-side of microarray substrate, the package substrate with the opening may have those points created on the backside surface of the microarray substrate. Thus, the package substrate with the opening may reduce an area of the microarray substrate when the two package substrates have the same biomaterial probe region. In addition, when the two package substrates have the same area as the microarray substrate, the integration of the biomaterial probe per unit area may be increased.
In one embodiment, the bottom may include at least one concave portion disposed in a region to which the bottom surface is attached. A cross section of the concave portion may have a triangular, rectangular, semicircular or elliptical shape as discussed above. In another embodiment, at least two concave portions may be used. By disposing the concave portion on the bottom, a surface area of the bottom is greater than a surface area of the bottom surface. In this case, when adhesive is disposed in a space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit in order to adhere the microarray substrate and the package substrate to each other, the adhesive fills and covers the concave portion.
In one embodiment, the sidewall is connected to the bottom, and faces a side surface of the microarray substrate. A height of the sidewall may vary, but may be substantially equal to a height of the microarray substrate. Generally, since the microarray package device is based on a fluorescent image detection system using an optical scanner, the microarray package device including the microarray substrate may be compatible with the optical scanner in terms of the field of view and depth of focus. When the microarray package device deviates from a photographing region, or is severely inclined in a height direction, or when the microarray substrate is deformed due to physical external stress, an image obtained therefrom may be incorrect, thus, a reliable analysis result may not be obtained. In order to prevent the deviation of microarray substrate from an allowable range of an image acquisition region of the optical scanner, the microarray substrate may be fixed to the bottom and side wall. When the microarray substrate is fixed to the microarray accommodation unit, the microarray substrate is fixed to the bottom and the sidewall, a location of the microarray substrate may not deviate from the permissible range of an image acquisition region of the optical scanner.
In one embodiment, the sidewall may include at least one protrusion that protrudes towards a side surface of the microarray substrate. In one embodiment, the protrusion may protrude from the sidewall to the side surface of the microarray substrate. In an alternative embodiment, the protrusion may extend from the bottom. Thus, the side surface of the microarray substrate may be fixed to the microarray accommodation unit by the protrusion, and a portion of the sidewall except for the protrusion maintains a predetermined distance from the side surface of the microarray substrate. Thus, a space is formed between the sidewall and the microarray substrate.
In one embodiment, the method may include adhering the microarray substrate and the package substrate to each other by forming a space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit so as to fill and cover the concave portion.
In one embodiment, the adhesives may be a UV curable adhesive. When the microarray substrate and the package substrate are adhered to each other by the adhesive, the adhesive may contract at an adhesion surface between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit since the adhesive is hardened, thereby causing deformation of the microarray substrate and/or the package substrate. When the microarray substrate formed of silicon and the package substrate formed of plastic are adhered to each other by the UV curable adhesive, the adhesive may contract due to the hardening thereof, and thus a volume of the adhesive may be reduced, thereby causing deformation of the microarray substrate and/or the package substrate. Due to the deformation, flatness of the microarray package device may be deteriorated, and thus it may be difficult to obtain reliable analyzing results from the optical scanner. However, in the microarray package device according to an embodiment of the present disclosure, the adhesive is disposed in the space between the bottom surface of the microarray substrate and the bottom of the microarray accommodation unit, and fills and covers the concave portion, thereby reducing the contraction of the adhesive and the deformation of the microarray substrate and/or the package substrate due to the hardening of the adhesive. When the adhesive fills and covers the concave portion, the adhesive contacts a greater area of the bottom of the package substrate than that of the bottom surface of the microarray substrate. Thus, contraction due to the hardening of the adhesive may be reduced, thereby reducing the deformation of the microarray substrate and/or the package substrate.
BRIEF DESCRIPTION OF THE DRAWINGS
These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a cross-sectional view of an embodiment of a microarray package device prior to assembling a microarray substrate and a package substrate, according to the present disclosure [J3] ;
FIG. 2 is a cross-sectional view of the embodiment of a microarray package device of FIG. 1 after assembling the microarray substrate and the package substrate;
FIG. 3 is a cross-sectional view illustrating an embodiment where adhesives are distributed in a space between a side surface of the microarray substrate and a sidewall of the package substrate of the microarray package device, according to a capillary phenomenon;
FIG. 4 is a cross-sectional view of another embodiment of a microarray package device including a sidewall including a protrusion, according to the present disclosure;
FIG. 5A is a top plan view of an embodiment of a package substrate, according to the present disclosure;
FIG. 5B is a top plan view of an embodiment where a microarray substrate is adhered to a package substrate by adhesives 300 , according to the present disclosure; and
FIGS. 6A through 6D are images illustrating results of measuring analysis results of a microarray analyzing device using a microarray package device, wherein the measuring is performed by an optical scanner, according to an embodiment of the present disclosure.
DETAILED DESCRIPTION
Embodiments now will be described more fully hereinafter with reference to the accompanying drawings, in which embodiments are shown. These embodiments may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Like reference numerals refer to like elements throughout.
It will be understood that when an element is referred to as being “on” another element, it can be directly on the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being “directly on” another element, there are no intervening elements present. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the present disclosure.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” or “includes” and/or “including” when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element's relationship to another elements as illustrated in the Figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the Figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
Exemplary embodiments are described herein with reference to cross section illustrations that are schematic illustrations of idealized embodiments. As such, variations from the shapes of the illustrations as a result, for example, of manufacturing techniques and/or tolerances, are to be expected. Thus, embodiments should not be construed as limited to the particular shapes of regions illustrated herein but are to include deviations in shapes that result, for example, from manufacturing. For example, a region illustrated or described as flat may, typically, have rough and/or nonlinear features. Moreover, sharp angles that are illustrated may be rounded. Thus, the regions illustrated in the figures are schematic in nature and their shapes are not intended to illustrate the precise shape of a region and are not intended to limit the scope of the disclosure.
All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the disclosure and does not pose a limitation on the scope thereof unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the embodiments as used herein.
Hereinafter, the embodiments will be described in detail with reference to the accompanying drawings.
FIG. 1 is a cross-sectional view of an embodiment of a microarray package device before assembling a microarray substrate 100 and a package substrate 200 , according to the present disclosure. FIG. 2 is a cross-sectional view of the embodiment of a microarray package device of FIG. 1 where the microarray substrate 100 and the package substrate 200 are assembled.
The microarray package device is used for analyzing a material via a microarray analyzing device (not shown), and the microarray substrate 100 is fixed to the package substrate 200 . The microarray package device may be installed to a microarray analyzing device (not shown). A material, e.g., a solution, including a target material, e.g., a biomolecule to be detected, may be introduced to the microarray substrate 100 , and then analyzed by the microarray analyzing device. In one embodiment, the microarray analyzing device may include, for example, an optical scanner, although alternative embodiments include alternative configurations using alternative devices.
A biomaterial probe (not shown) is disposed on a front surface 110 of the microarray substrate 100 . The target material may include any biomaterial to be detected, although the target material is not limited to biomaterial. In one embodiment, the biomaterial probe may include at least one biomaterial monomer. The microarray substrate 100 may be used in various reactions such as a biological or biochemical reaction. The microarray substrate 100 may be formed of a material, for example, quartz, silicon, glass, metal, plastic, ceramic, or other materials with similar characteristics, for coupling the biomaterial probe thereto, wherein the biomaterial probe is capable of being coupled to the target material. For example, in one embodiment the microarray substrate 100 may be formed of silicon, quartz or glass. Embodiments of the microarray substrate 100 may have a flat, bead, or spherical shape, but the disclosure is not limited thereto. For example, in one embodiment the microarray substrate 100 may have a flat shape. In addition, the microarray substrate 100 may include a predetermined region where the biomaterial probe is disposed. The region may be determined according to the use and kind of microarray substrate 100 .
The package substrate 200 may be formed of a material, for example, plastic, that is capable of being coupled to a bottom surface 120 of the microarray substrate 100 . In the present embodiment, the package substrate 200 is flush with the microarray substrate 100 . The package substrate 200 includes a microarray accommodation unit 210 to which the microarray substrate 100 is fixed. The microarray accommodation unit 210 may have a length, area or volume that varies according to a predetermined length, area or volume of the microarray substrate 100 . The microarray accommodation unit 210 may include a bottom 220 and a sidewall 230 that constitute, i.e., define, a space in which the microarray substrate 100 is fixed.
The bottom 220 is a portion to which the bottom surface 120 of the microarray substrate 100 is attached. The bottom 220 may include an opening 400 formed through the package substrate 200 . The opening 400 may define a fixing point for fixing the microarray substrate 100 on the bottom surface 120 of the microarray substrate 100 during measurements of focusing and leveling, which are performed by the microarray analyzing device.
At least one concave portion 240 is disposed on the bottom 220 . Referring to FIGS. 1 and 2 , a cross section of the concave portion 240 may have a rectangular shape, a triangular shape, a semicircular shape, an elliptical shape or various other similar shapes. By disposing the concave portion 240 on the bottom 220 , a surface area of the bottom 220 is greater than a surface area of the bottom surface 120 of the microarray substrate 100 , within an area including the attached bottom surface 120 of the microarray substrate 100 . That is, in the region where the bottom 220 and the microarray substrate 100 are aligned, the bottom 220 has a larger surface area. In this case, when adhesives 300 are disposed in a space between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 in order to adhere the microarray substrate 100 and the package substrate 200 to each other, the adhesives 300 fill and cover the concave portion 240 .
The sidewall 230 is connected to the bottom 220 of the microarray accommodation unit, and faces a side surface 130 of the microarray substrate 100 . Referring to FIGS. 1 and 2 , in the presented embodiment, a height of the sidewall 230 may be substantially equal to a height of the microarray substrate 100 , however, alternative embodiments may include alternative configurations. When the microarray substrate 100 is adhered to the microarray accommodation unit 210 , the microarray substrate 100 is fixed to the bottom 220 , and is simultaneously fixed by the sidewall 230 , and thus a location of the microarray substrate 100 does not deviate from an allowable range of an image acquisition region of the optical scanner. In one embodiment, the sidewall 230 is directly adjacent to, and contacts, the side surface 130 of the microarray substrate 100 . Embodiments include configurations wherein one or more of the sidewalls 230 on opposing sides of the microarray substrate 100 may contact the side surfaces 130 of the microarray substrate.
In order to adhere the microarray substrate 100 and the package substrate 200 to each other, the adhesives 300 are disposed in the space between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 , and fill and cover the concave portion 240 . In one embodiment, the adhesives 300 may be ultraviolet (“UV”) curable adhesives.
When the microarray substrate 100 and the package substrate 200 are adhered to each other by the adhesives 300 , the adhesives 300 may be contracted at an adhesion surface between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 since the adhesives 300 may shrink as they are hardened, e.g., during curing or drying, thereby causing deformation of the microarray substrate 100 and/or the package substrate 200 . When the microarray substrate 100 formed of silicon and the package substrate 200 formed of plastic are adhered to each other by the UV curable adhesives 300 , the adhesives 300 may be contracted due to the hardening of the adhesives 300 , and thus a volume of the adhesives 300 may be reduced, thereby causing deformation of the microarray substrate 100 and/or the package substrate 200 . Due to the deformation, flatness of the microarray package device may deteriorate, and thus it may be difficult to obtain reliable analysis results from the microarray analyzing device, e.g., the optical scanner.
However, in the microarray package device according to the present embodiment, the adhesives 300 are disposed in the space between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 , and fill and cover the concave portion 240 , thereby reducing the contraction of the adhesives 300 and the deformation of the microarray substrate 100 and/or the package substrate 200 due to the hardening of the adhesives 300 . When the adhesives 300 fill and cover the concave portion 240 , the adhesives 300 contact a greater area of the bottom 220 of the package substrate 200 than that of the bottom surface 120 of the microarray substrate 100 . Thus, a distortion due to contraction caused by the hardening of the adhesives 300 may be reduced, thereby reducing the deformation of the microarray substrate 100 and/or the package substrate 200 .
The microarray package device may be manufactured by providing the microarray substrate 100 on which the biomaterial probe is disposed on the front surface 110 of the microarray substrate 100 ; providing the package substrate 200 including the microarray accommodation unit 210 including the bottom 220 corresponding to the bottom surface 120 of the microarray substrate 100 and including at least one concave portion 240 disposed in a region to which the bottom surface 120 is attached, and the sidewall 230 connected to the bottom 220 and corresponding to the side surface 130 of the microarray substrate 100 ; and adhering the microarray substrate 100 and the package substrate 200 to each other by disposing adhesive 300 in the space between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 so as to fill and cover the concave portion 240 .
FIG. 3 is a cross-sectional view illustrating an embodiment where the adhesives 300 are distributed in a space between the side surface 130 of the microarray substrate 100 and the sidewall 230 of the package substrate 200 of the microarray package device, according to a capillary phenomenon.
When the microarray substrate 100 and the package substrate 200 are adhered to each other by the adhesives 300 , since the adhesives 300 disposed between the adhesion surface between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 are in a fluid state, the adhesives 300 may be distributed in a narrow space between the side surface 130 of the microarray substrate 100 and the sidewall 230 of the package substrate 200 according to a capillary phenomenon. Thus, the adhesives 300 may contract due to the hardening of the adhesives 300 between the side surface 130 of the microarray substrate 100 and the sidewall 230 of the package substrate 200 , and the microarray substrate 100 and/or the package substrate 200 may be deformed. Thus, flatness of the microarray package device may deteriorate, and thus it may be difficult to obtain reliable analysis results from the microarray analyzing device, e.g., the optical scanner.
FIG. 4 is a cross-sectional view of another embodiment of a microarray package device including the sidewall 230 including a protrusion 250 which prevents distortion of the microarray substrate 100 or the package substrate 200 due to a capillary phenomenon according to the present disclosure.
The sidewall 230 includes at least one protrusion 250 that protrudes towards the side surface 130 of the microarray substrate 100 . A shape of the protrusion 250 is not particularly limited. The protrusion 250 protrudes from the sidewall 230 to the side surface 130 of the microarray substrate 100 . In addition, in another embodiment, the protrusion 250 may extend from the bottom 220 . Thus, the side surface 130 of the microarray substrate 100 may be fixed to the microarray accommodation unit 210 by the protrusion 250 , and a predetermined space may be formed between the sidewall 230 and the side surface 130 of the microarray substrate 100 except for a region corresponding to the protrusion 250 .
In the microarray package device according to the present embodiment, since at least one protrusion 250 protruding towards the side surface 130 of the microarray substrate 100 is disposed on the sidewall 230 of the microarray accommodation unit 210 , the microarray substrate 100 is fixed by the protrusion 250 and does not deviate from an allowable range of an image acquisition region of the optical scanner. That is, the protrusion 250 prevents lateral movement of the microarray substrate 100 from outside of a predetermined range. In addition, since the space between the sidewall 230 and the side surface 130 of the microarray substrate 100 in regions not corresponding to the protrusion 250 has a predetermined width, the distribution of the adhesives 300 due to a capillary phenomenon may be prevented. Thus, the contraction of the adhesives 300 due to the hardening of the adhesives 300 may be reduced between the side surface 130 of the microarray substrate 100 and the sidewall 230 , thereby reducing the deformation of the microarray substrate 100 and/or the package substrate 200 . Although the present embodiments have been illustrated such that the protrusion 250 is separate from the sidewall 230 of the package substrate 200 , alternative embodiments include configurations wherein the protrusion 250 is formed as a single, solitary and indivisible component of the package substrate 200 , e.g., the protrusion 250 and the package substrate 200 may be simultaneously formed via an injection molding process.
FIG. 5A is a top plan view of the package substrate 200 , according to an embodiment of the present disclosure. FIG. 5B is a top plan view of an embodiment where the microarray substrate 100 is adhered to the package substrate 200 by the adhesives 300 , according to the present disclosure.
Referring to FIGS. 5A and 5B , the package substrate 200 includes the concave portion 240 disposed on the bottom 220 of the microarray accommodation unit 210 to which the microarray substrate 100 is fixed, and the protrusion 250 disposed on the sidewall 230 of the microarray accommodation unit 210 . As illustrated in FIGS. 5A and 5B , the concave portion 240 is illustrated as being a continuous element and the protrusion 250 is illustrated as being discontinuous; however, alternative embodiments include configurations wherein either the concave portion 240 and the protrusion 250 are both continuous, both discontinuous, or a combination of both continuous and discontinuous. When the microarray substrate 100 is fixed to the microarray accommodation unit 210 of the package substrate 200 by the adhesives 300 , the bottom surface 120 of the microarray substrate 100 is adhered to the bottom 220 including the concave portion 240 , and the side surface 130 of the microarray substrate 100 is laterally fixed by the protrusion 250 . Thus, the adhesives 300 are disposed in the space between the bottom surface 120 of the microarray substrate 100 and the bottom 220 of the microarray accommodation unit 210 , and fill and cover the concave portion 240 . In such an embodiment, the contraction of the adhesives 300 due to the hardening of the adhesives 300 may be reduced, and the deformation of the microarray substrate 100 and/or the package substrate 200 may be reduced. The microarray substrate 100 may be fixed by the protrusion 250 , and thus the microarray substrate 100 may not deviate from an allowable range of an image acquisition region of the microarray analyzing device, e.g., an optical scanner. Since the space between the sidewall 230 except for the protrusion 250 and the side surface 130 of the microarray substrate 100 is sufficiently wide, the distribution of the adhesives 300 may not occur, and the contraction of the adhesives 300 due to the hardening of the adhesives 300 between the side surface 130 of the microarray substrate 100 and the sidewall 230 may be reduced, thereby reducing the stress for deformation exerted to the microarray substrate 100 and/or the package substrate 200 .
FIGS. 6A through 6D are images showing measuring results from a microarray analyzing device using a microarray package device, wherein the measuring is performed by an optical scanner, according to an embodiment of the present disclosure.
A package substrate (96.0×30.0×3.0 mm3) formed of plastic, adhesives (such as a UV-adhesive, Loctite 3103, ˜10,000 cP, from Henkel™), a microarray substrate (15.2×23.2×0.7 mm3) formed of silicon, and a solution for nucleic acid hybridization were prepared. Two types of package substrates were prepared. That is, the first type package substrate was formed as a comparative embodiment and did not include a concave portion disposed on a bottom surface of a microarray accommodation unit and a protrusion disposed on a sidewall of the microarray accommodation unit, and the second type package substrate was formed as an embodiment of the present disclosure and included the concave portion disposed on the bottom surface of the microarray accommodation unit and the protrusion disposed on the sidewall of the microarray accommodation unit (the remaining configurations of the package substrates were the same). The solution included a predetermined labeled target DNA, 12×SSPET (1.8M NaCl, Triton X-100 0.2%), distilled water, and 100% concentration of formamide. Predetermined amounts of adhesives were respectively coated on the bottom surfaces of the microarray accommodation units of the first and second package substrates using an adhesive ejector. Each surface to which the adhesives were coated was adhered to the bottom surface of the microarray substrate, and about 1 kg of weight was applied to the microarray substrate while a biomaterial probe region of the microarray substrate may not be contaminated, and thus the microarray substrate was adhered to the package substrate. Then, ultraviolet rays were irradiated to the adhesives to cause the hardening of the adhesives.
The solution was introduced to the microarray package devices using the first and second type package substrates, and nucleic acid hybridization was performed for about 4 hours at a temperature of about 50° C. After the nucleic acid hybridization was performed, the resultant devices were primarily washed using a 3×SSPET solution for about 5 minutes, and were secondarily washed using a 0.5×SSPET solution for about 5 minutes. Thus, DNA where the nucleic acid hybridization was not performed and a fluorescent labels were removed from front surfaces of microarray substrates. Then, the solution remaining on the front surfaces of the microarray substrates was removed by a centrifugal separator (1500 rpm, 1 minute), the results of the nucleic acid hybridization of the front surfaces of the microarray substrates were observed using a microarray optical scanner to obtain image data.
In order to determine a degree of deformation of the microarray substrates and the first and second type package substrates, image data regarding a portion (hereinafter, referred to as “panel number 10”) that approximately corresponds to an edge of the surface of the microarray substrate, and a portion (hereinafter, referred to as “panel number 261”) that approximately correspond to a center of the surface of the microarray substrate were acquired. That is, the region 10 is disposed near an edge of the microarray substrate and the region 261 is disposed near a center of the microarray substrate, as seen from a top plan view.
FIGS. 6A and 6B are fluorescence images of a microarray substrate using a microarray substrate including the first type package substrate after hybridization. FIGS. 6C and 6D are fluorescence images of a microarray substrate using a microarray substrate including the second type package substrate after hybridization, wherein the second type package is an embodiment of a package substrate according to the present disclosure. In addition, FIGS. 6A and 6C show the image data regarding the edge of the microarray substrate (panel number 10), and FIGS. 6B and 6D show the image data regarding the center of the microarray substrate (panel number 261). As a result, when the image of the panel number 10 of FIG. 6A and the image of the panel number 261 of FIG. 6B are compared, the image of the panel number 261 of FIG. 6B was blurred. However, when the image of the panel number 10 of FIG. 6C and the image of the panel number 261 of FIG. 6D , the image of the panel number 261 of FIG. 6D had little or no blurring effects.
As described above, according to the one or more of the above embodiments of the present disclosure, the microarray package device may derive structurally stable and reliable experimental results, in an analyzing process of a microarray substrate.
In addition, as described above, a method of fabricating the microarray package device that may derive structurally stable and reliable experimental results, in an analyzing process of a microarray substrate is provided.
It should be understood that the exemplary embodiments described therein should be considered in a descriptive sense only and not for purposes of limitation. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments. | A microarray package device and a method of manufacturing the same. An effective microarray analyzing reaction is performed by using the microarray package device that provides structural stability and reliable experimental results. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Patent Application No. 61/367,598, titled “SYSTEMS AND METHODS FOR ADVANCED CARD PRINTING,” filed Jul. 26, 2010, which is hereby incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
This invention relates to magnetic cards and devices and associated payment systems.
A traditional card embosser physically punches a payment card number partially through one surface of a card such that the payment card number extends from the other surface of the card. Such a traditional card embosser decreases the structural integrity of the card and, as such, reduces the durability of the card.
A traditional card engraver physically engraves a payment card number partially through one surface of a card. Such a traditional card engraver decreases the structural integrity of the card and, as such, reduces the durability of the card.
It is therefore desirable to increase the whimsical and festive nature of a card without decreasing the structural integrity of the card.
SUMMARY OF THE INVENTION
Systems and methods of card printing are provided that increase the whimsical and festive nature of a card without decreasing the structural integrity of the card. Particularly embossed and/or engraved indicia may be provided on the surface of a card without decreasing the structural integrity of the card.
A card may include a dynamic magnetic communications device. Such a dynamic magnetic communications device may take the form of a magnetic encoder or a magnetic emulator. A magnetic encoder may change the information located on a magnetic medium such that a magnetic stripe reader may read changed magnetic information from the magnetic medium. A magnetic emulator may generate electromagnetic fields that directly communicate data to a magnetic stripe reader. Such a magnetic emulator may communicate data serially to a read-head of the magnetic stripe reader.
All, or substantially all, of the front as well as the back of a card may be a display (e.g., bi-stable, non bi-stable, LCD, LED, or electrochromic display). Electrodes of a display may be coupled to one or more capacitive touch sensors such that a display may be provided as a touch-screen display. Any type of touch-screen display may be utilized. Such touch-screen displays may be operable of determining multiple points of touch. Accordingly, a barcode may be displayed across all, or substantially all, of a surface of a card. In doing so, computer vision equipment such as barcode readers may be less susceptible to errors in reading a displayed barcode.
A card may include a number of output devices to output dynamic information. For example, a card may include one or more RFIDs or IC chips to communicate to one or more RFID readers or IC chip readers, respectively. A card may include devices to receive information. For example, an RFID and IC chip may both receive information and communicate information to an RFID and IC chip reader, respectively. A device for receiving wireless information signals may be provided. A light sensing device or sound sensing device may be utilized to receive information wirelessly. A card may include a central processor that communicates data through one or more output devices simultaneously (e.g., an RFID, IC chip, and a dynamic magnetic stripe communications device). The central processor may receive information from one or more input devices simultaneously (e.g., an RFID, IC chip, dynamic magnetic stripe devices, light sensing device, and a sound sensing device). A processor may be coupled to surface contacts such that the processor may perform the processing capabilities of, for example, an EMV chip. The processor may be laminated over and not exposed such that such a processor is not exposed on the surface of the card.
A card may be provided with a button in which the activation of the button causes a code to be communicated through a dynamic magnetic stripe communications device (e.g., the subsequent time a read-head detector on the card detects a read-head). The code may be indicative of, for example, a feature (e.g., a payment feature). The code may be received by the card via manual input (e.g., onto buttons of the card) or via a wireless transmission (e.g., via light, electromagnetic communications, sound, or other wireless signals). A code may be communicated from a webpage (e.g., via light and/or sound) to a card. A card may include a display such that a received code may be visually displayed to a user. In doing so, the user may be provided with a way to select, and use, the code via both an in-store setting (e.g., via a magnetic stripe reader) or an online setting (e.g., by reading the code from a display and entering the code into a text box on a checkout page of an online purchase transaction). A remote server, such as a payment authorization server, may receive the code and may process a payment differently based on the code received. For example, a code may be a security code to authorize a purchase transaction. A code may provide a payment feature such that a purchase may be made with points, debit, credit, installment payments, or deferred payments via a single payment account number (e.g., a credit card number) to identify a user and a payment feature code to select the type of payment a user desires to utilize.
A dynamic magnetic stripe communications device may include a magnetic emulator that comprises an inductor (e.g., a coil). Current may be provided through this coil to create an electromagnetic field operable to communicate with the read-head of a magnetic stripe reader. The drive circuit may fluctuate the amount of current travelling through the coil such that a track of magnetic stripe data may be communicated to a read-head of a magnetic stripe reader. A switch (e.g., a transistor) may be provided to enable or disable the flow of current according to, for example, a frequency/double-frequency (F2F) encoding algorithm. In doing so, bits of data may be communicated.
Electronics may be embedded between two layers of a polymer (e.g., a PVC or non-PVC polymer). One or more liquid polymers may be provided between these two layers. The liquid polymer(s) may, for example, be hardened via a reaction between the polymers (or other material), temperature, or via light (e.g., an ultraviolet or blue spectrum light) such that the electronics become embedded between the two layers of the polymer and a card is formed.
Layers of colored liquid polymer may be placed on the obverse and reverse surfaces of the card and hardened via a variety of methods. For example, the polymer may be hardened via a reaction with a material (e.g., chemical), temperature, or via light (e.g., an ultraviolet or blue spectrum light). Various layers of colored polymer may be provided in order to form indicia on the obverse and reverse side of the card. Such a printing technique may be utilized, for example, on a mobile telephonic device used for payments.
Layers of colored polymer may be built up, for example, in order to form indicia that extends outwardly from the card. Similarly, layers may be built up to form indicia that is formed via troughs in the layers of colored polymer. Both troughs and extensions may be provided to form indicia. Such indicia may take the form of, for example, a payment card number (e.g., debit account number, pre-paid account number, rewards account number, credit account number, or gift account number). Such indicia may take the form of a user's name, one or more security codes, expiration date, bank issuer logo, technology provider logo, network association logo, security indicia, or any other type of indicia.
The layer of solid polymer above and/or below the embedded electronics (e.g., a layer of PVC or non-PVC) may be for example, approximately 3 thousandths to 6 thousandths of an inch thick (e.g., approximately 5 thousandths of an inch thick). The layers of colored liquid polymer sprayed onto the surface of such layers of solid polymer may be, for example, approximately one tenth of a thousandth of an inch to one half of a thousandth of an inch (e.g., approximately 0.15 of a thousandth of an inch). Different layers of colored liquid polymer may be different thicknesses. For example, one layer may be between, for example, one quarter of a thousandth of an inch and one half of a thousandth of an inch (e.g., approximately one quarter of a thousandth of an inch) and another layer may be between one tenth and two tenths of a thousandth of an inch (e.g., approximately two tenths of a thousandth of an inch). The liquid polymer may be hardened, for example, via a reaction (e.g., a reaction with a material, temperature, the atmosphere, or light). The solid layer of polymer above and below the electronics may be, for example, transparent or non-transparent (e.g., a non-transparent white). The colored layers of liquid polymer may be transparent or non-transparent and may include the colors of approximately white, yellow, blue, red, and black. Transparent liquid polymer may also be sprayed onto the surface of the card and hardened. Additional layers of material may be provided anywhere on the card (e.g., between a solid layer of polymer and sprayed layers of liquid polymer that is later hardened).
Accordingly, printing may be selectively applied anywhere on the surface of a card. Accordingly, a solid layer of transparent polymer may be provided and the electronics package may include a display, light source, and/or a light sensor. No printing may be selectively applied about such a display, light source, and/or a light sensor. In this manner, a printed card may be provided that has no printing over areas where maximum transparency is desired (e.g., around components that provide or receive light).
BRIEF DESCRIPTION OF THE DRAWINGS
The principles and advantages of the present invention can be more clearly understood from the following detailed description considered in conjunction with the following drawings, in which the same reference numerals denote the same structural elements throughout, and in which:
FIG. 1 is an illustration of cards constructed in accordance with the principles of the present invention;
FIG. 2 is an illustration of a card constructed in accordance with the principles of the present invention;
FIG. 3 is an illustration of a card constructed in accordance with the principles of the present invention;
FIG. 4 are illustrations of cards constructed in accordance with the principles of the present invention;
FIG. 5 are illustrations of cards constructed in accordance with the principles of the present invention;
FIG. 6 are illustrations of cards constructed in accordance with the principles of the present invention;
FIG. 7 is an illustration of a card constructed in accordance with the principles of the present invention;
FIG. 8 is an illustration of a card constructed in accordance with the principles of the present invention; and
FIG. 9 is an illustration of a card constructed in accordance with the principles of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows card 100 that may include, for example, a dynamic number that may be entirely, or partially, displayed via display 112 . A dynamic number may include a permanent portion such as, for example, permanent portion 111 . Permanent portion 111 may be printed as well as embossed or laser etched on card 100 . Multiple displays may be provided on a card. For example, display 113 may be utilized to display a dynamic code such as a dynamic security code. Display 125 may also be provided to display logos, barcodes, as well as multiple lines of information. A display may be a bi-stable display or non bi-stable display. Permanent information 120 may also be included and may include information such as information specific to a user (e.g., a user's name or username) or information specific to a card (e.g., a card issue date and/or a card expiration date). Card 100 may include one or more buttons such as buttons 130 - 134 . Such buttons may be mechanical buttons, capacitive buttons, or a combination or mechanical and capacitive buttons. Card 100 may include button 199 . Button 199 may be used, for example, to communicate information through dynamic magnetic stripe communications device 101 indicative of a user's desire to communicate a single track of magnetic stripe information. Persons skilled in the art will appreciate that pressing a button (e.g., button 199 ) may cause information to be communicated through device 101 when an associated read-head detector detects the presence of a read-head of a magnetic stripe reader. Button 198 may be utilized to communicate (e.g., after button 198 is pressed and after a read-head detects a read-head of a reader) information indicative of a user selection (e.g., to communicate two tracks of magnetic stripe data). Multiple buttons may be provided on a card and each button may be associated with different user selections. Light sensor 127 may be provided, for example, to receive information from a display (e.g., a display of a mobile telephonic device or a laptop computer). Display 125 may allow a user to select (e.g., via buttons) options on the display that instruct the card to communicate (e.g., via a dynamic magnetic stripe communications device, RFID, or exposed IC chip) to use a debit account, credit account, pre-paid account, or point account for a payment transaction. Colored liquid polymer may be provided on the surface of the card in layers to form, for example, full-color indicia.
Architecture 150 may be utilized with any card. Architecture 150 may include processor 135 . Processor 135 may have on-board memory for storing information (e.g., drive code). Any number of components may communicate to processor 135 and/or receive communications from processor 135 . For example, one or more displays (e.g., display 140 ) may be coupled to processor 135 . Persons skilled in the art will appreciate that components may be placed between particular components and processor 135 . For example, a display driver circuit may be coupled between display 140 and processor 135 . Memory 142 may be coupled to processor 135 . Memory 142 may include data that is unique to a particular card. For example, memory 142 may store discretionary data codes associated with buttons of card 150 . Such codes may be recognized by remote servers to effect particular actions. For example, a code may be stored on memory 142 that causes a promotion to be implemented by a remote server (e.g., a remote server coupled to a card issuer's website). Memory 142 may store types of promotions that a user may have downloaded to the device and selected on the device for use. Each promotion may be associated with a button. Or, for example, a user may scroll through a list of promotions on a display on the front of the card (e.g., using buttons to scroll through the list). A user may select the type of payment on card 100 via manual input interfaces corresponding to displayed options on display 125 . Selected information may be communicated to a magnetic stripe reader via a dynamic magnetic stripe communications device. Selected information may also be communicated to a device (e.g., a mobile telephonic device) having a capacitive sensor or other type of touch sensitive sensor.
Card 100 may include, for example, any number of light sensors 127 . Light sensors 127 may be utilized such that a display screen, or other light emitting device, may communicate information to light sensors 127 via light.
Any number of reader communication devices may be included in architecture 150 . For example, IC chip 152 may be included to communicate information to an IC chip reader. IC chip 152 may be, for example, an EMV chip. As per another example, RFID 151 may be included to communicate information to an RFID reader. A magnetic stripe communications device may also be included to communicate information to a magnetic stripe reader. Such a magnetic stripe communications device may provide electromagnetic signals to a magnetic stripe reader. Different electromagnetic signals may be communicated to a magnetic stripe reader to provide different tracks of data. For example, electromagnetic field generators 170 , 180 , and 185 may be included to communicate separate tracks of information to a magnetic stripe reader. Such electromagnetic field generators may include a coil wrapped around one or more materials (e.g., a soft-magnetic material and a non-magnetic material). Each electromagnetic field generator may communicate information serially to a receiver of a magnetic stripe reader for particular magnetic stripe track. Read-head detectors 171 and 172 may be utilized to sense the presence of a magnetic stripe reader (e.g., a read-head housing of a magnetic stripe reader). This sensed information may be communicated to processor 135 to cause processor 135 to communicate information serially from electromagnetic generators 170 , 180 , and 185 to magnetic stripe track receivers in a read-head housing of a magnetic stripe reader. Accordingly, a magnetic stripe communications device may change the information communicated to a magnetic stripe reader at any time. Processor 135 may, for example, communicate user-specific and card-specific information through RFID 151 , IC chip 152 , and electromagnetic generators 170 , 180 , and 185 to card readers coupled to remote information processing servers (e.g., purchase authorization servers). Driving circuitry 141 may be utilized by processor 135 , for example, to control electromagnetic generators 170 , 180 , and 185 .
Architecture 150 may also include, for example, light sensor 143 . Architecture 150 may receive information from light sensor 143 . Processor 135 may determine information received by light sensor 143 .
FIG. 2 shows card 200 that may include solid layers 211 and 212 , laminate 230 (e.g., laminate that was provided as liquid form and then hardened via a reaction), electronics packages 222 , 223 , and 224 . Electronic packages may be provided on a flexible, multiple layer (e.g., several layer) circuit board 221 . Printed polymer layers 201 - 203 and 206 - 208 may be provided (e.g., sprayed) onto the surface of layers 211 and 212 , respectively in a liquid form. The liquid may be hardened via a reaction (e.g., via light, a gas in the atmosphere, another material, or temperature). Each one of printed layers 201 - 203 and 206 - 208 may include one, multiple, or several colors. Such colors may include, for example, white, black, red, blue, magenta, and/or yellow. The layers may be applied at different thicknesses. Accordingly, full-color indicia (e.g., images) may be provided to increase, for example, the whimsical and festive nature of the card as well as increase the structural integrity of the card by providing additional layers of protection to layers 211 and 212 . Persons skilled in the art will appreciate that card 200 may be less than, for example, approximately 35 thousandths of an inch (e.g., less than approximately 33 thousandths of an inch). For example, the card may be approximately between 30 and 34 thousandths of an inch.
FIG. 3 shows card 300 . Card 300 may include, for example, buttons 341 - 343 , and light sensor 330 . Card 300 may include printing selectively applied via one, multiple, or several layers to the surfaces of card 300 . For example, printing may be provided across the obverse surface of the card except over display 350 and light sensor 330 . The printing may provide issuer logo 310 and network association logo 370 as well as payment card number 351 , expiration date 362 , and name 363 . Information 351 , 362 , and 363 may be provided, for example, as troughs in the printing or as extensions of the printing. Accordingly, information 351 , 362 , and 363 may have a three-dimensional perspective. Alternatively, for example, information 351 , 362 , and 363 may be printed to be flush with the rest of the printing such that no three dimensional perspective is provided.
FIG. 4 shows card portions 410 , 420 , 430 , 440 , and 450 . Card portion 410 includes polymer layer 411 and printed layers 412 , 413 , 414 , 415 , 416 , and 417 . Persons skilled in the art will appreciate that printed layers 415 , 416 , and 417 extend and may be provided to provide text (e.g., name, account number, expiration date, and/or security code) or three dimensional portions of an image. Card portion 420 may include printed layers 422 - 425 on top of polymer layer 421 . Persons skilled in the art will appreciate that additional layers of material may be provided between polymer layer 421 and printed layer 422 . Card portion 430 may be provided with printed layers 433 , 434 , and 435 . Person skilled in the art will appreciate that layers 433 - 435 may provide extended lettering/images on a thinner card than if, for example, one or more printed layers are printed between layer 431 and layer 433 . Providing a layer between layer 431 and layer 433 , however, may provide a stronger bond of layer 433 to the card. Persons skilled in the art will appreciate that a printed layer may be provided as a colored liquid plastic that hardens after a reaction (e.g., a reaction to a low-wavelength blue or ultraviolet light). Card portion 440 may include layer 441 and printed layers 442 - 449 . Card portion 450 may include layer 451 and layers 452 - 459 . Person skilled in the art will appreciate that layering vertically and decreasing the area of layers as height increases may provide, for example, a card that is more rounded and durable for certain types of impacts.
FIG. 5 shows card portions 510 and 520 . Card portion 510 may include layer 511 and printed layers 512 - 517 . Persons skilled in the art will appreciate that the portion of layer 513 (as well as layers 513 and 512 ) located under and within the proximity of extended portions (e.g., extended layers 515 , 516 , and 517 ) may be provided to have a different color than layers 515 , 516 , and 517 . Accordingly, if layers 515 - 517 chip off, for example, the indicia represented by layers 515 - 517 may still be determined. Similarly, the area under as well as about layers 515 - 517 may be of the same color as layers 515 - 517 , but different from, for example, the surrounding portions of layers 512 - 514 . Card portion 520 may be, for example, a bird's eye view of the obverse side of a card. Printing 521 may be of a first color while printing 522 and 523 may be of a different color. Printing 533 may be representative of, for example, one, multiple, or several layers and may be any color (e.g., white or black). Printing 522 and 521 may be of the same layer. Printing 524 may be the same color (or a different color) as printing 521 , but printing 524 may be a different color. Accordingly, for example, if layers 525 are extensions and are chipped off, for example, any indicia (e.g., alphanumeric character) of printing 524 may still be read via printing 525 . Printing 521 , 527 , and 528 may each be different colors.
FIG. 6 shows card portions 610 , 620 , 630 , 640 , and 650 . Portion 610 may include, for example, layer 611 and printed layers 612 - 614 . Indicia may be provided, for example, via troughs formed via layers 612 - 614 . Portion 620 may include layer 621 and printed layers 622 - 624 . Portion 630 may include layer 631 and printed layers 632 - 636 . Portion 640 may include layer 641 and printed layers 642 - 649 . Portion 650 may include layer 651 and printed layers 652 - 659 .
FIG. 7 shows card 700 that may include layer 751 , printed layer 752 - 755 . Persons skilled in the art will appreciate that one, multiple, or several layers may be printed over the entire surface of a card after troughs and/or extensions are formed, for example, to form indicia such as payment account numbers, names, expiration dates, loyalty numbers (e.g., frequent flier numbers), status, and other indicia such as images. Such a layer may provide additional structural integrity to a trough or an extension. Extensions may be operable to be imprinted on carbon paper via a payment card imprinter that uses carbon paper to copy information that extends from the surface of a card.
FIG. 8 shows card 800 that includes layer 801 , layer 807 , electronic component(s) 806 , electronic component(s) 808 , and printed layers 802 - 805 . No printing may be provided above electronic component(s) 806 and layer 807 may be transparent such that, for example, a user may view electrical component(s) 808 . Printing may be provided over a component (or a layer over a component). Extensions may be provided around the perimeter of any component in order to, for example, protect the area above the component from scratching or provide a tactile perimeter for users in low visibility conditions. For example, an extended perimeter may be provided around a button so a user may feel the button in low visibility conditions. An extended perimeter may be provided about a display such that if a user places a card on the top of a table the extensions do not allow the surface of the area above a display to touch the surface of the table. Extensions may be formed, for example, by one or more printed areas around a component. For example, a printed layer may be provided on the entire surface of a card (e.g., a white printed layer) and another printed layer (e.g., a layer of a different color) may be provided around a component (e.g., a button) to provide a perimeter around that component. The additional layer may also be a layer printed across the entire surface of a card except over a component (e.g., a button). More than one button may be provided with a perimeter. For example, two, five, or more than five buttons may be provided with a perimeter.
FIG. 9 shows card 900 . The surface may include, for example, printing without printing about one or more of areas 920 , 930 , and 940 . Areas 920 and 940 may correspond to a display and/or hologram. Area 930 may correspond to, for example, a signature panel.
Persons skilled in the art will also appreciate that the present invention is not limited to only the embodiments described. Instead, the present invention more generally involves dynamic information and printing. Persons skilled in the art will also appreciate that the apparatus of the present invention may be implemented in other ways then those described herein. All such modifications are within the scope of the present invention, which is limited only by the claims that follow. | Layers of colored polymers are applied to a surface of a card and are hardened and adhered to a card via light such as ultraviolet or light having a wavelength in the blue spectrum. The layers may be applied to form three dimensional indicia on the surface of the card. For example, letters, numbers, logos, and other indicia (e.g., pictures) may be printed three dimensionally onto the surface of the card. Troughs may be formed via such layering such that indicia is provided as indentations into the added layers. Extensions may be formed via such layering such that indicia is provided as extensions from the added layers. Indicia may be provided via extensions and/or indentations. As such, embossed and/or engraved indicia may be provided on the surface of a card without impacting the structural integrity of the card. | 1 |
TECHNICAL FIELD
[0001] The present invention relates to a fumigant/sterilant, a method of producing such a fumigant/sterilant and a method of fumigation/sterilisation.
[0002] It is particularly suitable for post-harvest fumigation and sterilisation of pathogens in soil and/or stored commodities but it will be appreciated that the invention is not limited to this particular field of use.
BACKGROUND OF THE INVENTION
[0003] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
[0004] Methyl Bromide is a well-known and widely used fumigant. However, this chemical has recently been listed on the Montreal Protocol as an ozone depletory and will not be available after 2005 in developed countries and after 2015 in developing countries. It is becoming imperative to find practical alternatives.
[0005] Other known chemical fumigants such as Methyl IsoThioCyanate, Telone®, Propylene Oxide and Methyl Iodide have been demonstrated as alternatives to Methyl Bromide as pre-plant and post-harvest fumigants. For example, Methyl Iodide (chemical formula CH 3 I), also known as Iodomethane, is a liquid with a boiling point of 42° C. and is an effective soil fumigant for such crops as strawberries, vegetables, melons and nursery products. Similarly, the other above-mentioned Methyl Bromide alternatives are also available in liquid form.
[0006] Although the above list of fumigants is currently used as alternatives to Methyl Bromide in soil fumigation their use in confined space commodity fumigation is not well-known. There remains a need for a post-harvest stored product fumigant that has all the advantages of Methyl Bromide yet can be more easily and effectively applied during fumigation. Furthermore, a fumigant that can be conveniently packed in gas cylinders will make for simple substitution with the Methyl Bromide product.
[0007] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
DISCLOSURE OF THE INVENTION
[0008] According to a first aspect, the present invention provides a fumigant/sterilant comprising an effective amount of cyanogen mixed with a predetermined quantity of carbon dioxide such that in use, the fumigant/sterilant remains below its flammability limit.
[0009] The Applicants have found that such cyanogen (C 2 N 2 ) is a potential Methyl Bromide alternative for fumigation/sterilisation and in particular for soil and stored commodities such as timber. Cyanogen is a very flammable liquefied gas and is reported to be subject to spontaneous combustion in air. While, in some cases, use of a flammable gas in soil and in stack fumigation of timber is an acceptable risk, its use in enclosed spaces, as required for commodity fumigation is a serious health and safety issue.
[0010] The Applicants have found, however, that it is possible to combine cyanogen with carbon dioxide such that in use it remains entirely below its flammability limit.
[0011] The liquefied flammable active chemical, ie cyanogen may be mixed with gaseous carbon dioxide in high pressure industrial gas cylinders as a prepackaged product, or may be mixed on site.
[0012] The fumigant preferably includes 1 to 26 wt % of cyanogen with the corresponding 99 to 72 wt % of carbon dioxide. In a further preferred form, the fumigant includes 1 to 20% cyanogen mixed with a corresponding 99 to 80% of liquid carbon dioxide.
[0013] Such a fumigant/sterilant will consistently remain below the flammability limit of cyanogen and is therefore suitable for a variety of uses including post-harvest fumigation and/or sterilisation of soil and commodities.
[0014] In addition to remaining below the flammability of cyanogen in air, formulating the active chemical with carbon dioxide improves the application and benefits of cyanogen by achieving superior dispensing, dispersion and efficacy in the fumigated commodities.
[0015] According to a second aspect, the present invention provides a method of producing a fumigant/sterilant comprising mixing an effective amount of cyanogen with a predetermined quantity of carbon dioxide such that in use, the fumigant/sterilant remains below its flammability limit.
[0016] As discussed above, such mixing can be achieved on site or alternatively, the method of fumigation may be accomplished by providing pre-packaged fumigants/sterilants comprising a high pressure cylinder of liquid cyanogen and liquid carbon dioxide in the desired quantities. Such a liquid cyanogen/carbon dioxide mix will, upon release, disperse into the atmosphere, act as an effective fumigant/sterilant and remain below the flammability limit of cyanogen in air.
[0017] According to a third aspect, the present invention provides use of a fumigant/sterilant of the first aspect, for fumigating and/or sterilising soil or commodities.
[0018] Unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.
DETAILED DESCRIPTION OF THE INVENTION
[0019] A preferred embodiment of the present invention will now be described, by way of example only.
[0020] In the search for a suitable replacement of Methyl Bromide, the Applicants revisited the chemical cyanogen. As mentioned above, cyanogen is a very flammable liquefied gas and accordingly, it was necessary to determine if it was at all possible to provide a fumigant based on cyanogen which, in use, ie upon release, would pose a significant safety risk. Most fuel vapours and gases are only flammable or explosive at concentrations between their lower (LEL) and upper (UEL) explosion limits. These limits are normally determined by mixing known proportions of the fuel gas with fresh air, containing approximately 21% v/v oxygen. These mixtures are tested for propagation of flame after exposing the mixture to a suitable ignition source.
[0021] The flammability range of concentration tends to reduce as the oxygen content is reduced. The UEL and LEL approach each other and merge at an oxygen concentration beyond width propagation of an explosion is not possible for all proportions of fuel gas in the diluent gas. This oxygen concentration is referred to as the limiting oxygen concentration (LOC).
[0022] The Applicants proposed to determine whether it was possible to prepare a mixture of cyanogen in a suitable inert diluent gas such that when it is mixed with air, it remains below its LEL for all proportions while still remaining effective as a fumigant/sterilant. In use, the maximum amount of active chemical, ie cyanogen is preferred to increase efficacy of the fumigant/sterilant. However, this must be balanced against maintaining a safe operation level below the LEL.
[0023] Cyanogen is a flammable and highly poisonous gas with the following properties
[0024] Chemical formula—C 2 N 2
[0025] Molecular weight—52.4 g/mol
[0026] Flammability limits in air—6-32% v/v
[0027] Exposure limits—TWA 10 ppm
[0028] LC 50 350 ppm/1 hour inhalation—rat
[0029] The apparatus for testing cyanogen flammability in air is shown in FIG. 1 . The apparatus allows continuous metering and mixing of known proportions of cyanogen, carbon dioxide and air. This permitted a number of ignition tests to be made in a relatively short period.
[0030] The apparatus comprises sources of compressed air 1 , carbon dioxide 2 and the active chemical cyanogen 3 . Calibrated flow tubes 4 , 5 and 6 respectively measure the flow rates of air, carbon dioxide and cyanogen and hence the composition of the mixtures. The resultant mixture flows through tube 7 where it is diverted to an oxygen analyser 8 to determine its content, and an ignition tube 9 with ignition source 10 for flammability testing.
[0000] Test Procedure
[0031] After suitable calibration of the cyanogen, air and carbon dioxide flow meters, flammability limit tests were conducted by introduction of a known flow of cyanogen gas into the known flow of air. Gas flow rates were altered to provide a range of values and at least two minutes were allowed to elapse for each adjustment of the flow and any ignition tests to ensure constant concentration.
[0032] Similarly, for the tests involving the addition of carbon dioxide, the proportions of air and CO 2 were set using the previously arrived calibration material and at least two minutes were allowed to elapse between adjustment of the CO 2 /air proportions and ignition tests.
[0033] Ignition tests involved switching a high voltage across an approximately 5 mm gap 10 within the flow ignition tube 9 . A test mixture was judged to be ignitable if a clear propagation of the flame away from the spark was observed. The resultant series of tests was used to “map” the limits of flammability of cyanogen in air, and the cyanogen/CO 2 mixtures in air.
[0034] By way of comparison, two ignition sources were tested to compare the LEL and UEL of the apparatus with the known LEL and UEL of cyanogen in air, ie 6% and 32% v/v.
[0035] Ignition source 1 found an LEL of between 7.5 and 8.1% and a UEL of 25.3 and 28.3%. Ignition source 2 found an LEL of between 5.8 and 6.6% and a UEL of 40.7 and 41.9.
[0036] It was determined that the flammability testing should be undertaken using ignition source 2 as this was more closely matched to the literature values for the LEL, ie the lower limit of explosability.
[0037] A large number of individual tests were conducted with varying cyanogen/CO 2 /air contents. The resultant graph shown in FIG. 2 provides an accurate plot of the flammability limits for cyanogen/CO 2 mixtures in air. This plot shows the characteristic “nose” shaped zone of flammability and includes the practically determined LEL and UEL of cyanogen and carbon dioxide mixtures in air.
[0038] Turning to FIG. 2 , it is now possible to determine what proportion of cyanogen in carbon dioxide will remain inert in all proportions with air. Line A shown in FIG. 2 has the maximum slope that can be achieved whilst still remaining wholly below the experimentally determined lower explosive limits and passing through the origin. This slope indicates that the maximum proportion of cyanogen in carbon dioxide which is inert in all proportions with air, ie approximately 26%.
[0039] Subsequent testing indicated that a maximum of around 26% v/v of cyanogen in carbon dioxide gas was inert in all proportions of air. For reasons of safety, the Applicant has determined a preferred content of around 20% v/v as this gives an additional margin of safety.
[0040] Accordingly, it can be seen that the present Applicants have developed a fumigant/sterilant comprising cyanogen and which in use will remain below its flammability limit in air in all proportions and still remain effective as a fumigant/sterilant.
[0041] The fumigant/sterilant of the invention is useful in a wide variety of environments. There are also many benefits of the flow from using carbon dioxide to dispense the cyanogen. Carbon dioxide provides the required pressure to spray the active chemical as required. In particular, the carbon dioxide supplies the force to dispense the mixture into confined gas tight spaces used for commodity fumigation/sterilisation. The carbon dioxide gas directs and disperses the liquid chemical and vaporises the liquid in space fumigation.
[0042] The use of carbon dioxide with cyanogen also improves efficacy of the cyanogen due to synergism. In particular, even at low levels, the Applicants have found carbon dioxide to be a synergist for many stored product fumigants and its reaction with moisture to form carbonic acid, also assists in the reduction of microbial levels, an issue in sterilisation.
[0043] Carbon dioxide enables the simple transport of the liquid fumigant from a container to a specific treatment zone. Of course, as discussed above, the cyanogen carbon dioxide may be mixed on site or placed into industrial gas cylinders. The thus resultant fumigant and method of fumigation provides a significant advance over conventional techniques. While it is a substitute for methyl bromide product and allows for easy substitution, it is not limited to such use.
[0044] It will be understood that the disclosed fumigant/sterilant, and method of production can be embodied in forms other than that described herein without departing from the spirit of scope of the invention. | A fumigant/sterilant comprising an effective amount of cyanogens mixed with a predetermined amount of carbon dioxide such that, in use, the fumigant/sterilant remains below its flammability limit. A method of producing said fumigant/sterilant is also provided. | 0 |
This application is a division of application Ser. No. 10/741,646 filed Dec. 19, 2003 now abandoned which is a continuation-in-part of application Ser. No. 10/453,002, filed Jun. 3, 2003 now abandoned claiming the benefit of the filing date of provisional application Ser. No. 60/385,082, filed Jun. 3, 2002 entitled SILICA-CALCIUM PHOSPHATE COMPOSITE FOR IMPROVED SYNTHETIC GRAFTED RESORBABILITY AND TISSUE REGENERATION, which are incorporated by reference herein.
FIELD OF THE INVENTION
This invention relates to the administration of pharmaceuticals and more particularly to a method and sustained release composition for the administration of a pharmaceutical directly at the site of a bone defect.
BACKGROUND OF THE INVENTION
Silica-based bioactive glasses and calcium phosphate ceramics have long been known to serve as synthetic materials useful in the promotion of bone formation in repairing bone fractures and the like. These materials are considered bioactive because they bond to bone and enhance bone tissue formation with a variable degree of success.
An estimated 11 million people in the United States have at least one medical device implant. Two types of implants, fixation devices (usually fracture fixation) and artificial joints are used in orthopedic treatments and oral and maxillofacial procedures. Approximately 80% of the fracture fixation requires adjuvant grafting. Among the joint replacement procedures an increasing number are revision surgeries with their adjuvant need for bone grafting.
Current approaches to difficult bone repair problems include utilization of autografts, allografts and synthetic grafts. Although at present auto graft material is preferentially used, there is limitation in its use, including donor site morbidity, limited donor bone supply, anatomical and structural problems and elevated levels of resorption during healing. The use of allografts has a disadvantage of eliciting an immunalogical response due to genetic differences and the risk of reducing transmissible diseases. Considerable attention has been directed to the use of synthetic materials for bone graft, most notably hydroxyapatite, tricalcium phosphate and bioactive glass. The synthetic graft material is also used to form coatings on implants, such as pins and the like, to promote attachment of new bone growth to the implement. In addition, these materials are also used as fillers in biopoloymer composites and drug delivery vehicles.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a new resorbable silica-calcium phosphate bioactive composite (SCPC) that finds utility as a sustained release composition for the release of a pharmaceutical composition over a sustained period of time. As used herein the term “pharmaceutical composition includes any drug, peptide, anti-microbial peptide, enzyme and other growth factors that are used in the treatment, or prevention of disease or as a component of a medication. The composite can be mixed with other materials such as resins, bioglass, ceramics and the like to improve the physical properties of the delivery system.
More particularly, the SCPC is effective in the treatment of various diseases associated with bone reconstruction, such as osteomyelities, by application of the composite carrying a pharmaceutical composition directly in the bone tissue engineering scaffold to provide maintenance of a localized source of the drug and to facilitate bone tissue development and delivery of the drug over a period of time. Several drugs that are used for treatment of diseases can not be administered through the gastrointestinal tract due to their poor physicochemical properties or due to a high first-pass metabolism in the liver or degradation in the acidic atmosphere of the stomach. Digestive enzymes in the intestine or enzymes in the gut wall are responsible for the pre-systemic degradation of many drugs. Conventional administration of such drugs by repetitive injections is inconvenient and causes fluctuation of the blood drug level. In cases of trauma associated with bone loss, one major complication besides the need for bone reconstruction is the development of osteomyetities promoted by bacterial and fungal infection. About of 30% of the cases reported are treated with conventional therapy. Conventional treatment involves the repeated surgical removal of dead bone tissue coupled with repeated irrigation of the wound and prolonged systemic administration of antibiotics. Despite this aggressive approach, amputation is not an uncommon final solution particularly because the therapeutic efficiency of administrated drugs is strongly restricted due to the limited blood flow to the skeletal tissue. As a consequence, the development of more efficient therapy becomes very important.
The improved SCPC contains a relatively high concentration of silica and defines a surface that can contain four different phases; 1) silica modified with calcium and/or phosphorous, 2) unmodified silica/silanol groups required to nucleate calcium phosphate precipitation, 3) calcium phosphate modified with silica and 4) unmodified calcium phosphate. These four different phases ensure the availability of a surface with superior bioactivity as compared to calcium phosphate ceramic or bioactive glass conventionally used as a scaffold to promote bone tissue growth. In addition the presence of sodium in the form of β-NaCaPO 4 has a synergistic effect on the absorbability of protein that contributes to improved bioactivity.
While the resorption and bioactivity of bioactive glass is limited by the diffusion of Ca and P ions from the glass bulk to the surface, the resorption and bioactivity of the SCPC does not depend on the bulk composition. In addition to providing an immediate bioactive surface layer that enhances protein adsorption and cell function, the silicon released from the surface may have a stimulatory effect on bone cell function.
The bioactivity and the resorbability of the SCPC is affected and controlled by its chemical composition, its crystalline structure, the degree of the alkaline environment presented by the SCPC, its porosity and its thermal treatment temperature. For example disruption of the crystalline structure of the bioactive phases caused by the exchange of silica in the calcium phosphate phase and the exchange of phosphate into the silica phase improves the bioactivity of the SCPC. Moreover, the corrosion rate and resorbability are enhanced by this ion exchange in the bioactive phases. Similarly the porosity of the SCPC, which can be controlled during its formation by particle size of the ingredients, the presence of a fugitive agent or a foaming agent, and/or the pressure applied when forming green shapes prior to sintering, improves bioactivity with increasing porosity. It is preferred that the size of the pores be less than 800 μm and it has been found that good results are achieved when pore size ranges from about 0.1 μm to 500 μm The presence of an alkaline environment, such as provided by the presence of sodium ions, has been found to increase the bioactivity of the SCPC. Likewise the sintering temperature effects a change in the bioactivity and resorbability of the SCPC.
In the SCPC that has high calcium phosphate content, the silica is present both in amorphous form and in crystalline form. The crystal form can comprise L-quartz and/or α-cristobalite (tetragonal crystal structure). The silica may be present in amounts ranging from 0.3094 moles to 0.9283 moles. The calcium phosphate portion of the SCPC can be present in many forms such as for example, hydroxyapatite, tricalcium phosphate, dibasic calcium phosphate, calcium pyrophosphate (β-Ca 2 P 2 O 7 (H)) and/or β-NaCaPO 4 (rhenanite). The precise structure of the SCPC will depend on the initial chemical concentration of each component and on the thermal treatment protocol.
DESCRIPTION OF THE FIGURES
FIG. 1 is a plot of adsorbed protein versus the temperature treatment of several samples of composite made in accordance with the invention and conventional bioglass;
FIG. 2 is a plot of the cumulative concentration of vancomycin hydrochloride against time of release; and
FIG. 3 is a bar graph showing the relative activity of vancomycin hydrochloride at various release times.
DESCRIPTION OF THE INVENTION
The SCPC is prepared by forming an aqueous or non-aqueous paste of an organic or inorganic silica salt equivalent to about 0.3 moles to about 0.9 mole of silica and a calcium phosphate. Preferably the silicate salt is sodium silicate although other silicate salts can be used, particularly with the inclusion of a sodium salt or sodium oxide to provide sodium ions to the composite. The calcium phosphate is preferably bicalcium phosphate. The paste may be pressed into pellets for more convenient handling. In the alternative, the sodium silicate and bicalcium phosphate may be mixed as a dry powder.
The mixture, be it in the form of pellets or other formed shape or as a dried powder, is sintered at temperatures ranging from 130° C. to 1200° C. Following thermal treatment, the SCPC material is ready for use such as by forming as granules or into a shape, such as a block, sphere or sheet or to form at least a portion of a suitable prosthesis for implant or direct application on bone being repaired. For example, the composite can be mixed with a ceramic, bio-resin or bioglass to enhance the physical properties of the delivery system. In addition, the delivery system can be deposited as a layer on a device such as a pin for insertion in the bone being repaired.
It is highly preferred that the bioactive composite be porous. Good results can be achieved when porosity ranges from 10 percent to as high as 80 percent by volume of the composite. For the higher porosities it is preferred to include a suitable pore former such as a fugitive material that is consumed during the thermal treatment process. Likewise, pore formation can be initiated in the raw composite mix by including a foaming agent or a fugitive solvent. Pore forming and fugitive agents for use in ceramic composites are well known and are commercially available and the selection of a suitable agent is clearly understood. In many cases the solvent of the composite paste will itself form pores in sufficient number and size as it leaves the paste during thermal treatment. It is preferred that the pores be less than 800 μm to aid in maintaining the structural integrity of the finished composite. The bioactive composite may have a pore size of between about 0.1 μm to about 500 μm and good results are achieved with pore sizes ranging from about 10 μm to about 300 μm
The SCPC has been tested for adsorption of serum protein, a necessary first step to the production of new bone growth around the SCPC, and it was found that protein adsorption varied with the sintering temperature which the material was pretreated at during processing. It was found that protein adsorption dropped as the sintering temperature increased from 130° C. to about 690° C. and thereafter sharply increased between 690° C. and 800° C. Although it is not fully understood, this may be attributed to the transformation of silica from amorphous phase to a crystalline phase which may inhibit protein adsorption onto the surface of the SCPC pretreated in the temperature range 130-690° C., however, the silica is transformed from L-quartz into α-cristobalite (after thermal treatment above 690° C.) which is associated with a significant increase in serum protein adsorption. In addition, the formation of β-NaCaPO 4 which also begins forming at about 690° C. and increases as the treatment temperature increases above about 690° C. is also associated with a significant increase in serum protein adsorption. Regardless of the thermal treatment, however, the SCPC of the present invention absorbs more protein than the standard bioactive glass alone. Also, the disruption of the structure of the SCPC caused by the exchange of silica in the calcium phosphate phase and the exchange of phosphate into the silica phase improves protein adsorption.
Silica containing calcium phosphate composites (SCPCs) have been prepared as described above The SCPCs, identified as C3S1, C1S1 and C1S3 were sintered at temperatures ranging between 355° C. and 800° C. The phase compositions at several sintering temperatures have been determined and are set out in Table 1. The compositions were tested for protein absorption as reported by Ahmed, El-Ghannam and Fouda, biomaterials Forum, 27 th Annual Meeting Transactions, 23, May-June 2001.
TABLE 1
SiO 2
Sample
(Mole)
Temp (° C.)
Phase Composition
C3S1
0.3094
355
L-quartz + β-Ca 2 P 2 O 7 +
β-Ca 3 (PO 4 ) 2 + B-NaCaPO 4
C1S1
0.6193
355
L-quartz + γ-Ca 2 P 2 O 7 +
β-Ca 3 (PO 4 ) 2 + B-NaCaPO 4
C1S3
0.9283
355
A-cristobalite + β-NaCaPO 4
C3S1
0.3094
690
A-cristobalite) + + β-Ca 2 P 2 O 7 +
β-NaCaPO 4
C1S1
0.6193
690
A-cristobalite + β-NaCaPO 4 + L-Quartz
C1S3
0.9283
690
A-cristobalite + β-NaCaPO 4 +
Na 2 Si 3 O 5
C3S1
0.3094
800
A-cristobalite + + β-Ca 2 P 2 O 7 +
β-NaCaPO 4
C1S1
0.6193
800
A-cristobalite + β-NaCaPO 4 + L-quartz
C1S3
0.9283
800
A-cristobalite + β-NaCaPO 4 + L-quartz
The composition of the samples after thermal treatment was determined by X-ray diffraction analysis and scanning electron microscopy. The shift in the 20 in the position of the characteristic signals of the silica and calcium phosphate phases is indicative of the silicate-phosphate ion substitution. The ion substitution exchange resulted in significant decrease in the crystallization temperature in both the silica and calcium phosphate phases. The formation of these crystalline phases at lower temperature increased the bioactivity of the SCPC.
Particles (90-250 μm) from each of the samples were separately immersed in a simulated body fluid comprising fetal bovine serum for 3 hours at 37° C. After immersion the protein was extracted using 1% SDS. Protein concentration was determined using a gold staining dot block technique. For a comparison, a control experiment using bioactive glass particles of the same particle size range was run in parallel. The results are set forth in FIG. 1 where the X-axis represents the temperature at which the ceramic was pretreated at during sintering. After the samples were cooled down to room temperature they were immersed in protein solution. The adsorbed protein was determined as described above. Samples containing a-cristobalite and β-NaCaPO 4 adsorbed statistically significant higher amounts of serum protein than samples containing L-quartz and pyrophosphate. As the amount of the cristobalite increased the adsorption of protein increased.
The composition of the present invention, particularly the C1S3 material, has a strong stimulatory effect on stem cell differentiation into osteoblasts and can be used as a delivery system for mesenchymal stem cells.
The following examples illustrate the system for delivery of an antibiotic. It should be understood that the delivery system is not so limited and will be used for the delivery of any drug molecule, peptides, enzymes and other growth factors for the treatment and prevention of disease.
EXAMPLE 1
One approach to increase the efficiency of bone disease treatment is the use of sustained release systems that include drug supports in synthetic and natural materials. The advantage of a sustained release system of antibiotic in the treatment of osteomyelities is the maintenance of a localized increase of the drug and thus a more effective control of bacterial and fungal growth. Other potential advantages include drug targeting, improved compliance and comfort.
Vancomycin hydrochloride (Vancocine®) solution of 8 mg/ml was prepared in Tris buffer solution (pH 7.21). One milliliter of the drug solution was micropipetted on 0.2 g SCPC particles (C1S3 and C3S1) of grain size 300-425 μm in 20 ml glass vials. The particles were immersed in the drug solution and incubated at 37° C. for 24 hours. The particles were then removed, washed with 1 ml Tris buffer solution (pH 7.21) for 30 sec and dried at 37° C. overnight. For comparison, control samples (C3S1 and C1S3) were immersed in drug-free solution and run in parallel. All samples were performed in triplicates.
To evaluate the kinetics of drug release from the SCPC, the SCPC particles loaded with the drug were immersed in 12 ml of simulated body fluid (SBF), as described in Example 1, and incubated at 370 C. The SBF volume (12 ml) was selected such that its pH does not change during immersion. 2 ml of the SBF were withdrawn and replaced by another fresh 2 ml SBF after 1, 3, 6, 24, and 48 h. At 72 h, 50% of the SBF were replaced day to day up to 4 weeks.
The concentration of vancomycin hydrochloride released from the SCPC into the SBF was calculated by measuring the absorbance of vancomycin hydrochloride at 280 nm using a spectrophotometer. The eluted SBF solution samples were frozen at −4° C. for the microbiological assay.
The mean cumulative release of vancomycin hydrochloride as a function of elution time for C1S3 showed drug release at nearly constant rate for 6 h after immersion followed by first-order release up to 3 days. The average release rate over the entire first-order stage is 33.19699 μg/h. Later, a slower release stage takes place with an average release rate of 1.2 μg/h for the time period 3-28 day. The average release rate from 5-28 day is 1.3
The C1S3 composite showed sustained release of an effective dose of vancomycin hydrochloride over a period of 672 hours (28 days). A biphasic release kinetic is observed; a first-order release followed by a zero order release. The transition from first-order to zero-order release occurred at the interval from day 1-9. The average release rate over the first order regions in the ranges 3-24 h and 24-120 h, 5-9 days are 46.28531 and 11.50703, and 4.24778 μg/h respectively. The average release rate in the time interval 1-28 days was 2.18 μg/h. A plot of the results appears in FIG. 2 which is a plot of the cumulative concentration of the vancomycin hydrochloride released over a period expressed as hours.
The controlled release profile of vancomycin hydrochloride (fast initial release followed by a slower long term release of effective dose up to day 28) indicates that the C1S3 composite exhibits utility as a carrier for antibiotics to treat bone infections. The beneficial two-stage release was observed for all composites (C1S3, C1S1 and C3S1) and makes the composite material superior to other antibiotic-loaded ceramics characterized by a burst release that is usually observed.
Bioactivity of the Released Vancomycin Hydrochloride
The average release rate of vancomycin hydrochloride released during the 28 days immersion in simulated body fluid exceeds the minimum inhibitory concentration for most pathogens commonly isolated in orthopedic infections. The minimum inhibitory concentration, minimum bactericidal concentrations, and breakpoint sensitivity of vancomycin hydrochloride for Staphylococcus aureus were 1.18, 2.34, and 5 mg/L respectively.
EXAMPLE 2
The bioactivity of the vancomycin hydrochloride released from C1S3 was determined using standard disk susceptibility protocol. The disk-susceptibility protocol includes inoculation of agar plate with bacteria ( Staphylococcus aureus ).
Paper disks (6 mm in diameter) were impregnated separately in the solutions which contain the drug released from the delivery systems of Example 1 above after different release time intervals. The impregnated disks were placed separately on the agar plate inoculated with bacteria and the inhibition zone around the disc was measured as a function of time. In addition, the relative activity of the antibiotic released from the composite was calculated using the equation: The relative activity was reported as: Relative activity=(diameter of the sample inhibition zone/maximum inhibition zone)×100
The results, summarized in FIG. 3 , indicate an average relative activity of the antibiotic over the 28 day test period to be in excess of about 80%.
The foregoing examples are by way illustration only and should not be taken as limiting the invention. Although preferred embodiments have been described herein in detail, it is understood by those skilled in the art that variations may be made thereto without departing from the scope of the invention as defined by the claims appended hereto. | A resorbable silica-calcium phosphate bioactive composite that finds utility for drug delivery. The bioactive composite is loaded with a pharmaceutical composition and releases a therapeutically effective amount of a pharmaceutical composition for periods of up the 28 days. | 0 |
TECHNICAL FIELD
[0001] The present invention relates to the pharmaceutical field, and specifically relates to a pharmaceutical composition and use thereof in preparing a medicament for treating hypertension and metabolic syndrome.
BACKGROUND ART
[0002] Hypertension is one of the most common cardiovascular diseases, and is closely related to some of the most fatal human diseases, such as coronary heart disease, cerebrovascular diseases, etc. Although the incidence of hypertension in China is not as high as that in Western countries, it increases year by year. With the improvement of living standards and the degradation of the environment, the number of patients suffered from cardiovascular diseases such as hypertension, hyperlipemia and hypercholesterolemia keeps increasing. According to the report, the number of hypertension patients in China has reached 150 million by the end of 2003, and increases at a rate of 5 million per year. Great attention has been paid all over the world to the researches on hypertension, ranging from pathogenesis to clinical prevention and treatment of the disease. Hypertension mainly impairs the blood vessels of humans, rendering arterial angiosclerosis and arteriarctia, which are generally called “arteriosclerosis”. When hypertension is combined with diabetes mellitus, the damage to blood vessels would become accelerated and more severe, and the conditions of patients would be worsened rapidly, to which active treatment should be applied.
[0003] Amlodipine is a calcium channel blocker that prevents calcium from transmembranely entering myocardial cells and vascular smooth muscle cells, and thus has anti-hypertension effect. Amlodipine exists as two isoforms, levo-amlodipine and dextro-amlodipine, wherein the activity of levo-amlodipine is 1000 times as high as that of the dextroisomer, and twice as high as that of the racemate. Amlodipine exhibits higher selectivity on vascular smooth muscle than that of nifedipine, and can increase cardiac output and coronary flow of the patients suffered from myocardial ischemia, increase myocardial oxygen supply and decrease oxygen consumption, and improve locomotive ability. Additionally, amlodipine may also activate LDL receptor, reduce the accumulation of fat in artery wall, inhibit the synthesis of collagens, and thus has anti-arteriosclerosis effects. The anti-hypertension effect of amlodipine is based on the mechanism of direct relaxation of the vascular smooth muscle. Although the exact angina-relieving mechanism thereof has not been ascertained, amlodipine can expand peripheral arteriola and coronary artery, reduce peripheral resistance, release coronary artery spasm, decrease cardiac after-load, reduce cardiac energy consumption and oxygen requirement, and thus relieve angina.
[0004] Rosuvastatin calcium is a synthesized statin drug which was developed by Shionogi Co., Ltd. (Shionogi Company, Osaka) and assigned to AstraZeneca UK Limited in April, 1998. Rosuvastatin is a selective 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and may be used in the treatment of atheroma, hyperlipemia, familial hypercholesterolemia and similar diseases. The molecular formula of rosuvastatin calcium is shown as follows:
[0000]
[0005] In view of the clinically testing results and the comparison data among statins, rosuvastatin calcium is indeed a “super statin”, which has extremely good antilipemic effects, and is so far the most potent antilipemic drug.
[0006] Chinese Patent Application CN200510094723.3 discloses a pharmaceutical composition comprising 5-40 wt. % of amlodipine besylate and 5-40 wt. % of rosuvastatin calcium, and a method for preparing the same.
[0007] Chinese Patent Application CN200610028434.8 discloses a pharmaceutical composition comprising a therapeutically effective amount of amlodipine and a therapeutically effective amount of rosuvastatin calcium, and a method for preparing the same.
[0008] Although the combination of amlodipine and rosuvastatin could bring both antihypertensive and antilipemic effects as described in the above two patent applications, these effects are not sufficient for hypertensive patients who may have high risk of cardiovascular diseases, as chronic hypertension may result in damages to key organs such as cardiovascular system and kidney. Accordingly, the objective of antihypertensive treatment is not only to reduce the blood pressure to desired level, but also to rectify the coexisting risk factors such as cardiovascular diseases. Meanwhile, a suitable medicament shall be selected to improve metabolic disorders and prognosis of the patients. Therefore, it is desired in clinical treatment to find a multidrug combination therapy which could treat hypertensive diseases, while effectively controlling the incidence of associated cardiovascular diseases, and more potently improving the survival and prognosis of hypertensive patients.
SUMMARY OF THE INVENTION
[0009] The objective of the present invention is to provide a novel pharmaceutical composition for treating hypertension or metabolic syndrome, while effectively controlling the incidence of associated cardiovascular diseases, and more potently improving the survival and prognosis of hypertensive patients. While the blood pressure is reduced to desired level by the antihypertensive therapy, the coexisting risk factors such as cardiovascular diseases are rectified, metabolic disorders and prognosis of the patients are improved, and the survival rate of the hypertensive patients is increased.
[0010] The present invention provides a pharmaceutical composition, which comprises the following active ingredients:
[0011] 1) amlodipine or a pharmaceutically acceptable salt thereof;
[0012] 2) pioglitazone or a pharmaceutically acceptable salt thereof; and
[0013] 3) rosuvastatin or a pharmaceutically acceptable salt thereof.
[0014] In one embodiment of the present invention, the pharmaceutically acceptable salt of amlodipine is selected from besylate, maleate, hydrochloride, formate, acetate, hydrobromate, aspartate, methanesulfonate, sulfate or tartrate.
[0015] In one embodiment of the present invention, amlodipine is levo-amlodipine or a mixture of levo-amlodipine and dextro-amlodipine.
[0016] In one embodiment of the present invention, the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof is 1:(0.1˜18):(0.1˜16), wherein the weight of the pharmaceutically acceptable salt of amlodipine is calculated as amlodipine, the weight of the pharmaceutically acceptable salt of pioglitazone is calculated as pioglitazone, and the weight of the pharmaceutically acceptable salt of rosuvastatin is calculated as rosuvastatin.
[0017] Preferably, the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof is 1:(0.1˜9):(0.1˜8), wherein the weight of the pharmaceutically acceptable salt of amlodipine is calculated as amlodipine, the weight of the pharmaceutically acceptable salt of pioglitazone is calculated as pioglitazone, and the weight of the pharmaceutically acceptable salt of rosuvastatin is calculated as rosuvastatin.
[0018] Preferably, the weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, pioglitazone or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof is 1:(0.1˜4.5):(0.1˜4), wherein the weight of the pharmaceutically acceptable salt of amlodipine is calculated as amlodipine, the weight of the pharmaceutically acceptable salt of pioglitazone is calculated as pioglitazone, and the weight of the pharmaceutically acceptable salt of rosuvastatin is calculated as rosuvastatin.
[0019] In one embodiment of the present invention, the pharmaceutically acceptable salt of pioglitazone in the pharmaceutical composition of the present invention is preferably pioglitazone hydrochloride.
[0020] In one embodiment of the present invention, the pharmaceutically acceptable salt of rosuvastatin in the pharmaceutical composition of the present invention is preferably rosuvastatin calcium.
[0021] In view of recent progress of clinical research in antihypertensive therapy and the trend of the development of hypertensive diseases, the present invention inventively introduces pioglitazone, an anti-diabetes insulin sensitizer, into the existing antihypertensive therapy and achieves extraordinary treatment effects. The experiments demonstrate that the pharmaceutical composition of the present invention not only exhibits significant antihypertensive benefits, but also effectively reduces the damage to key organs such as cardiovascular system and kidney caused by chronic hypertension, effectively rectifies the coexisting risk factors such as cardiovascular diseases, improves metabolic disorders and prognosis of the patients, and achieves good and unexpected synergistic effects in the treatment and control of various cardiovascular complications caused by hypertension. The determination result of cardiac hypertrophy and carotid intima-media thickness in rats demonstrates that the pharmaceutical composition provided by the present invention can reverse cardiac hypertrophy and effectively control the incidence of cardiovascular diseases, which proves its advantages in prevention and treatment of cardiovascular diseases. Meanwhile, the determination result of urinary microalbumin in rats demonstrates that the pharmaceutical composition of the present invention also has renoprotective effects, and can effectively delay the damage to the kidney of hypertension patients.
[0022] It has been confirmed by a great deal of experimental researches that combined administration of one of a mixture of levo-amlodipine and dextro-amlodipine or a pharmaceutically acceptable salt thereof, or the besylate, maleate, hydrochloride, formate, acetate, hydrobromate, aspartate, methanesulfonate, sulfate or tartrate of amlodipine with pioglitazone or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof can also reverse cardiac hypertrophy in rats, exhibit remarkable antihypertensive effects, effectively reduce the damage to key organs such as cardiovascular system and kidney caused by chronic hypertension, effectively rectify the risk factors such as cardiovascular diseases, reduce urinary microalbumin, and protect kidney from damage caused by hypertension. Meanwhile, it can also improve metabolic disorders and exhibit treatment effects in the treatment of metabolic syndrome.
[0023] Accordingly, the present invention provides a use of the pharmaceutical composition of the present invention in preparing a medicament for treating hypertension or metabolic syndrome.
[0024] The present invention also provides a method for treating hypertension or metabolic syndrome with the pharmaceutical composition of the present invention, which comprises administration of an effective amount of the pharmaceutical composition of the present invention to a patient in need of such treatment.
[0025] The present invention also provides a pharmaceutical composition as described above for treating hypertension or metabolic syndrome.
[0026] The term “metabolic syndrome” refers to a pathological condition in which several metabolic disorders coexist in one single patient, and includes obesity (abdominal obesity), insulin resistance, impaired glucose regulation, diabetes mellitus, hypertension, dyslipidemia, microalbunminuria and hyperuricemia, etc. The pharmaceutical composition of the present invention can effectively reduce total cholesterol (TC), high-density lipid cholesterol (HDLC), glycated hemoglobin (HbAlC), fasting blood glucose (FBG), fasting insulin (FINS) and fibrinogen (Fg) in patients with metabolic syndrome, effectively control associated symptoms of cardiovascular diseases, and reduce invalidism rate and fatality rate.
[0027] The term “effective amount” refers to a dosage of the pharmaceutical composition that could produce desired treatment effects in a patient.
[0028] The pharmaceutical composition of the present invention can be formulated into a solid pharmaceutical formulation, such as tablets, capsules, granules, pills, dripping pills, etc., depending on the properties of the drug and the requirements of convenient administration for the patients. Said tablets include general tablets, coated tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, effervescent tablets, chewable tablets, multi-layered tablets, disintegrating tablets, dispersible tablets, sublingual tablets, buccal tablets, implant tablets, soluble tablets, sustained-release tablets, etc. The solid pharmaceutical formulation is employed in the present invention since it has the advantages of convenient carrying and usage, simple and feasible administration route, and good compliance of the patients.
[0029] In one embodiment of the present invention, the pharmaceutical composition of the present invention may be in the form of, but not limited to, tablets, capsules or granules.
[0030] The pharmaceutical composition of the present invention can be formulated following traditional techniques with the addition of traditional additives such as excipients (e.g., lactose, sucrose, glucose, mannose, sorbitol, starch, dextrin, crystalline cellulose, arabic gum, dextran, etc.), lubricants (magnesium stearate, calcium stearate, talc powder, micronized silica gel, boric acid, sodium dodecylsulfate, etc.), binders (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, etc.), disintegrating agents (low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl starch, cross-linked polyvinylpyrrolidone, etc.), emulsifiers (bentonite, magnesium hydroxide, aluminum hydroxide, sodium dodecylsulfate, etc.), stabilizers (methyl p-hydroxybenzoate, benzyl alcohol, phenylethyl alcohol, phenol, sorbic acid, dehydroacetic acid, etc.), flavoring agents (sucrose, flavors, aspartame, cyclodextrin, etc.), diluents, etc.
[0031] Additionally, the pharmaceutical composition of the present invention can also be formulated into sustained-release tablets according to the requirements of the patients, so as to regulate blood pressure effectively and safely, maintain a relatively stable plasma drug concentration and longer acting term by slow release, and have the advantages of reduced toxicity and side effects and convenient administration.
[0032] The sustained-release tablets prepared from the pharmaceutical composition of the present invention uses cellulose derivatives or vinyl polymer as the sustained-release matrix, wherein the matrix may be one or more of methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and acrylic resin.
[0033] The advantages of the pharmaceutical composition according to the present invention lie in the following aspects:
[0034] 1. The present invention inventively introduces pioglitazone, an anti-diabetes insulin sensitizer, or a pharmaceutically acceptable salt thereof into the existing antihypertensive therapy, and achieves very good synergetic antihypertensive effects. The combined administration of amlodipine, a calcium channel blocker (CCB), or a pharmaceutically acceptable salt thereof, with pioglitazone, an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof exhibits good synergetic antihypertensive effects in experimental researches and clinical observations.
[0035] 2. The pharmaceutical composition significantly reduces the incidence and degree of adverse effects. The tri-drug combination administration of an antihypertensive drug+an antihyperglycemic drug+an antilipemic drug results in significant synergetic effect in the treatment of hypertension, which significantly reduces the administration dosage, and significantly reduces the incidence and degree of adverse effects as well.
[0036] 3. Long-term administration of the pharmaceutical composition of the present invention leads to beneficial effects on the long-term survival rate of hypertension patients. It is the most significative clinical problem addressed by the present invention to provide positive effects on the prognosis of the patients. Traditional antihypertensive drugs do not have good prevention and treatment effects on the complications caused by hypertension, such as brain stocks, kidney damage, coronary heart disease, etc., while the pharmaceutical composition of the present invention can treat hypertension, while effectively control the incidence of associated cardiovascular diseases, further improve the survival and prognosis of hypertension patients, reduce the blood pressure to desired level in the antihypertensive treatment, rectify the coexisting risk factors such as cardiovascular diseases, improve metabolic disorders and prognosis of the patients, and increase the survival rate of hypertension patients.
[0037] 4. The pharmaceutical composition of the present invention has various applications. Due to the synergetic effect, the present invention is suitable for various types of hypertension patients, especially patients with stroke-prone hypertension and hypertension-combined kidney damage. Additionally, the present invention also exhibits good effects on hypertension-combined coronary heart disease and angina, peripheral vascular disease, senile hypertension, gestational hypertension and resistant hypertension.
[0038] 5. The pharmaceutical composition of the present invention achieves desired effects in the treatment of metabolic syndrome, which has high morbidity in the current society.
DETAILED DESCRIPTION
[0039] Hereinafter, the invention will be explained in more detail with the following examples. However, the scope of the present invention is not limited thereto. Any changes and modifications that are obvious for those skilled in the art are intended to be included within the scope of the present invention. All references cited herein are hereby entirely incorporated to the description by reference.
[0040] In the following examples, amlodipine refers to amlodipine or a pharmaceutically acceptable salt thereof, levo-amlodipine refers to levo-amlodipine or a pharmaceutically acceptable salt thereof; the weight of the pharmaceutically acceptable salt of amlodipine is calculated as amlodipine, and the weight of pioglitazone hydrochloride is calculated as pioglitazone.
Example 1
Common Tablets
[0041]
[0000]
Rosuvastatin calcium
10 g
Amlodipine
10 g
Pioglitazone hydrochloride
15 g
Starch
140 g
Dextrin
120 g
50% Ethanol
Appropriate amount
Magnesium stearate
1.0 g
[0042] Manufacture process: Prescribed amounts of rosuvastatin calcium, amlodipine, pioglitazone hydrochloride, starch and dextrin were weighed and uniformly mixed. To the mixed powder, an appropriate amount of 50% ethanol was added, and uniformly mixed to obtain a soft material, which was allowed to pass through an 18-mesh nylon screen to prepare wet granules. The wet granules were dried at about 60° C. The moisture content of the dried granules should be controlled below 1.5%. The dried granules were further granulated with a 20-mesh screen, uniformly mixed with magnesium stearate and pressed to obtain the final product.
Example 2
Capsules
[0043]
[0000]
Rosuvastatin calcium
10 g
Levo-amlodipine
10 g
Pioglitazone hydrochloride
10 g
Microcrystalline cellulose
300 g
Micronized silica gel
12 g
[0044] Manufacture process: Prescribed amounts of rosuvastatin calcium, levo-amlodipine, pioglitazone hydrochloride, microcrystalline cellulose and micronized silica gel were weighed and pulverized, screened with a 100-mesh screen, uniformly mixed, and then directly filled into capsules to obtain the final product.
Example 3
Double-Layer Tablets
[0045]
[0000]
Rosuvastatin calcium
40 g
Mannitol
10 g
Lactose
40 g
Microcrystalline cellulose
20 g
6% PVP in 95% ethanol solution
120 g
Magnesium stearate
2 g
[0046] Manufacture process a: Rosuvastatin calcium was screened with a 100-mesh screen, and mannitol, lactose and microcrystalline cellulose were screened with an 80-mesh screen. Prescribed amounts of rosuvastatin calcium, mannitol, lactose and microcrystalline cellulose were weighed and uniformly mixed, to which an appropriate amount of 6% polyvinylpyrrolidone (PVP) in 95% ethanol solution was added to prepare granules. The granules were dried at 60° C. and the dried granules were screened with a 16-mesh screen. Prescribed amount of magnesium stearate was added to the dried granules.
[0000]
Amlodipine
10 g
Pioglitazone hydrochloride
45 g
Pregelatinized starch
50 g
Mannitol
50 g
6% PVP in 95% ethanol solution
100 g
Micronized silica gel
5 g
[0047] Manufacture process b: Amlodipine and pioglitazone hydrochloride were screened with a 100-mesh screen, and pregelatinized starch and mannitol were screened with an 80-mesh screen. Prescribed amounts of amlodipine, pioglitazone hydrochloride, pregelatinized starch and mannitol were weighed and uniformly mixed, to which an appropriate amount of 6% PVP in 95% ethanol solution was added to prepare granules. The granules were dried at 60° C. and the dried granules were screened with a 16-mesh screen. Prescribed amount of micronized silica gel was added to the dried granules.
[0048] The granules manufactured from the manufacture processes a and b were pressed with a double-layer pressing machine to obtain double layer tablets.
Example 4
Dispersible Tablets
[0049]
[0000]
Rosuvastatin calcium
5 g
Levo-amlodipine
10 g
Pioglitazone hydrochloride
5 g
Calcium carboxymethylcellulose
15 g
Crosslinked polyvinylpyrrolidone
15 g
Microcrystalline cellulose
140 g
10% Starch slurry
Appropriate amount
Magnesium stearate
6 g
[0050] Manufacture process: Prescribed amounts of rosuvastatin calcium, levo-amlodipine and pioglitazone hydrochloride were screened with a 100-mesh screen, and calcium carboxymethylcellulose, crosslinked polyvinylpyrrolidone and microcrystalline cellulose were screened with an 80-mesh screen. The above components were uniformly mixed and an appropriate amount of 10% starch slurry was added to prepare granules. Magnesium stearate was added to the granules and the mixture was pressed to obtain the final product.
Example 5
Granules
[0051]
[0000]
Rosuvastatin calcium
40 g
Amlodipine
5 g
Pioglitazone hydrochloride
45 g
Starch
200 g
Dextrin
50 g
Sucrose powder
50 g
80% Ethanol
Appropriate amount
[0052] Manufacture process: Prescribed amounts of rosuvastatin calcium, amlodipine, pioglitazone hydrochloride, starch, dextrin and sucrose powder were weighed and uniformly mixed. To the mixed powder, an appropriate amount of 80% ethanol was added, and uniformly mixed to prepare a soft material, which was allowed to pass through an 18-mesh nylon screen to prepare wet granules. The wet granules were dried at about 60° C., finished with a 20-mesh screen, and packaged to obtain the final product.
Example 6
Disintegrating Tablets
[0053]
[0000]
Rosuvastatin calcium
1 g
Levo-amlodipine
10 g
Pioglitazone hydrochloride
1 g
Crosslinked sodium
10 g
carboxymethylcellulose
Microcrystalline cellulose
100 g
Polyvinylpyrrolidone
20 g
5% PVP in 60% ethanol solution
Appropriate amount
Micronized silica gel
5 g
[0054] Manufacture process: Prescribed amounts of rosuvastatin calcium, levo-amlodipine and pioglitazone hydrochloride were weighed, granulated in a fluidized bed with microcrystalline cellulose as a filler, crosslinked sodium carboxymethylcellulose and polyvinylpyrrolidone as disintegrating agents, 5% PVP in 60% ethanol solution as a binder, and micronized silica gel as a glidant, and then pressed to obtain the final product.
Example 7
Sustained Release Tablets
[0055]
[0000]
Rosuvastatin calcium
10 g
Levo-amlodipine
10 g
Pioglitazone hydrochloride
5 g
Hydroxypropylmethyl cellulose
80 g
Polyvinylpyrrolidone
100 g
Lactose
85 g
Micronized silica gel
100 g
[0056] Manufacture process: Prescribed amounts of rosuvastatin calcium, levo-amlodipine and pioglitazone hydrochloride were uniformly mixed with prescribed amounts of hydroxypropylmethyl cellulose and lactose. Polyvinylpyrrolidone was then added as a binder to prepare granules, which were dried at 40° C. to 80° C. to obtain dried granules. Prescribed amount of micronized silica was added as a lubricant to the dried granules, uniformly mixed, and pressed to obtain the final product.
Example 8
Capsules
[0057]
[0000]
Rosuvastatin calcium
32 g
Levo-amlodipine
2 g
Pioglitazone hydrochloride
36 g
Microcrystalline cellulose
300 g
Micronized silica gel
12 g
[0058] Manufacture process: Prescribed amounts of rosuvastatin calcium, levo-amlodipine, pioglitazone hydrochloride, microcrystalline cellulose and micronized silica gel were pulverized, screened with a 100-mesh screen, uniformly mixed, and then directly filled into capsules to obtain the final product.
Example 9
Treatment Effects of the Pharmaceutical Composition of the Present Invention on Blood Pressure and Cardiac Hypertrophy in Spontaneously Hypertensive Rats
1. Experimental Animals and Animal Groups
[0059] Forty-eight spontaneously hypertensive rats (male, body weight (300±20) g, provided by Pharmacological Center for New Medicine of Shandong New Time Pharmaceutical Co., Ltd.) were fed for one week for acclimation, and then randomly divided into six groups with eight animals in each group.
[0060] Model control group: intragastric administration of same volume of physiological saline;
[0061] P group: 1 mg/(kg·d) of pioglitazone;
[0062] A+R group: 2 mg/(kg·d) of amlodipine+1 mg/(kg·d) of rosuvastatin calcium;
[0063] P+R group: 1 mg/(kg·d) of pioglitazone+1 mg/(kg·d) of rosuvastatin calcium;
[0064] A group: 2 mg/(kg·d) of amlodipine;
[0065] Pharmaceutical composition of the present invention: 2 mg/(kg·d) of amlodipine+1 mg/(kg·d) of pioglitazone+1 mg/(kg·d) of rosuvastatin calcium;
[0066] Each group was given intragastric administration once every day for ten weeks. During the experiment, the diet, survival status and behaviors of the animals were recorded, and the animals were weighted once every day and the doses of administration were adjusted according to the body weights. Animals were sacrificed after ten weeks, and their hearts were taken out to determine the weights of left ventricles and calculate left ventricular indexes.
2. Experimental Methods and Results
2.1 Effects of the Pharmaceutical Composition of the Present Invention on the Blood Pressure of Spontaneously Hypertensive Rats
[0067] Temperature was controlled between 18° C. and 22° C., humidity was controlled between 45% and 65% with natural light indoors. Tail arterial blood pressure of a conscious rat was measured with Intelligent Non-invasive Blood Pressure Monitor BP-2006A (provided by Beijing Softron Co., Ltd.). Blood pressures were measured five times between two and five hours after intragastric administration in the first week, the third week and the sixth week, respectively. The average value of the blood pressures was used as the blood pressure of the sample.
[0000]
TABLE 1
Effects of the pharmaceutical composition of the present invention on the blood
pressure of spontaneously hypertensive rats ( X ± S, n = 8) (mmHg)
After treatment
Groups
Before treatment
First week
Third week
Sixth week
Model group
152 ± 8.1
158 ± 9.2
164 ± 8.7
178 ± 9.2
A + R Group
150 ± 12.3
151 ± 10.5
152 ± 9.6 •
150 ± 7.0 •
P group
151 ± 7.6
157 ± 8.6
162 ± 10.3
170 ± 8.8
P + R group
149 ± 9.4
156 ± 8.9
160 ± 9.2
165 ± 11.3 •
A Group
150 ± 9.0
152 ± 9.5
154 ± 11.4 •
156 ± 10.9 ••
Pharmaceutical composition of
153 ± 13.7
149 ± 7.1
140 ± 16.2 ••▾ * #
135 ± 7.6 ••▾ * #
the present invention
• p < 0.05, compared with the model group,
•• p < 0.01, compared with the model group,
▾ p < 0.05, compared with the A group,
*p < 0.05, compared with the P + R group; and
# p < 0.05, compared with the A + R group.
[0068] The above results indicated that the combination of rosuvastatin, amlodipine and pioglitazone has a synergetic effect on lowering the blood pressure of spontaneously hypertensive rats. As shown from the data of blood pressures measured in the third week and the sixth week, the combined administration of the three drugs exhibited good synergetic effects, no matter the administration of amlodipine and rosuvastatin calcium in combination with pioglitazone, or administration of pioglitazone and rosuvastatin calcium in combination with amlodipine.
2.2. Measurements of Heart Weight, Left Ventricle Weight, Body Weight and Left Ventricular Hypertrophy Index (Left Ventricular Weight/Body Weight):
[0069] After being sacrificed with 10% potassium chloride (2 mmol/L, 1 ml/rat), the rats were weighed. Heart was taken out and aortas and connective tissues outside of the heart were removed. The heart was cleaned by washing, dried with a filter paper, and weighted. The left ventricular was weighed after the atria were removed, and a ratio of left ventricular weight to body weight was calculated.
[0000]
TABLE 2
Effects of the pharmaceutical composition of the present invention
on cardiac hypertrophy of spontaneously hypertensive rats
( X ± S, n = 8) (g)
Left ventricular
Body
Left ventricular
weight/body
Groups
weight
weight
weight (×10 −3 )
Model group
301 ± 12
1.06 ± 0.19
3.52 ± 0.27
A + R Group
304 ± 13
0.91 ± 0.16 •
2.99 ± 0.15 ••
P group
298 ± 12
0.99 ± 0.10
3.33 ± 0.19
P + R group
308 ± 14
0.97 ± 0.13
3.15 ± 0.28 •
A Group
297 ± 15
0.92 ± 0.17
3.10 ± 0.15 ••
Pharmaceutical
303 ± 14
0.75 ± 0.15 ••▾ * #
2.48 ± 0.25 ••▾ * #
composition of the
present invention
• p < 0.05, compared with the model group,
•• p < 0.01, compared with the model group,
▾ p < 0.05, compared with the A group,
*p < 0.05, compared with the P + R group; and
# p < 0.05, compared with the A + R group.
[0070] The results indicated that the combination of rosuvastatin, amlodipine and pioglitazone could effectively reverse left ventricular hypertrophy in spontaneously hypertensive rats, and combined administration of the three drugs exhibits a good synergetic effect in the treatment of cardiac hypertrophy in spontaneously hypertensive rats. Good synergetic effects could be achieved by administration of amlodipine and rosuvastatin calcium in combination with pioglitazone, or administration of pioglitazone and rosuvastatin calcium in combination with amlodipine.
Example 10
Treatment Effects of the Pharmaceutical Composition of the Present Invention on Urinary Microalbumin and Carotid Intima-Media Thickness of the Carotid Arteries in Spontaneously Hypertensive Rats
1. Experimental Animals and Animal Groups
[0071] Forty-eight spontaneously hypertensive rats (male, body weight (300±20) g, provided by the Pharmacological Center for New Medicine of Shandong New Time Pharmaceutical Co., Ltd.) were fed for one week for acclimation, and then randomly divided into six groups with eight rats in each group.
[0072] Model control group: intragastric administration of same volume of physiological saline;
[0073] P group: intragastric administration of 2 mg/(kg·d) of pioglitazone;
[0074] LA+R group: intragastric administration of 1 mg/(kg·d) of levo-amlodipine+1 mg/(kg·d) of rosuvastatin calcium;
[0075] P+R group: intragastric administration of 2 mg/(kg·d) of pioglitazone+1 mg/(kg·d) of rosuvastatin calcium;
[0076] LA group: intragastric administration of 1 mg/(kg·d) of levo-amlodipine;
[0077] Pharmaceutical composition of the present invention: intragastric administration of 1 mg/(kg·d) of levo-amlodipine+2 mg/(kg·d) of pioglitazone+1 mg/(kg·d) of rosuvastatin calcium;
[0078] Each group was given intragastric administration once every day and fed with high sugar and high fat diets for six months. During the experiment, the diet, survival status and behaviors of the animals were recorded, and the animals were weighed once every week and the doses of administration were adjusted according to the body weights.
2. Experimental Methods and Results
2.1. Measurements of Urinary Microalbumin:
[0079] Reagents:
[0080] 1.10% (v/v) glacial acetic acid solution (pH 2.8).
[0081] 2. 0.303 mol/L glycine-glacial acetic acid buffer solution (pH 3.0): 22.72 g of glycine was weighed and diluted with 10% glacial acetic acid solution to 1000 ml, to which 100 mg of NaN 3 was added. The buffer solution can be kept for one year at room temperature after sealed.
[0082] 3. Bromophenol blue (1.924 mmol/L) stock solution: 257.36 mg of BPB was precisely weighed and dissolved to 200 ml with absolute ethanol. The stock solution can be kept for one year in a refrigerator at 4° C.
[0083] 4. Bromophenol blue (0.231 mmol/L) developing agent: to 60 ml of BPB stock solution, 2.5 ml Triton X-100 was added, and then diluted to 500 ml with glycine-glacial acetic acid buffer solution. The developing agent can be kept for one year at room temperature after sealed.
[0084] Collection and detection of samples: rats were taken out and fed in a metabolic cage at the fourth week, the eighth week, the twelfth week and the sixteenth week, respectively, and twelve-hour overnight urinary collection was performed. Urinary amounts were precisely recorded. 4 ml of urine was sampled, treated with sodium azide, and centrifuged at 2000 r/min for 10 min. Supernatant was collected and stored in a freezer at −20° C. before urinary albumin measurement. 2 ml of stored urine of rat was sampled, and 1 ml developing agent was added and uniformly mixed (avoiding the generation of air bubbles). The absorbance A was determined with a UV spectrophotometer at 600 nm.
[0000]
TABLE 3
Effects of the pharmaceutical composition of the present invention
on urinary microalbumin in spontaneously hypertensive rats
( X ± S)
Groups
n
Absorbance A (600 nm)
Model group
8
0.687 ± 0.216
A + R Group
8
0.603 ± 0.232
P group
8
0.568 ± 0.125 •
P + R group
8
0.575 ± 0.161 •
A Group
8
0.617 ± 0.177
Pharmaceutical
8
0.411 ± 0.158 ••
composition of the
present invention
• p < 0.05, compared with the model group,
•• p < 0.01, compared with the model group.
[0085] The results indicated that the combination of rosuvastatin, amlodipine and pioglitazone could decrease urinary microalbumin and protect kidney from the damage caused by hypertension, and exhibited desired effects. Good synergetic effects on urinary microalbumin of spontaneously hypertensive rats were achieved either by administration of amlodipine and rosuvastatin calcium in combination with pioglitazone, or by administration of pioglitazone and rosuvastatin calcium in combination with amlodipine.
2.2. Measurements of Carotid Intima-Media Thickness of the Carotid Arteries
[0086] After the animal was anesthetized and fixed, Even's blue (60 mg/kg) dye was injected via a femoral artery. After 30 minutes, myocardial perfusion was performed with 0.9% physiological saline as a perfusate at a perfusion pressure of 13.3 kPa until the effluent became clear. Then, 4% paraformaldehyde in physiological saline was perfused for 10 minutes for in situ fixation (the perfusion pressure was the same as above). The section of Even's blue-stained carotid artery was taken and further fixed with formalin solution, and three parts, i.e. the front, the middle and the rear parts, respectively, were sampled and embedded in paraffin, and then sliced discontinuously to obtain 8 to 10 layers, which were stained with HE. Three vascular sections were randomly selected and input into a computer image processing system so as to perform a computerized image measurement, thereby calculating the maximum intima thickness, the intima-media thickness, and the ratio of the intima to media thickness.
[0000]
TABLE 4
Effects of the pharmaceutical composition of the present invention on
intima-media thickness in spontaneously hypertensive rats
( X ± S, n = 8)
Maximum intima
Ratio of intima to
Groups
thickness (mm)
media thickness
Model group
0.142 ± 0.031
2.432 ± 0.456
A + R Group
0.094 ± 0.025 •
1.683 ± 0.328 •
P group
0.130 ± 0.026
2.246 ± 0.361
P + R group
0.110 ± 0.028 •
1.923 ± 0.422 •
A Group
0.116 ± 0.030 •
2.125 ± 0.357 •
Pharmaceutical composition
0.062 ± 0.014 ••▾ * #
1.102 ± 0.243 ••▾ * #
of the present invention
• p < 0.05, compared with the model group,
•• p < 0.01, compared with the model group,
▾ p < 0.01, compared with the A group,
*p < 0.05, compared with the P + R group; and
# p < 0.05, compared with the A + R group.
[0087] The results indicated that the combination of rosuvastatin, amlodipine and pioglitazone could effectively improve the intima-media thickness in spontaneously hypertensive rats, and had a good synergetic effect on the carotid intima-media thickness of carotid in spontaneously hypertensive rats. Good synergetic effects were achieved by administration of amlodipine and rosuvastatin calcium in combination with pioglitazone, or by administration of pioglitazone and rosuvastatin calcium in combination with amlodipine.
Example 11
Treatment Effects of the Pharmaceutical Composition of the Present Invention on Patients Suffered from Metabolic Syndrome
1. General Information
[0088] Eighty-eight metabolic syndrome patients were selected from those received treatment in Linyi People's Hospital from May 2007 to May 2008, and randomly divided into a control group and an experimental group.
[0089] Control group: twenty-eight males and sixteen females, whose ages were between 62 and 71 and whose body mass indexes (BMI) were between 25.5 and 30;
[0090] Experimental group: twenty-four males and twenty females, whose ages were between 60 and 70 and whose body mass indexes (BMI) were between 24.5 and 31;
[0091] Before the treatment, all patients were subjected to blood lipids (including total cholesterol (TC), high-density lipid cholesterol (HDLC)) analysis, and detection of glycated hemoglobin (HbAlC), fasting blood glucose (FBG), fasting insulin (FINS) and fibrinogen (Fg).
[0092] Patients suffered from metabolic syndrome were selected according to the diagnostic standards for type-II diabetes mellitus and hypertension made by WHO in 1999 and referring to the diagnostic standards for metabolic syndrome made by US National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) in 2000, while cases of primary hypertension, heart failure (above grade II), diseases in liver, kidney and blood system and like were excluded.
2. Treatment Strategy:
[0093] Patients in the control group were administrated with 15 mg of pioglitazone once every day, and patients in the experimental group were administrated with 5 mg of amlodipine, 7.5 mg of pioglitazone and 5 mg of rosuvastatin calcium, i.e. the proportions as described in Example 1, once every day. After eight weeks of continuous treatment, all of the above parameters were re-determined, in which blood glucose was determined with hexokinase method, blood lipid was determined with esterase method, fibrinogen was determined with coagulation method and chromogenic substrate assay, HbAlC was determined with chromatography, and fasting insulin was determined with chemiluminescence immunoassay.
[0094] Statistical analysis: SPSS software was employed, and test of significance was performed by using a paired sample t test.
3. Treatment Results:
[0095]
[0000]
TABLE 5
Changes of Fg, FINS, HbA1C and TC/HDLC before and after treatment
( X ± S)
Before treatment
After treatment
Parameters
Control group
Experimental group
Control group
Experimental group
FBG (mmol/L)
7.12 ± 2.06
7.08 ± 2.13
6.63 ± 1.65
6.04 ± 1.38* #
FINS (mlU/L)
32.4 ± 7.21
31.6 ± 8.32
25.68 ± 5.34
19.48 ± 5.10* #
HbAlC (%)
6.89 ± 0.65
6.93 ± 0.62
6.39 ± 0.56
5.87 ± 0.52* #
TC/HDLC
4.11 ± 1.26
4.08 ± 1.22
3.75 ± 0.84
3.32 ± 0.67* #
(mmol/L)
Fg (mg/dl)
419.6 ± 89.62
425.0 ± 84.37
392.6 ± 64.51
347.3 ± 58.46* #
*p < 0.05, compared with the experimental group before treatment; and
# p < 0.05, compared with the control group after treatment.
[0096] It can be seen from Table 5 that the values of FBG FINS, HbAlC, TC/HDLC and Fg in the patients suffered from metabolic syndrome before and after treatment with pharmaceutical composition of the present invention show significant differences. Compared with the pioglitazone group, the values of FBG, FINS, HbAlC, TC/HDLC and Fg after treatment with pharmaceutical composition of the present invention also show significant differences. These results indicated that the pharmaceutical composition of the present invention has a reliable and significant treatment effect on metabolic syndrome. | The present invention provides a pharmaceutical composition comprising the following active ingredients: 1) amlodipine or a pharmaceutically acceptable salt thereof, 2) pioglitazone or a pharmaceutically acceptable salt thereof, and 3) rosuvastatin or a pharmaceutically acceptable salt thereof. The present invention also provides use of the pharmaceutical composition in preparing a medicament for treating hypertension or metabolic syndrome. The pharmaceutical composition of the present invention can treat hypertension or metabolic syndrome, while effectively controlling the incidence of associated cardiovascular diseases and more potently improving survival prognosis in hypertensive patients. When blood pressure is lowered to desired level, the risk factors such as cardiovascular diseases are rectified, metabolic disorders and prognosis of patients are improved, and survival rate of hypertensive patients is raised. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention lies in the field of cardiac pacing apparatus and, more particularly, in the area of electrodes, or catheters, used in a cardiac pacing system, for delivering stimulating signals generated by an electronic pacer to the heart.
2. Description of the Prior Art
This specification discloses an electrode as used in cardiac pacing. In much of the literature, the term catheter is employed to describe the same apparatus. For example, the electrode of this invention may also be suitably described as a unilateral catheter having a single electrode, in which description the term electrode would refer to the stimulating tip. In this specification, the term electrode is used with the same meaning as catheter, referring to the entire device for conducting stimulating pulses.
A chronic problem with electrodes as used in cardiac pacing is proper fixation of the distal tip within the heart so that good contact is made with the inner lining of the heart, which is necessary to provide good pacing. The term fixating is used to describe the procedure of fixing the electrode tip relative to the inner lining of the heart so that proper stimulation is assured with reasonable permanency. In the case of ventricular pacing, it is known that the stimulating contact element cannot be loosely positioned within the ventricle, but must be fixed against or at least within a minimum distance from the endocardium. Another important reason for obtaining good fixation is so that the threshold for stimulation remains substantially constant throughout the lifetime of electrode usage. Clearly, if the distal stimulating contact is permitted to shift in position relative to the endocardium, the threshold will likewise shift, with potentially disasterous results.
In the prior art, a large number of fixation type designs have been utilized, generally with indifferent success. In some endocardial electrodes, the design is such that the blood can work itself into the electrode and thus block the fixation mechanism. Another disadvantage of most fixation systems is that they pierce or grasp the endocardium so as to cause physical damage. This is particularly serious for atrial electrodes, due to the thin atrial walls. There exist a number of issued patents describing electrodes designed to screw into the heart tissue. However, there has remained a great need in this art for an endocardial catheter which can be safely and securely positioned so as to provide the physician with means for obtaining an optimally low threshold, and which will minimize damage to the endocardium both at time of insertion and later.
SUMMARY OF THE INVENTION
It is a primary objective of this invention to provide electrode apparatus adapted to engage the inner lining of a patient's heart without piercing it, so as to enable speedy and stable fixation for cardiac pacing.
It is a further objective of this invention to provide an electrode having a distal portion formed so as to provide openings designed to interact with the trabaeculae in a manner such that the stimulating contact can be screwed to an optimal position, so as to provide means for stable low threshold pacing.
In accordance with the above objectives, there is disclosed an endocardial pacing electrode adapted with a specially configured spiral or helically wound tip, the tip being closed upon itself or otherwise configured so that it has no sharp points and is not inserted into the endocardium. The spiral configuration provides open grooves such that the cardiac muscles on the inside of the heart can be worked within such grooves by turning of the electrode at time of insertion. In this manner, the tip is screwed, or rotated until the caridac muscle lays in close contact with the stimulating surface or tip of the electrode, thereby providing optimal patient stimulating threshold conditions. A predetermined portion of the spiral pacing tip may be insulated, leaving a second predetermined portion which acts as the actual pacing contact, thereby providing a desirable amount of pacing surface which is reliably placed in contact with the heart muscle. The main length of the electrode suitably comprises an axially hollow lead which connects to the pacing contact at the distal end and to a pacing generator at the proximal end, and which permits insertion of a mandrin through the center thereof, allowing twisting or rotating manipulation of the electrode at the proximal end in order to properly position the electrode within the heart.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a detailed view, partly in cross section, of the distal end of a first embodiment of the pacing electrode of this invention.
FIG. 2 is a perspective view of the embodiment of FIG. 1, looking at the end of the electrode tip from an acute angle.
FIG. 3 is a detailed view, partly in cross section, of the distal end of another embodiment of the pacing electrode of this invention.
FIG. 4 is a diagrammatic sketch of the entire electrode, with a cut away portion showing the position of the mandrin within the electrode.
FIG. 5 is a diagrammatic view of the distal end of a shouldered embodiment of the pacing electrode of this invention.
FIG. 6 is a diagrammatic view of yet another embodiment of the pacing electrode of this invention.
FIG. 7 is a diagrammatic view of an embodiment of the pacing electrode of this invention, wherein the stimulating contact has a rounded tip, and does not close on itself.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1, there is shown a detailed view of the proximal end portion of a first embodiment of the electrode of this invention. The main length of the electrode is contained within a tube or casing 12 of Teflon or other suitable material, as illustrated also in FIG. 4. A lead, or conductor 14 in spiral form extends the length of the catheter, terminating at the distal portion as shown in FIG. 1. In the embodiment of FIG. 1, a second spiral, or helical coil 16 is positioned surrounding the conductor 14, and in close electrical contact therewith, both conductors 14 and 16 at this point being tightly encased by outer tube 12. The tube 14, at the distal end shown in FIG. 1, has a shoulder 17 which permits enclosure of additional coil 16 as well as conductor 14. Coil 16 is extended outside of casing 12 to form the spiral pacing contact 20. As shown in FIG. 1, spiral contact 20 extends for approximately 11/2 loops or cycles, to the far distal end where it turns and coils back through a like distance and extends through the center of conductor 14, the extended portion being designated as 26. Portion 26 may additionally be soldered or otherwise connected to coil 14, to ensure electrical contact between the spiral portion 20 and the conductor 14. The casing 12 extends over the distal end, as shown at 13, sealing off the remainder of the electrode from the spiral tip.
The configuration of spiral portion 20 is seen in perspective form in FIG. 2 which illustrates the open type structure of the contact which permits close insertion of the contact into the muscle tissue, or trabaeculae. It is seen that the contact tip is not sharp, has no end points, but rather is round, continuous, and closes upon itself in a closed spiral configuration, with open grooves 28. The tip has a configuration such that it can be screwed under the trabaeculae or inner muscles of the heart, in either the ventricle or atrium. Thus, what is provided is an electrode tip which is adapted to interface with the trabaeculae in a maximum-contact relationship, thereby ensuring optimal threshold for pacing.
Referring to FIG. 3, there is shown an alternate embodiment of the invention without the shoulder portion shown in FIG. 2. In this embodiment, the contact portion 20 which extends beyond the end of casing 12 is substantially in the same spiral form as shown in FIG. 1. The tip has a tightly wound portion 21 which is forced into the proximal end of conductor 14, where it is held in tight mechanical and electrical contact with conductor 14.
It has been determined that it is desirable that the surface of the contacting tip of the catheter be preferably about 10-15 mm 2 . At the same time, the contact tip portion must have enough turns to provide the open spaces to optimize contact between the tip and the trabaeculae. If the conductor wire of which the spiral is made is 0.5 mm thick, a single turn of such wire has a surface of about 14 mm 2 . Accordingly, for the configuration as shown in FIG. 1, a portion of the spiral tip is insulated preferably so that the remaining exposed portion extends a full loop, or the length of the tip for a longer contact tip. As shown, insulating material 24 is provided substantially from the far end portion of the looped tip along one path back to the encased portion of the catheter. With this design, substantially the entire length of the tip has an uninsulated or conductive portion, such that if the muscle tissue is positioned into any of the open grooves within the spiral, it will be in contact with a conductive portion of the catheter tip. The tip insulation coating is suitably comprised of a material such as Teflon, polyetheen, polyamide, polytetrafluorathyleen, fluorethylpropyleen, silicon rubber, and other like materials. The thickness of the insulation is suitably about 50 microns. The material of the helically wound wire forming the spiral shaped tip can be platinum, platinum-iridium, elgiloy, or any other non-toxic conductive material.
Referring to FIG. 4, there is shown a diagrammatic view of the overall electrode of this invention. The electrode 10 suitably has extending therethrough a mandrin or stylet 24, which is positioned axially within the helical conductor 14. Conductor 14 need not be of a helical configuration, but could be either some other configuration of hollow conductor or even a solid conductor. However, in order to utilize the advantage provided by a mandrin, it is suitable and preferred that conductor 14 be hollow, as in the helical configuration shown. The mandrin extends substantially to the end portion of the electrode, terminating just proximal of the tip 20. With this configuration, the pacing surface 22 can very easily be fixated within the heart by turning the proximal end of the electrode clockwise, thereby screwing or rotating the distal end under the endocardial muscle. The open structure of the spiral tip permits entry of the trabaeculae within the tip, providing efficient placement and fixation and also establishing an environment for fast ingrowing of the heart tissue within the tip, such that permanent fixation is achieved rapidly. As can be seen, the open structure of the spiral tip permits the cardiac muscles to work themselves between the turns when the electrode is rotated, such that the muscles lay in close contact with the stimulating surface. In contrast to other fixation mechanisms, the pacing electrode of this invention does not damage the endocardium, and consequently causes reduced tissue reaction. Also, due to the close contact which is made, the chronic or long term pacing threshold can be established at an optimally low level. An additional advantage of the electrode of this invention arises from the absence of any sharp parts, such that the electrode can be inserted into the patient's cardiovascular system without the need of any protecting tube or other device.
While the preferred embodiments of this invention have been illustrated as shown in the drawings and described hereinabove, it is to be understood that variations may be adopted using the essential features of the invention. For example, the spiral stimulating tip may comprise a conventional length as well as a spiral shaped shoulder immediately therebehind, or any other configuration comprising spiral loops. The number of loops in the spiral, as well as the pitch and diameter thereof, may be modified as, for example, for use in the ventricle and atrium respectively. The insulation on a portion of the tip is optional, and need not be used for some tip configuration. Further, in the manufacture of the catheter, the spiral tip may be initially positioned just inside of the casing 12, and upon insertion of the distal end of the catheter into the patient's heart, the tip may be pushed out of the casing by forward pressure applied through the stylet. With this embodiment, the tip may be initially formed such that when it is freed from the constraint of the casing it expands slightly, thereby achieving a diameter in excess of the diameter of the casing. In another arrangement, the tip may be rotatable relative to the casing, with the mandrin being keyed into the tip so that the physician rotates the mandrin so as to rotate the tip.
FIGS. 5, 6 and 7 illustrate some of the alternate embodiments of the invention. In FIG. 5, an insulated spiral loop 31 is located just proximal of the distal stimulating tip 33. In this configuration, the fixating and stimulating mechanisms are separated, with loop portion 31 serving the fixation function, while tip 33 is a conventional type of stimulating contact tip. In FIG 6, there is shown a configuration where a looped portion 37 is placed at the far distal end, and a stimulating ring 35 is positioned proximal thereto. Again, in this configuration the fixation and stimulating portions are separated, but their relative positions are reversed as compared to the configuration of FIG. 6.
The configuration of FIG. 7 shows a spiral tip which does not close upon itself, but rather terminates with a rounded surface 39. It is in fact a modification of the configuration of FIG. 5, with the casing 12 stopping where the spiral loop starts, the spiral loop being connected to conductor 14 and rounded portion 39. As used herein, rounded means without any sharp or blunt edge, such that a rounded tip or contact element is defined as one with no sharp or blunt edge on any part thereof. This configuration is more suitable for temporary pacing applications, since the tip may be more easily withdrawn by reverse screwing, even after in-growing tissue has appeared.
In all of the embodiments illustrated, better contact can be achieved by screwing the electrode after insertion into the heart, the screwing or rotating operation being continued until a good threshold position is achieved. As the physician turns the electrode, the spiral tip advances through and between the trabaeculae, without actually penetrating, and threshold is monitored. The procedure continues until there is confidence that the optimum position for good threshold has been obtained. The positioning is then stopped, with the entire tip in optimal position without the endocardium, that is, with none of it mechanically inserted into the endocardium. The fact that there is no insertion provides the added advantage that there is reduced mechanical or physical damage of the endocardium, which permits a lower steady state threshold when fixation is achieved. | An endocardial pacing electrode adapted to be screwed under the inner muscles of the heart in order to be fixed in stimulating contact with the same, the electrode having a spiraled or helically wound tip which is rounded so that the tip engages but does not enter the trabaeculae. A portion of the electrode tip may be covered with an insulating material, leaving a predetermined portion which constitutes the stimulating surface area. The length of the electrode proximal to the tip is hollow to permit insertion of a mandrin, for rotating the electrode around the mandrin and positioning the tip for optimum contact for low stimulation threshold. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to rotary shredder apparatus with provision for ejecting hard to shred waste in a self-clearing cycle.
2. Description of the Prior Art
It is well understood in the processing of waste material, like municipal waste, that large uncrushables and hard to shred material is encountered. In instances when the uncrushables and hard to shred material is encountered the shredder jams the shafts on which the shredding, cutting and ripping discs are carried. Often the apparatus must be stopped and the material causing the jam removed by hand. The hand unloading results in loss of productivity of the apparatus to reduce the waste material.
Shredder apparatus known to have means for relieving jams when material gets into the shredding cutters is exemplified by Culbertson, et al U.S. Pat. No. 4,034,918 of July 1977 and by Cunningham, et al U.S. Pat. No. 3,808,062 of Feb. 25, 1975. However, in these examples, the apparatus is operated in a series of shaft reversal cycles in an effort to shred or reduce the offending material sufficiently to eventually send it through the apparatus. The foregoing examples have led to the type of shredding machine which is able to disgorge the hard to shred material, as disclosed in Hardwick et al U.S. Pat. No. 4,351,485 of Sept. 28, 1982. In this patent the shredding shafts are not in a common plane but the plane is inclined to the horizontal so one shaft is lower than the other. Upon shaft reversal the lowest shaft is rotated in a direction to move the material through a side door which opens upon shaft reversal. In this manner, hard to shred or cut material is moved out of the hopper.
A problem with the apparatus of U.S. Pat. No. 4,351,485 is that material may not clear from the higher one of the shafts and upon reversal of both shafts, the highest shaft can retain or withhold the unwanted material away from the lower shaft. Another problem is that the waste material can accumulate over the lower shaft position which results in an uneven distribution of the waste material in the hopper which can prolong the time necessary to process the material as the high shaft works against the low shaft.
BRIEF DESCRIPTION OF THE INVENTION
The apparatus of this invention operates to clear out uncrushables, hard to shred and large waste material by causing the normally contra-rotating shafts to perform predetermined reverse-forward cycles, or to convert the shafts and the shredding discs thereon to act as a conveyor to move such material toward an outlet which has been opened only if the predetermined cycles of reverse-forward rotation has failed to overcome the material.
An important object of the invention is to provide rotary shredding apparatus with an operating method for clearing uncrushables and similar objectionable waste material by following the steps of normally rotating the counter-rotating cutter shafts to draw the waste material down between the cutter shafts which is capable of being ripped and shredded, sensing the presence of uncrushables when the cutter shafts stop due to such material, and converting the operation of the cutter shafts into a mode in which they rotate in the same directions to have the cutters act as conveyors to move the objectionable material through a discharge which has opened in response to the converting of the cutters into a conveyor.
The foregoing object is carried out by an embodiment of apparatus having a pair of parallel spaced-apart driven cutter shafts carrying co-acting and overlapped disc-type cutter elements, and in which each shaft is connected to a reversible hydraulic motor means operatively contained in hydraulic fluid circuit means having pumping means for each motor means, hydraulic fluid flow reversing means in the fluid circuit for each motor means, means for opening a discharge door in the material receiving hopper, and electrical control means including sensor means responsive to stoppage of the cutter shafts for selecting predetermined modes of response resulting in the control means operating the cutter shafts in a mode to convey the material through the discharge door for self-clearing action.
BRIEF DESCRIPTION OF THE DRAWINGS
The preferred embodiment and modification thereof are shown in the accompanying drawings, wherein:
FIG. 1 is a vertical sectional view of shredder apparatus by which the principles of the invention may be carried out;
FIG. 2 is a plan view of the apparatus seen along line 2--2 in FIG. 1;
FIG. 3 is a schematic electrical and hydraulic control system adapted to operate the apparatus of this invention; and
FIG. 4 is a vertical sectional view of a modified shredder in which a number of variations have been made which differ from the view of FIG. 1.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In the normal shredding of municipal waste large uncrushables are constantly encountered. Such uncrushables will generally jam any slow speed shear-type shredder and it is necessary to manually unload this sort of material which results in down time and loss of productivity. A partial solution to the problem of clearing uncrushables from shredding machines is disclosed in Hardwick et al U.S. Pat. No. 4,351,485 where tramp material causing a crash-stop results in disengaging the drive motor so an access door can be opened for manual removal, but if the jam is less serious, the cutters can be run through a series of reversals in an attempt to clear the obstruction without opening the hopper access door.
The present apparatus is arranged to self-clear uncrushables by means which will detect a jam condition and discharge material of uncrushable character by converting the rotary cutter shafts and cutter discs into a conveyor for moving the material out of the hopper through a discharge opening controlled by a movable door. No manual removal of the uncrushable material is necessary as the removal is carried out as indicated through using the rotating cutter discs and shafts as a conveyor to support and move such material to and through a side door in the wall of the hopper.
The apparatus is constructed with a hopper 10 made up of sheet or plate material to form side walls 11 and 12, a top closure 13, and an opening 14 to allow the material feed belt 15 to have its discharge end extending through the opening 14 on a pulley 16. The wall 11 carries a door 18 movable on a horizontal hinge 19 so it can swing outwardly of the hopper 10 in response to the action of a pair of hydraulic cylinders 20 (one being seen in FIG. 1) constituting motor means supported by suitable brackets 21. One end wall 21 supports a bearing 21A for shaft 28, a gear box 22 in which gears form the connection between a hydraulic low speed, high torque radial piston motor 23 and a shaft 24 in the bottom open end of the hopper 10. The opposite end wall 25 supports a bearing 25A for shaft 24, and a second gear box 26 connecting the hydraulic low speed radial piston motor 27 to a second shaft 28 in the hopper 10. As will be referred to presently, the shafts 24 and 28 are disposed in a horizontal plane so that the use thereof as a conveyor will be aided.
Shaft 24 carries a plurality of disc-type cutters 29 formed with cutting teeth 30. Shaft 28 carries a plurality of disc-type cutters 31 formed with cutting teeth 32. The cutters 29 and 31 interleaf with each other and have close running side surfaces to develop a shearing action. The motors 23 and 27 operate through the respective gears in boxes 22 and 26 so that shaft 24 turns faster than shaft 28. The shaft speed differential can be achieved by selective gear rations in boxes 22 and 26, or it can be achieved by one pump having a greater displacement than the other. This relative difference in rotation causes the cutters to develop a ripping and tearing action during shredding. However, when difficult material like rubber is encountered the cutters tend to pull into synchronism and the action is essentially one of shearing, and because of this type of action the clearance between cutter side faces is set for approximately 0.005 inches.
When uncrushables are encountered the cutters jam and stop shaft rotation. The stoppage of either shaft 24 or 28 is detected, as will be explained presently, and the control system of FIG. 3 will be operative to cycle the motors 23 and 27 in a reverse-forward mode for a predetermined number of cycles, usually three, to try to shred the material causing the jam. If in the cyclic mode the jam continues to be present, the control system goes into an ejection mode which has several phases. The first phase is to cause the shafts to rotate in opposite directions so the teeth move away from each other to disgorge the material from between the shafts. The next phase is to return shaft 24 to its normal forward rotation so that the teeth 30 will drive or force the uncrushable material onto the cutters 31 on shaft 28. In this mode both shafts are rotating in the same direction (clockwise) to move the material toward the hopper side wall 12. The next mode involves energizing the hydraulic cylinder means 20 to open the side door 18 and at the same time the rotation of both motors 23 and 27 is reversed to cause the cutters 29 and 31 to turn in a counterclockwise direction so the material will be conveyed toward the open side 11 and discharged from the hopper 10. The side door 18 covers a large opening so large objects and uncrushables can easily be discharged by the action of the cutters being converted to a conveyor by rotating in the same direction.
As long as the shredder can function to shred material without jamming the material will drop out below the shafts 24 and 28 and be collected on a belt conveyor 33 for delivery to a collection zone. When it is necessary to cause the shredder to operate as explained when a jam occurs, the material discharged through the door, when door 18 is opened, will fall onto a second belt conveyor 34 and be delivered to a different collection zone. The cycle for discharging uncrushables or clearing the shredder of a jam condition is normally adjusted for a limited time, as experience determines, and when the time runs out the shredder is returned to its normal condition of counter-rotating shafts in which the cutter teeth turn toward each other.
OPERATION OF THE APPARATUS
Turning now to FIG. 3, there is disclosed the schematic electrical and hydraulic control system for the apparatus described in FIGS. 1 and 2. The radial piston drive motor 23 for the cutter shaft 24 is provided with a common type of four way - three position valve 40 operated in response to solenoid 41 for normal forward rotation, and in response to solenoid 42 for normal reverse rotation. The hydraulic fluid is supplied from pump 43 driven by electric motor 44 to deliver the fluid from reservoir 45 through a filter 46 to the valve 40. A pressure relief control 47 of common type is connected into the delivery conduit 48 to by-pass the motor 23 upon a pressure rise above the desired operating pressure. In the neutral position of the valve 40 there is a flow cross-over so the flow can return directly to the reservoir when it is not desired to operate the motor 23. The return to reservoir 45 is through a water cooled exchanger 49 and a check valve 50 is in the return conduit 51 for a purpose to appear.
The second radial piston motor 27 for cutter shaft 28 is provided with a common type of four way - three position valve 52 operated in response to solenoid 53 for normal forward rotation, and in response to solenoid 54 for normal reverse rotation. The hydraulic fluid is supplied from pump 55 driven by electric motor 56 to deliver the fluid from reservoir 45 through a filter 57 to the valve 52. A pressure relief control 58 of common type is connected into the delivery conduit 59 to by-pass the motor 27 upon a pressure rise above the desired operating pressure. In the neutral position of valve 52 there is a cross-over so the flow can return directly to the reservoir 45 when it is not desired to operate motor 27. The return to reservoir 45 is through the water cooled exchanger 49 for the motor 23. A check valve 60 is inserted in return conduit 61. It is important to set the check valves 50 and 60 so there will be no cross-over flow between the hydraulic valves 40 and 52.
The heat exchanger 49 receives cooling water through a valve 62 controlled by a solenoid 63 which normally shuts off the water flow when the hydraulic systems for the motors 23 and 27 are not in operation.
It was disclosed in FIG. 1 that the discharge door 18 in the side wall 11 of the hopper 10 is moved between its open and closed positions by a pair of cylinder and piston motor means 20. These motor means 20 operate in synchronism in response to a common four way - three position valve 65. This valve 65 differs from the previously described valves 40 and 52 in that in the neutral position the motor means 20 are held in whatever position attained when the valve 65 goes to its neutral position. In normal operation, a pump 66 driven by an electric motor 67 delivers pressure fluid in conduit 68 through a filter 69 to the valve 65. A pressure relief valve 70 is connected into conduit 68 to protect the motor means 20. Valve 65 is operated in a door opening direction by solenoid 71, and in the door closing direction by solenoid 72.
The several pieces of operating equipment just referred to are under the direction and control of a programmable controller 75 which has its main power supplied from lead 76. The controller comprises certain subcontrols which are identified by suitable legends. The subcontrol 77 initiates the starter and forward modes of operation. For example, the starter mode is intended to energize the respective electric motors 44, 56 and 67 to develop hydraulic pressure in the respective systems, and to energize solenoid 63 to supply cooling water to the exchanger 49. The operator normally presses a start button to condition the respective hydraulic systems. A start signal (not shown) indicates that the hydraulic systems are functional, and at that time, if waste material is available, a forward shred button (not shown) needs to be pressed to energize solenoid 41 at valve 40 for motor 23 and to energize solenoid 53 at valve 52 for motor 27 so that pressure fluid is delivered to drive the radial piston motors 23 and 27 in counter-rotating directions so the cutter teeth 30 and 32 turn toward each other. If the waste material can be reduced without problems, the forward or shred mode will continue unchanged, and the valve 65 in control of the motors 20 for door 18 will not be moved out of its neutral setting with the door closed.
Now, if some waste material is received in the hopper 10 that is too tough for the cutter teeth 30 and 32 to shear through, or that causes the gears in gear boxes 22 and 26 to momentarily stop turning, motion sensor means 78 or 79, or both, will detect that stoppage and generate signals which are received in sub-circuit 80 to be monitored in terms of how long the stoppage persists. The sub-circuit 80 works in association with a sub-circuit 81 which, when signalled, will deenergize the forward solenoids 41 and 53 at valves 40 and 52 respectively, and energize solenoids 42 and 54 to reverse the pressure fluid flow to motors 23 and 27 so the cutter teeth 30 and 32 will disgorge the tough material. This reversal is followed by restoration of the forward mode, and the timer can be set usually to operate the motors 23 and 27 through several forward and reverse cycles in an effort to overcome the difficult material. Usually three such cycles will be sufficient to determine if the apparatus can shred, tear or shear the material.
It is to be understood here that the shredding, tearing action of the teeth 30 and 32 is developed by operating the motor 23 at a shaft speed of about 20 RPM and motor 27 at a shaft speed of 27 RPM. Also, the motor-gear ratio for gear box 22 is about 4 to 1, while the motor-gear ratio for gear box 26 is about 2.96 to 1. These parameters are about what is desired, but no limitation is to be implied therefrom. The principle that governs is that the shafts 24 and 28 are revolving at different speeds so the ripping, tearing and shredding action occurs at all times. An exception does occur when rubber or rubbery material is dumpted into the hopper 10. This type of material has the tendency to drag the faster shaft down so both shafts reach about the same speed, and at that time material is subjected mainly to shearing action.
Returning to the condition when the apparatus encounters material such as uncrushables, the sensors 78 and/or 79 generate a signal which is received in sub-circuit 80 to indicate a jam that has persisted beyond the designated time in the sequence of forward-reverse cycling of motors 23 and 27 controlled in sub-circuit 81. Now, the controller 75 will call for the discharge mode which is in sub-circuit 82. This sub-circuit 82 depends upon functions in sub-circuits 77 and 81. The discharge mode combines a number of functions which converts the shredder shafts and cutters into a conveyor. The first phase of this mode is to operate the solenoid valve 52 so its motor 27 will rotate shaft 28 in a clockwise direction, and to operate solenoid valve 40 so its motor 23 will rotate shaft 24 also in a clockwise direction. Now both shafts 24 and 28 will be rotated in the same direction to move the uncrushable material toward the hopper wall 12. After a very short time period, the sub-circuit 82 will execute a second phase of the function which is to energize solenoid 71 so the motors 20 will retract and swing door 18 outwardly to its open (dotted) position. At the same time in this second phase the motors 23 and 27 are caused to rotate shafts 24 and 28 in counterclockwise directions by energizing solenoids 41 and 54 to have the cutters 29 and 31 form a conveyor to carry the uncrushable material to the discharge opening now opened by door 18. The discharge sequence is continued for a predetermined period of time and is then stopped and the door 18 is returned to its closed position by sub-circuit 82 energizing solenoid 72 before returning the valve 65 to its neutral position. At the same time the controller 75 will return the valves 40 and 52 to positions of normal shredding operation under the control by sub-circuit 77.
MODIFIED EMBODIMENT
It is apparent from FIG. 1 that when the door 18 is opened and waste material is continually brought to the hopper 10 by conveyor 15, a quantity of material will be discharged along with the uncrushables. It is also apparent from FIG. 1 that the side wall 12 of the hopper supports a set of comb teeth 83, and that the door 18 supports a similar set of comb teeth 84. These comb teeth 83 and 84 prevent material wedging between adjacent cutter discs 29 or 31, and are well known in this art.
The modification of FIG. 4 includes many components which are repeated from FIG. 1 and will be similarly designated so as to avoid repetitious description. The principal feature of FIG. 4 needing disclosure is in the arrangement of the discharge door 18A and the comb teeth 84A. The door 18A is operated by cylinder motor means 20A which retract in order to close the door 18A and extend to open the door inwardly. This requires a modification in the controller sub-circuit 82 which should be understood from the foregoing disclosure. Another modification is the shape of the comb teeth 84A so that sufficient clearance is obtained when the door 18A opens and moves the teeth 84A upwardly in the hopper. The purpose for swinging the door 18A inwardly into the hopper 10 is to allow the door to block off incoming waste material from the cutter shafts and not allow a quantity of recoverable waste material to be discharged with the uncrushables.
RESUME
The foregoing disclosure is directed to a unique method of operating a self-clearing shredder apparatus to clear out uncrushables without requiring manual operations and with a minimum of down time of the apparatus. The method embodies the steps of going from normal shredding operation to a step of sensing the presence of uncrushables which cause stoppage of the rotary shafts, followed by the steps of forward-reverse cycling of the cutter shafts in an effort to rip or shear through the material to try to clear the uncrushables, shifting the operation to rotating the shafts in common directions to convert the cutters into a co-acting mode to form a conveying surface and to open a discharge so the uncrushables can be removed from the apparatus.
In order to accomplish this unique method, the apparatus is seen to have a pair of parallel spaced-apart driven cutter shafts carrying cutter elements, which shafts and elements are driven by hydraulic motor means, one connected to each shaft, connected into hydraulic fluid circuits having fluid flow reversing means subject to a programmable controller for selecting predetermined modes of response when sensor means respond to the presence of uncrushables resulting in the stoppage of the motor drive means.
There has been set forth and described what is considered to be a preferred embodiment of the present invention for the disposal of waste material and the self-clearing of uncrushables from the apparatus. It is possible to make modifications in the selection of components and controls without departing from the principles of this invention as presently illustrated, but the same is not intended to impose limitations on the spirit in which this disclosure is made. | A self-clearing shredding apparatus for disposal of waste material which includes hard to crush or shred objects, in which the apparatus is provided with individually driven pair of cutter shafts in a common horizontal plane for reducing the waste material or for converting the cutter shaft operation to one in which they perform the duty of a conveyor to transport the objects which are objectionable through a side opening. The apparatus which performs the above activity is connected up to a programmable controller which causes the apparatus to operate in a prescribed method. | 1 |
REFERENCE TO RELATED APPLICATIONS
This application is a Continuation-in-Part of Ser. No. 09/233,505, filed on Jan. 19, 1999, U.S. Pat. No. 6,045,420 the contents of which are herein incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to the field of marine water craft, particularly to high speed power boats utilizing a surface piercing propeller drive system mounted within a propeller tunnel formed integral to the hull of the boat, and most particularly to inclusion, within a wall of said tunnel, of a means for providing air thereto; said means being judiciously placed for linearization of the relationship between vessel velocity and engine speed.
BACKGROUND OF THE INVENTION
Surface piercing drive technology and propeller tunnels are an established art which the inventor helped pioneer having been awarded U.S. Pat. No. 4,689,026, the contents of which are incorporated herein by reference. The drive systems can be highlighted by their ability to provide enhanced boat performance by use of the surface piercing propellers while safely placing such propellers beneath the hull of the water craft.
The obvious disadvantages of the surface piercing propellers may be found in reference to U.S. Pat. No. 5,667,415 issued to Arneson. The surfacing propeller is well known for its speed, as well as its lack of thrust at low speed, overloading its power source at preplane speeds and low thrust in reverse. Arneson has successfully commercialized surface piercing propellers which position a propeller near the surface of the water at a location outward from the transom of a boat. Air is drawn into and through the propellers and through the principles of compression/cavitation the propeller is able to function according to its design characteristics, thus leading to enhanced speed and performance derived from the surface piercing technology. Disadvantages to the surface piercing technology are mainly directed to the location of the propeller which is typically at the back of the boat. This interferes with the use of the back of the boat for fishing, diving or swimming and exposes the propeller to a position that is most dangerous. Representative disclosures relating to surface piercing technology can be found in U.S. Pat. Nos. 4,645,463 and 4,909,175.
Other disadvantages are the need to rotate the drives since they operate as a rudder and the inability to operate such drive systems at low speed which became the subject of the Arneson U.S. Pat. No. 5,667,415 previously mentioned. In this registration the invention discloses the use of a shroud that is placed around the propeller which prevents “walking” of the propeller at low speed but also protects individuals or marine life from impacting the propellers.
The directing of air to the propeller while it is beneath the boat provides a known benefit and is the subject of various types of prior art such as the following: U.S. Pat. Nos. 2,434,700; 3,702,485; U.S. Pat. No. Re. 23,105; U.S. Pat. No. Re. 38,522; U.S. Pat. Nos. 130,391; 807,769; 815,270; 1,081,876, 1,117,357; 1,262,942; 1,401,963; 2,138,831; 3,450,090; 4,031,846; 4,363,630; 4,383,828; 22,080; 965,870, 1,916,597; 1,966,029; 3,793,980; 3,937,173; 4,300,889; 4,443,202; 5,141,456; 5,405,278; 5,171,175; 5,667,415; 5,679,037; 4,977,845; 4,371,350; 4,993,349; 5,482,482; 5,588,886; and 4,941,423.
What is lacking in the art is the teaching of a surface drive technology that forms air passageways that enhance surface piercing propeller operation at all speeds and conditions and that particularly provides for a linearization of the relationship between vessel velocity and engine speed.
SUMMARY OF THE INVENTION
The present invention is directed to marine vessels having a surface piercing propeller(s) in a defined enclosure. In its simplest form, the present invention provides at least one surface piercing propeller positioned within a depression, termed a tunnel, formed within the vessel's hull, which tunnel has at least one surface or wall which runs generally parallel to a longitudinal axis of said vessel and is contiguous with a bottom side of said hull and a top side of said tunnel. The wall contains at least one opening through which air is supplied. This opening is placed so as to be gradually uncovered from water as the vessel's forward speed increases. Judicious placement of the opening enables the relationship between the vessel's velocity and the engine speed to define and maintain an essentially linear relationship as the vessel accelerates from rest to its maximum velocity and during the transition from displacement mode to planing mode.
In a further embodiment, the configurations define an air induction system that allows each of the critical performance parameters to be optimized and controlled to suit the hull configuration to which it is applied. This air induction technique was developed because of the obvious advantages and disadvantages of current surfacing propeller drive systems. It was observed that the characteristics of surfacing propellers and the engines used to drive them suffered compatibility problems in their current applications. This observation lead to the need to identify and control critical design elements. The design of surfacing propellers, per se, relies upon very refined science; however their incorporation with a particular hull design requires that a degree of intuitive art be applied. The engines must follow the laws of thermodynamics and be operated in a cost effective manner; thus their operating characteristics are considered a given. In order to make the technologies compatible, it is critical that the interrelationship of their operational parameters be understood. The prior art either completely fails to address the control of air, or the mechanisms that have been employed are cumbersome and require constant operator intervention. This invention recognizes and discloses the relationship between efficient engine operation and air requirements of surface piercing propellers, and provides a method of application of this technology which results in enhanced operation of both the surfacing propeller and its prime mover.
Previous techniques have merely addressed the requirement for air, but have failed to appreciate either the need to control the amount of air supplied or the criticality of timing to the air supply/propeller relationship. The application of the parameters described herein provides the propeller with the environment required by a surfacing propeller. Engine characteristics can be compensated for by using these propeller to air relationships to assist the engine in attaining its torque and rpm design targets. The uniqueness of this invention is that it requires no moving parts, controls or operator intervention. The ability to vary the amount and timing of air to the propeller is achieved by the shape and location of the air induction system, in combination with the nature of water flow and the natural angle change that a marine vessel goes through as it transitions from static to on plane speeds. These features are molded in surfaces of the hull and can be designed to expand the operating window of the vessels it is applied to. The operational characteristics that are gained are 1) seamless transition from idle to planing speed, 2) stable speed at any sea state and throttle setting, and 3) effective reverse with directional control.
The propeller enclosing tunnel may be a single surface or it may be defined by a series of surfaces, each of which provide an enhancement to the operation of the vessel. In particular, the top of the tunnel may be formed from a flat surface which is used for mounting the propeller strut and rudder. The flat surface also eliminates the need for different left and right strut fittings and provides a uniform surface for determination of propeller blade clearance.
A second surface may be formed angular to the first surface and positioned perpendicular thereto. The second surface enhances reverse thrust by deflecting prop wash and reducing the “damming” effect typical of a flat transom vessel. A third surface is in juxtaposition to the first surface and provides an angular wall at a right angle, shaped to shield the propeller from obtaining water during high speed acceleration. The aforementioned surfaces create an outer wall for the air tunnel used for transferring air from the transom to a position before the propeller. The angular wall of the tunnel includes a shaped opening that operates as a controlled air passageway to control the air in relation to water flow. This is shaped so as not to foul the air passageway during acceleration, low speed and/or rough sea conditions. However, as the boat accelerates the shaped passageway allows additional air to be transferred to the front face of the propeller. The tunnel and passageway is sized to the particular engine and hull characteristics so as to allow the engines to reach the optimum power curve for acceleration.
Thus, it is an objective of the instant invention to optimize the performance of surface piercing propellers placed beneath a boat.
It is a further objective of the instant invention to provide, in combination with a tunnel in the underside of the hull of a vessel, a means for providing air thereto; said means being judiciously placed for linearization of the relationship between vessel velocity and engine speed.
Yet another objective of the instant invention is to teach a particularly shaped enclosure which functions to control the timing and volume of air flow, in relation to the water flow, throughout the performance curve of the engine and to accommodate inept conditions during low speed operation, acceleration and/or rough sea conditions.
A still further objective of the instant invention is to provide a flat surface for mounting of the struts and rudder so as to eliminate the need for left or right version components.
Yet an additional objective of the instant invention is to provide a surface piercing propeller driven vessel having enhanced reverse thrust characteristics.
Still an additional objective of the instant invention is to correlate the design parameters of the shaped passageway in relation to engine and hull design to optimize boat performance by allowing the engine and hull to operate at optimum design characteristics.
Other objectives and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a close up of one side of FIG. 2 with the propeller and shaft removed for clarity;
FIG. 2 is an upside down isometric view of the rear portion of a boat having twin surfacing propellers and tunnels;
FIG. 3 is a stern view showing a common venting approach for a single propeller boat having a surfacing propeller semi-enclosed in a tunnel;
FIG. 4 is a stern view showing a common approach for twin propeller boats having a surfacing propeller semi-enclosed in a tunnel;
FIG. 5 is a stern view showing a common approach for twin propeller boats having a surfacing propeller semi-enclosed in a tunnel;
FIG. 6 is a rear section view of the stern portion of a boat having a surfacing propeller in a semi-enclosed tunnel; and
FIG. 7 is a rear section view of the stern portion of a boat having twin surfacing propellers in a semi-enclosed tunnel with all running gear removed.
FIGS. 8-13 are a series of cross-sectional views which depict the relationship between the water level and air supply to the propeller during various operating conditions.
FIG. 14 is a graph of the relationship between engine speed and velocity.
FIG. 15 is a chart of air ingress optimization characteristics.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1, an expanded partial view of the hull structure underside 8 inclusive of rudder 10 is shown. This area of the hull contains several surfaces 12 , 14 , 16 , 18 , 20 and 22 which have been constructed and arranged so as to act in concert to yield optimum performance and handling characteristics to the vessel in all phases of operation. In contrast to prior art attempts, the surfaces of the instant invention provide abrupt transitions and sharply angled surfaces. This design provides enhanced operation and facilitates construction and manufacturing. Surface 12 defines the roof of the plenum area. Many installations allow this surface to be above the static water line. This surface can also be angled up from its starting point, intersection with surface 14 , so as to provide easy escape of exhaust gases during conditions of full vessel load while the vessel is at rest. The angle is typically 1 to 2 degrees up from the static trim angle of the craft, however it is contemplated that this angle will be optimized in relation to the particular vessel. Surface 14 is designed to enhance reverse thrust by deflecting the propeller wash and thereby reducing the damming effect of the transom. This surface may be inclined along two angles. As best seen in FIG. 6, the first inclination, that of the top of surface 14 toward the aft or rear of the vessel, encourages reverse prop wash to continue past the cutwater 38 . Referring again to FIG. 1, it can be seen that the defined angle 19 , which is skewed from a plane parallel to transom 50 , will divert the rearward propwash in a manner that will encourage reverse and side maneuvering. Surfaces 16 and 18 have a two-fold purpose. Firstly, they define the vent wall that provides air to the propeller. Secondly, they act as a shield to limit the amount of water which reaches the propeller during acceleration and high speed operation. Surface 20 provides a flat surface which is parallel to the keel of the craft. This surface provides a consistent surface in the hull, independent of the number of drive systems, on which to mount a universal strut assembly 13 for support of the drive shaft. This approach allows economy of scale in its use of a common strut assembly for all installations of a particular class. Surface 22 provides a flat stable surface perpendicular to the shaft angle, which is convenient for mounting the shaft seal assembly of choice (not shown).
Further referring to FIG. 1 , 2 , 6 and 7 , several design features cooperate with the surface geometry so as to provide enhanced operating characteristics. Feature 30 enhances early air entry and exhaust percolation, although in many instances exhaust percolation is avoided by placing the surface 32 above the static water line. Feature 32 is judiciously placed so as to optimize the volume and timing of air entry to open area 40 . Area 40 is the entry to the main plenum (plenums)and is sized in accordance with such features as hull weight, horsepower and target speed. This overall open area can be predicted by the following formula:
Area 40 (per propeller)=((Area 11 ×0.5)+Area 54 )×0.9
where area 11 equals the surface area of the propeller and area 54 is the area between the propeller and the vent walls. This design feature must be judiciously positioned so as to prohibit propwash from reducing the timing and volume to open area 40 while simultaneously permitting enhanced high speed turning and reverse thrust.
Referring to FIG. 6, feature 34 is critical to controlling the flow of water as it passes this region. Appropriate positioning of this feature will insure cooperation with open area 42 so as to prevent water fouling of the inlet air stream moving there through. Area 42 provides the primary air supply to the propeller and is sized so as to allow attainment of maximum speed while preventing fouling by passing water. This over all open area can be predicted by the formula:
Area 42 =Area 40
Feature 36 provides a control area for early air induction into area 44 , which is approximately 15% of area 42 . This is sized so as to allow the propeller to reduce loading while the engine achieves its usable torque and rpm range. Judicious placement of this feature prevents water from fouling vent area 42 while at the same time limiting over ventilation. Feature 38 defines the cutwater. The placement of this feature is dictated by the hull design and represents the point at which the water detaches from the hull during high speed operation. Determining this feature is necessary in order to properly control propeller immersion.
Referring to FIG. 3 a rear view of the transom 50 is shown. The area 54 is the area between the propeller and the vent walls. This must be kept to a minimum to insure optimum performance and limit the required size for area 40 and 44 . The size of area 40 and 44 is a direct function of area 54 and will increase as area 54 increases. Location 17 is the exhaust outlet for the prime mover. This location is specific in that it is positioned in such a manner that the exhaust has free access to ambient air via plenum (plenums) 40 in static condition yet the forward action of the craft movement will draw the exhaust through area 42 and entrain the smoke and smell of the exhaust with the propwash.
FIGS. 8-12 are drawn to various embodiments illustrative of a simplified tunnel construction in stepped or non-stepped hulls, and are further inclusive of a means for air ingress. It is emphasized that these embodiments are merely illustrative of hull design and are not intended to be limited to any particular hull configuration. As will be hereafter described, the figures depict various combinations of 1)engine operation, 2)vessel velocity and 3)propeller orientation relative to the water's surface.
As further illustrated in FIG. 13, the particular placement of the air ingress means enable linearization of the relationship between vessel velocity and engine speed throughout the vessel's operating range.
Now referring to FIG. 8, a vessel 80 is shown at rest with the engine operating. The water line 82 is positioned such that engine exhaust 84 flows rearwardly and the main air ingress opening 86 is covered by water. The surfacing propeller 88 is submerged below the water line.
Referring to FIG. 9, the vessel 80 is depicted as having its engine in gear and at idle speed. The water line 82 undulates with the forward movement of the vessel, opening 86 remains covered by water and propeller 88 remains fully submerged.
With reference to FIG. 10, the vessel 80 is depicted as having its engine running and in gear and power is being applied in an amount sufficient to transition the vessel to a planing mode. This is signified by the vessel rising in the water and water begins to break loose at the cutwater. At this juncture, the water line 82 has dropped to a point at which the propeller 88 is only partially submerged and is transitioning to a surfacing propeller. The propeller's RPM increases, ambient air is drawn through the air ingress 86 , which is now only partially inhibited by water, and the engine exhaust is being drawn into and consumed by the prop wash. This reduces the smoke, sound and smell of engine operation.
As seen in FIG. 11, the vessel 80 is depicted as accelerating with a heavy load and a velocity in the range of about 15-30 MPH. Water has broken lose and is cutting clean at the cutwater. The air ingress 86 , is still partially inhibited by water, enabling the propeller 88 to remain deeply submerged, albeit in a surfacing mode, which enables the greatest thrust to be attained.
FIGS. 12 and 13 illustrate alternative hull designs depicted in full speed operation. The figures illustrate the water level 82 as it is positioned during high speed operating conditions. As the hull rises, the vessel 80 will have achieved its maximum velocity, in the range of about 35-75 MPH. The vessel has now risen to a point where the water is breaking clean at the cutwater. The air ingress opening 86 is fully uncovered by water and maximum air is being supplied to the propeller 88 , which is now in its most efficient surfacing position.
FIG. 14 is a graph of the engine RPM versus velocity in MPH. Line A describes a typical RPM vs MPH relationship for a vessel, e.g. a Sea Ray cruiser, incorporating propeller tunnels absent the air ingress means as instantly described. Lines B and C illustrate a vessel operated with an air ingress opening in accordance with the teachings of the instant invention. With reference to Line A, initially, the RPM rises quickly, although velocity does not change significantly, resulting in a fairly steep slope. As the vessel transitions from displacement to planing operation, in about the 10-25 MPH range, the slope becomes nearly flat, as the RPM remains at approximately 2000. Increased engine speed can not be achieved as the vessel struggles to lift from the water. Upon achieving a planing configuration, the slope again changes, signaling a greater increase in velocity with increasing engine speed. This flattening of the power curve, as the boat lifts from “the hole” to achieve planing operation has been accepted as conventional operation prior to the instant invention.
Now referring to lines B and C (which represent a vessel being operated on a reciprocal course during these tests) judicious placement of the air ingress opening, in accordance with the present invention, so as to provide differing degrees of air to the surfacing propeller during the normal course of acceleration from “at rest” to “maximum velocity” enable the instant inventor to achieve a nearly linear relationship between RPM and MPH throughout the operating range. Contrary to previously accepted theory, the inefficiencies of transitioning from displacement to planing operation, which have historically resulted in a significant hump in the power curve, have now been eliminated.
This is accomplished by appropriate placement of the air ingress opening in a particular vessel's propeller tunnel, such that 1)little or no air is initially provided to the water passing over the submerged surfacing propeller; 2)followed by a period where a portion of the opening becomes uncovered as the propeller begins to transition to surfacing mode; and 3) culminating in a configuration wherein the propeller, running in its most efficient surfacing mode, is supplied with a maximum volume of air. The smooth acceleration resulting from this combination of elements yields an efficiency of operation which has heretofore been unachievable.
FIG. 15 is a chart of air ingress optimization characteristics with references made to figures A and B. The chart provides optimization by way of example. For instance Figure B reference to the feature 40 illustrates that if feature 40 is too small, the tunnel VAC at Wide Open Throttle is high, acceleration is slow, WOT mph is slow, and the engine will overload in rough seas. However, when the feature 40 is correctly sized, the tunnel VAC is proper, acceleration is good, WOT mph is good, and there is no engine overload in rough seas. Figure A and B reference to feature 30 illustrates that if feature 30 is missing, the tunnel VAC has little effect but acceleration is poor. If feature 30 is correctly sized, the tunnel VAC is improved, the acceleration is good and the WOT mph is improved. Figure A and B reference to feature 44 illustrates that if feature 44 is missing, the tunnel VAC has little effect and acceleration is poor. If feature 44 is correctly sized, the tunnel VAC is has no effect but acceleration is good.
Figure A and B reference to feature 42 illustrates that if feature 42 is too small, the tunnel VAC is high, acceleration is poor, WOT mph is low, and the engine may be overloaded in rough seas. When feature 42 is properly sized, the tunnel VAC is correct, the acceleration is good and the WOT mph is good.
Figure A and B reference to feature 34 illustrates that if feature 34 is too small acceleration is poor, WOT mph is good but the engine may be overloaded in rough seas. When feature 34 is properly sized, the tunnel VAC is correct, the acceleration is good and the WOT mph is good.
Figure A reference to dimension Y illustrates that if feature Y is too small the acceleration is poor but WOT mph is excellent. If feature Y is too large, acceleration has no effect and WOT mph is poor. If feature Y is sized correctly, the acceleration is good and the WOT mph is good.
Figure A and B reference to area 14 illustrates that if area 14 is too small, acceleration is poor and WOT mph is poor.
It is to be understood that while a certain form of the invention is illustrated, it is not to be limited to the specific form or arrangement of parts herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown in the drawings and described in the specification. | The instant invention is directed toward a marine craft having a semi-enclosed surfacing type propeller in a tunnel that draws air through specific areas located and shaped to enhance performance and compensate for prime mover torque and horsepower characteristics. The invention further relates to the field of marine water craft, particularly to high speed power boats utilizing a surface piercing propeller drive system mounted within a propeller tunnel formed integral to the hull of the boat, and most particularly to inclusion, within a wall of said tunnel, of a means for providing air thereto; said means being judiciously placed for linearization of the relationship between vessel velocity and engine speed. | 1 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to methods for making glass discharge tubes having a flat elliptic cross-section. In particular, the present invention relates to a method for making an elliptic thin glass tube at high accuracy and low cost.
[0003] 2. Description of the Related Art
[0004] Glass tubes having a flat elliptic cross-section have been generally formed by tube drawing called a Danner process. In the method for making glass tubes by the Danner process shown in FIG. 7, a molten glass material that is melt in a melting furnace (not shown) at 1,300° C. to 1,500° C. in introduced into a platinum cylinder called a sleeve 74 to form a cylindrical glass tube, and the cylindrical glass tube passes through a shaping unit 72 at a temperature above the softening point of the glass in a production line. The shaping unit 72 has at least a pair of upper and lower rollers 73 . The glass tube is pressed by the upper and lower rollers 73 to be deformed into a flat elliptic cross-section.
[0005] Unfortunately, the flat elliptic glass tubes directly produced by the Danner process from the molten glass exhibits poor shaping stability. Furthermore, it is difficult to produce thin glass tubes with an inner diameter of about 0.5 mm to 5 mm with high accuracy by the Danner process.
[0006] General glass tubes produced under predetermined processes have high productivity, for example, several tens of tons every day; hence, yearly required amounts of glass tubes could be produced within several days. However, control of the shape of flat elliptic glass tubes requires many hours. Thus, production dedicated to fine discharge tubes inevitably consumes much expense.
SUMMARY OF THE INVENTION
[0007] An object of the present invention is to provide a method for readily making a flat elliptic thin glass tube at high accuracy and low cost prefaerably the tube having an inner diameter of about 0.5 mm to 5 mm.
[0008] The present inventors made flat elliptic glass tubes by sealing their two ends of inexpensive glass tubes with a circular cross-section formed by a Danner process and then shaping the glass tubes in a shaping unit that determines their outer shape. The cross-section and the thickness of each flat elliptic glass tube were proportionally contracted by a redrawing process to produce a flat elliptic thin glass tube for a discharge tube. The present invention has been accomplished based on these experiments.
[0009] According to the present invention, a method for making a flat elliptic thin glass tube for a discharge tube includes the following steps of (a) hermetically sealing a cylindrical glass tube; (b) heating and deforming the cylindrical glass tube in a mold by an increased internal pressure of the glass tube caused by the heating of the glass tube to form a flat elliptic glass tube, the mold having means for defining at least the minor axis of the flat elliptic glass tube; and (c) drawing while heating the flat elliptic glass tube to form the flat elliptic thin glass tube.
[0010] Preferably, in the step (b), the cylindrical glass tube is maintained at a temperature which is 70% to 90% of the softening point of the glass tube.
[0011] Preferably, in the step (c), the length of a region at a maximum temperature of a heating path for heating the flat elliptic glass tube is 10% or less of the total length of the heating path.
[0012] Preferably, the maximum temperature of the heating path is 1.07 times to 1.1 times the softening point of the flat elliptic glass tube.
[0013] Preferably, the maximum temperature of the heating path is 1.08 times to 1.09 times the softening point of the flat elliptic glass tube.
[0014] Preferably, the heating rate is in the range of 10° C./min to 300° C./min in a heating portion of the heating path.
[0015] Preferably, in the step (c), the feeding rate of the flat elliptic thin glass tube is 20 times to 400 times the feeding rate of the flat elliptic glass tube.
[0016] According to the present invention, a flat elliptic thin glass tube with a predetermined size and shape is readily produced at high accuracy and low cost by using a commercially available inexpensive cylindrical glass tube. Discharge tubes formed of this flat elliptic thin glass tube have a stable size and shape and thus exhibit uniform discharge characteristics. The discharge tubes are preferably used in a display apparatus.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] [0017]FIG. 1 shows a schemetivally perspective view of a display device including flat elliptic thin glass tubes produced by a method according to the present invention;
[0018] [0018]FIG. 2 shows a schemetivally perspective view of an apparatus for making a flat elliptic glass tube;
[0019] [0019]FIGS. 3A to 3 C show schemetivally cross-sectional views of the apparatus shown in FIG. 2;
[0020] [0020]FIG. 4 shows a schemetivally schematic illustration of an apparatus for making a flat elliptic thin glass tube;
[0021] [0021]FIG. 5 is a graph showing a temperature profile in a heating furnace used in an experiment for making a thin glass tube according to the present invention;
[0022] [0022]FIGS. 6A and 6B show a schemetivally front view and a schemetivally side view, respectively, of a redrawing apparatus for making a thin glass tube according to the present invention; and
[0023] [0023]FIG. 7 shows a schemetivally schematic illustration of a conventional Danner process for making an elliptic glass tube.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] [0024]FIG. 1 is a perspective view of a display device including flat elliptic thin glass tubes produced by the method according to the present invention. A rear support 1 composed of a resin or glass substrate is provided with a plurality of data electrodes 13 (three electrodes for displaying red, green, and blue colors, respectively are drawn in the drawing) thereon. Hereinafter, red, green and blue colors are referenced as R, G, and B, respectively. R tube, for example, means a tube for red color. R, G, and B flat elliptic thin glass tubes produced by a method described below are in contact with the respective data electrodes 13 . Plural pairs of display electrodes 11 perpendicular to electrodes 13 are arranged on a transparent sheet 3 ; the outer face of each flat elliptic thin glass tube 2 is in contact with the corresponding data electrode 13 at the bottom and with the display electrodes 11 at the top. The display electrodes 11 are covered with the transparent sheet 3 that functions as a front support. The transparent sheet 3 is bonded to the thin glass tubes with an adhesive layer (not shown). Although is not shown in the drawing, each display electrode 11 has a composite structure including a transparent electrode and a metal bus electrode to reduce its line resistance and the shading area so that visual light can be effectively emitted through the thin glass tubes.
[0025] Each thin glass tube is filled with discharge gas and has an electron-emitting layer 14 and three primary color fluorescents layers 16 R, 16 G, and 16 B on the inner wall. These fluorescents layers 16 R, 16 G, and 16 B are preliminarily formed on a fluorescent support 15 and the flourescent support 15 is placed at a predetermined position in the thin glass tube.
[0026] For performing display, selective discharge is generated between a data electrode 13 in contact with a selected thin glass tube and a pair of display electrodes 11 and then continuous discharge is generated between the pair of display electrodes 11 .
[0027] A method for making the above flat elliptic thin glass tube will now be described according to the steps.
[0028] Steps for Making Flat Elliptic Glass Tube
[0029] [0029]FIG. 2 is a perspective view of an apparatus for making the flat elliptic glass tube, and FIGS. 3A to 3 C are cross-sectional views of the apparatus.
[0030] Referring to the left in FIG. 2, both sides of a glass tube 21 (Pyrex # 7740 made by Corning, diameter: 10 mm, thickness: 1.0 mm, length: 500 mm, softening point: 821° C.) are sealed by melting. The sealed glass tube 21 is placed into a 500 mm long shaping unit 22 composed of carbon, quartz, or silicon carbide and having a rectangular cross-section of 8.6 mm by 11.8 mm. The two ends of the sealed glass tube 21 may put into the shaping unit 22 or may lie outside the shaping unit 22 , as shown in the drawing. FIG. 3A shows a state of the glass tube 21 in the shaping unit 22 .
[0031] The glass tube 21 in the shaping unit 22 is placed in a heating furnace (not shown in the drawing) and is heated to 640° C to cause deformation of the glass tube 21 into a shape (flat elliptic cross-section) all along the inner shape of the shaping unit 22 due to an increased inner pressure and the softening of the glass tube 21 , as shown in the right in FIG. 2 and FIG. 3A. After the deformation of the glass tube 21 , the glass tube 21 with the shaping unit 22 is cooled. A flat elliptic glass tube 23 is thereby formed. Since the glass tube is more rapidly cooled than air in the tube in the cooling process, the glass tube 23 maintains its flat elliptic cross-sectional shape. Preferably, the maximum temperature of the heating furnace is in the range of 600° C. to 720° C. for Pyrex glass or is in the range of 70% to 90% of the softening point for other glass materials.
[0032] Referring to FIG. 3B, the glass tube 21 that is placed into the shaping unit 22 may have an outer diameter larger than the short side of the shaping unit 22 . In such a case, the glass tube 21 in the shaping unit 22 is placed in the heating furnace in a state that one side plate 22 a of the shaping unit 22 is separated from other portions. A predetermined pressure 25 applied from the side 22 a causes deformation of the softened glass tube 21 into a flat elliptic cross-sectional shape along the cross-sectional shape of the shaping unit 22 .
[0033] Referring to the left in FIG. 3C, alternatively, a flat elliptic glass tube 26 may be used for forming the flat elliptic glass tube 23 having a desired cross-sectional shape.
[0034] In this embodiment, the both sides of the glass tube placed into the shaping unit are preliminarily sealed. Alternatively, an open glass tube may be used. In such a case, the open glass tube is placed into the shaping unit and is sealed in the shaping unit.
[0035] Steps for Making Flat Elliptic Thin Glass Tube
[0036] [0036]FIG. 4 is a schematic illustration of an apparatus for making a flat elliptic thin glass tube. The flat elliptic thin glass tube is formed of a flat elliptic glass tube 43 produced in the above steps. The flat elliptic glass tube 43 is heated in a heater 41 provided around a furnace wall 42 and redrawn while its shape being maintained to form a flat elliptic thin glass tube 44 having a predetermined size and shape. In an actual production apparatus, the heater 41 is divided into a plurality of segments (not shown in the drawing), each provided with a thermosensor 45 of a thermocouple. The temperature detected by the thermosensor 45 is fed back to control the current in the heater 41 for maintaining the furnace temperature within a predetermined range.
[0037] The flat elliptic glass tube 43 is fed in the direction shown by arrow A at a feed rate v, while the flat elliptic thin glass tube 44 is being drawn in the direction shown by arrow B at a drawing rate cxv where c is a drawing factor. Feeding of the flat elliptic glass tube 43 and the drawing of the flat elliptic thin glass tube 44 are performed by a plurality of rollers (not shown) disposed on both sides of the tubes. The drawing factor c depends on the material and the size of the flat elliptic glass tube 43 and is preferably in the range of 20 to 400. At a drawing factor c of less than 20 , the cross-sectional homothetic ratio is about 4.5; hence, the major axis of the flat elliptic glass tube 43 must be 4.5 mm in order to form a flat elliptic thin glass tube 44 with a major axis of 1 mm. This figure is not practical. At a drawing factor c exceeding 400 , the heating of the glass tube cannot follow the temperature of the heating furnace. As a result, the glass tube will break because of insufficient softening during drawing. Accordingly, the drawing factor c is preferably in the range of 20 to 400.
[0038] [0038]FIG. 5 is a graph showing a temperature profile in the heating furnace used in the experiment. The vertical axis represents the temperature in the heating furnace, whereas the horizontal axis is a distance from the entrance of the heating furnace. The temperature profile must have three regions, i.e., a heating region for raising the temperature of the glass tube, a holding region for holding a predetermined maximum temperature, and a cooling region for decreasing the temperature of the glass tube. In the heating region, the heating rate is in the range of 10° C./min to 300° C./min. A heating rate exceeding 300° C./min causes insufficient softening of the glass tube because of insufficient heating of the glass tube in the heating furnace. Thus, the glass would be broked by tensile force in the direction of B shown in FIG. 4 in the drawing process. A heating rate of less than 10° C./min requires an impractical longer heating furnace for sufficiently heating the glass tube.
[0039] The holding region is preferably short. At a long holding region, the softened glass tube tends to deform from the flat elliptical cross-section to a circular cross-section by surface tension of the glass. Thus, the length of the holding region is preferably 10% or less of the length of the heater of the heating furnace to maintain the flat elliptical cross-section. The temperature of the holding region is preferably in the range of 891° C.±10° C. for Pyrex and more preferably 891° C.±3° C. for Pyrex. For any other glass, the temperature is preferably in the range of 1.07 times to 1.1 times and more preferably 1.08 times to 1.09 times the softening point of the glass. If the holding region has an uneven temperature profile, the high temperature portion of the glass is drawn while the low temperature portion is not readily drawn, resulting in an uneven cross-sectional shape of the thin glass tube.
[0040] In the cooling region, the glass tube is slowly cooled until the temperature reaches the strain point (510° C. for Pyrex in this embodiment) to remove permanent strain in the glass tube.
[0041] [0041]FIGS. 6A and 6B are a front view and a side view, respectively, of a redrawing apparatus 61 . The redrawing apparatus 61 may be placed vertically or horizontally. The redrawing apparatus 61 has a slider 62 and a pair of drawing rollers 63 . As described above, the slider 62 feeds a glass tube 43 at a feed rate v while the drawing rollers 63 draw the thin glass tube 44 at a drawing rate cxv.
[0042] In this embodiment, the apparatus is used for making a thin glass tube made of Pyrex glass. Any other glass may be used in the present invention. Examples of usable glasses include soda lime glass, borosilicate glass, and quartz glass. The temperature profile of the heating furnace is preferably determined according to the softening point of the glass used. | A flat elliptic thin glass tube for a discharge tube is produced by the following steps: (a) a cylindrical glass tube is hermetically sealed; (b) the cylindrical glass tube is heated and deformed in a mold by an increased internal pressure of the glass tube caused by the heating of the glass tube to form a flat elliptic glass tube, the mold having means for defining at least the minor axis of the flat elliptic glass tube; and (c) the flat elliptic glass tube is heated and drawn to form the flat elliptic thin glass tube. | 2 |
BACKGROUND OF THE INVENTION
This application is a continuation-in-part application of U.S. application Ser. No. 389,867, filed on Aug. 4, 1989, now abandoned.
1. Field of the Invention
The present invention relates generally to invalid lift and transfer devices and more particularly to a mobile, lift-assisted device for transferring a patient from a remote location to a hospital or similar facility.
2. Background Description
A busy Emergency Medical Services (EMS) crew may handle as many as 20 calls during a work shift. Typically one or more such calls involve moving a patient from a field location, such as his home or the scene of an accident, to a health care facility such as an emergency room at a hospital.
Providing transport for the patient involves various procedures for appropriately securing the patient in different transport vehicles for transport to the hospital or other appropriate destination. Such transport involves a constant risk to the EMS crew and to the patient. The risk arises from the activity involving the EMS crew, usually two persons, lifting and moving the patients. There is also the danger that the patient may be dropped or roughly handled while being moved. As for the EMS crew, they are routinely faced with lifting situations which can and often do result in significant and even crippling back injuries. This can occur either because of repetitive lifting of average size patients or occasional lifting of large patients.
The dangers of lifting-related injury is compounded because an EMS crew must lift a patient approximately 7 times during the course of a call. For example, for lifting purposes only, in an emergency involving a 200 lb. man the crew must: 1) lift the patient to a mobile, wheeled device placed at its lowest height adjustment; 2) lift the device and patient to the maximum height adjustment, and then move the device and patient to an ambulance; 3) lower the device and patient back to the lowest height adjustment; 4) lift the device and patient into the ambulance; 5) upon arrival at the medical facility, remove the device and patient from the ambulance and lower them to the ground; 6) again lift the device and patient to the maximum height adjustment, and then move the device and patient into the facility; and 7) lift to transfer the patient from the device to a bed at the facility. During this very typical call the crew has lifted or lowered the patient seven times, thereby doing an amount of work equivalent to lifting more than 1400 pounds when the weight of the device is included.
A particularly difficult part of this process results from the fact that the typical device that is used in the field, e.g., a stretcher for transfer of patients via ambulances, is not well-designed for lifting and lowering. Because of the location of the undercarriage and supporting structure, the members of the EMS crew cannot simply stand on each side of the device and lift or lower it using proper lifting techniques with their legs. Rather, to avoid hitting the undercarriage with their knees, they must turn their bodies sideways, imposing a torquing motion on their backs as they lift and lower. This consequence results in a significant number of disabling back injuries to EMS personnel each year. In addition, because of the strength that is required to lift and lower a device with this type of motion, smaller people, particularly women, are effectively precluded from working as emergency medical technicians.
The foregoing illustrates that it would be advantageous to provide a patient transport device having a lift assisting mechanism, to overcome the need for an EMS crew to exert a great amount of lifting force during a routine emergency call.
Although several such patient transport devices have been proposed, all are too cumbersome to be practically implemented. One example of such a device is found in U.S. Pat. No. 2,833,587 to Saunders which discloses an adjustable height gurney which includes power cylinders provided in the legs of the upper frame and connected to two of the intersecting lever arms (one on each side of the gurney). To operate the cylinders, the EMS technician repeatedly works the handle of a grip up and down to actuate the hydraulic pump. As an alternative, a valve connects the power cylinders to the fluid reservoir, which valve may be opened by a hand lever connected thereto. Both mechanisms for actuating the hydraulic pump cause problems in operation. Use of the handle, which requires repeatedly working the handle up and down is time consuming and can be quite difficult when a patient is on the gurney. Further, in order to remove the gurney from the ambulance, or to place it in the ambulance, the EMS technicians must lift the stretcher, and the patient, from the ambulance to the ground, and visa versa. Then the technicians can use the grip or hand lever to raise the upper carriage. The gurney in the Saunders patent does not provide a means for raising and lowering the lower carriage, in addition to raising and lowering the upper carriage.
SUMMARY OF THE INVENTION
One object of the invention is to provide a mobile, lift-assisted patient transport device comprising a frame having an undercarriage interconnected with a patient supporting portion. The patient supporting portion is height adjustable between a first position adjacent the undercarriage and a second position, vertically displaced from the undercarriage. Self-contained power units are connected to the frame for adjusting the height of the patient supporting portion relative to the undercarriage. Switches are provided for actuating the self-contained power units whereby manual adjustment of the patient supporting portion relative to the undercarriage is avoided.
The foregoing and other aspects of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawing figures, wherein like numbers refer to like elements. It will be readily appreciated that the drawing figures are not intended as a definition of the invention but are for the purpose of illustration only.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. 1 is a side view illustrating an embodiment of the patient transport device of the present invention in a first or lowered position:
FIG. 2 is a side view illustrating an embodiment of the patient transport device of the present invention in a second or raised position;
FIG. 3 is a side view illustrating an embodiment of the patient transport device of the present invention having movable sections thereof adjusted relative to each other; and
FIG. 4 is a plan view illustrating an embodiment of an adjustable portion of the patient transport device of the present invention;
FIG. 5 is an enlarged view of an upper frame portion of the patient transport device of the present invention;
FIG. 6A illustrates the raised position of the patient transport device according to an embodiment including pneumatic cylinders disposed on the undercarriage;
FIG. 6B illustrates the top view of the patient transport device along the line B--B shown in FIG. 6A;
FIG. 6C illustrates the lowered position of the embodiment shown in FIG. 6A;
FIG. 7A illustrates an hydraulic/electric design according to a second embodiment of the present invention;
FIG. 7B illustrates the top view of the patient transport device along the line B--B shown in FIG. 7A;
FIG. 7C illustrates the lowered position of the embodiment shown in FIG. 7A;
FIG. 8A illustrates a third embodiment according to the present invention including a vertically disposed pneumatic cylinder;
FIG. 8B illustrates the top view of the patient transport device along the line B--B shown in FIG. 8A;
FIG. 8C illustrates the lowered position of the embodiment shown in FIG. 8A;
FIG. 9A illustrates a fourth embodiment of the present invention including a vertically disposed hydraulic cylinder;
FIG. 9B illustrates the top view of the patient transport device along the line B--B shown in FIG. 9A;
FIG. 9C illustrates the lowered position of the embodiment shown in FIG. 9A;
FIG. 10A illustrates a fifth embodiment of the present invention including an angled pneumatic cylinder;
FIG. 10B illustrates the top view of the patient transport device along the line B--B shown in FIG. 10A;
FIG. 10C illustrates the lowered position of the embodiment shown in FIG. 10A;
FIG. 11A illustrates a sixth embodiment of the present invention including an angled hydraulic cylinder;
FIG. 11B illustrates the top view of the patient transport device along the line B--B shown in FIG. 11A;
FIG. 11C illustrates the lowered position of the embodiment shown in FIG. 11A;
FIG. 12A illustrates a seventh embodiment of the present invention including an electric screw rod;
FIG. 12B illustrates the top view of the patient transport device along the line B--B shown in FIG. 12A;
FIG. 12C illustrates the lowered position of the embodiment shown in FIG. 12A;
FIG. 13A illustrates an eighth embodiment of the present invention including a vertical pneumatic air bag;
FIG. 13B illustrates the top view of the patient transport device along the line B--B shown in FIG. 13A; and
FIG. 13C illustrates the lowered position of the embodiment shown in FIG. 13A.
DETAILED DESCRIPTION
Referring now to the drawings, in FIGS. 1 and 2 a mobile, lift-assisted patient transport device designed for field use comprises a frame generally designated 10 and preferably formed of tubular aluminum. The frame 10 includes an undercarriage 12, or terrain engaging portion, pivotally interconnected via a scissors linkage 24, 26 at pivot point 14 and joint 14a with a patient supporting portion 16. The two legs 24 and 26 of the scissors linkage are hinged together at a central pivot point 27. The frame 10 is height adjustable between a first position (FIG. 1), wherein the patient supporting portion 16 is adjacent the terrain engaging portion 12, and a second position (FIG. 2), wherein the patient supporting portion 16 is remote from the terrain engaging portion 12. As can be seen in FIG. 5, joint 14a is movable within a groove 15 formed on the patient supporting portion 16. In an alternative embodiment (not shown), the joint 14a may be formed with a groove on the inside thereof. A pivotable member is provided in the groove which facilitates movement of the joint along the rail of the patient supporting portion 16.
The terrain engaging portion 12 includes tubular members 18 which telescopingly cooperate with tubular members 20 to form a horizontal rectangular frame. These two members move toward and away from each other in response to actuation of a self-contained lift assisting means 22 carried by the terrain engaging portion 12 via interconnecting arms 30 (see FIG. 4). Actuation of the lift assisting means 22 causes the terrain engaging portion 12 to move between the dotted line and solid line positions A and B, respectively, illustrated in FIG. 4. When the two members 18 and 20 move toward one another to the solid line position B, and the terrain engaging portion 12 is on the ground, pivotal movement of the linkages 24 and 26 raises the patient supporting portion 16 to the second position illustrated in FIG. 2. When the members 18 and 20 move away from one another to the dotted line position A, the pivotal movement of the linkages 24 and 26 lowers the patient supporting portion 16 to the first position illustrated in FIG. 1. To remove the patient transport device from the ambulance, the EMS technicians roll it out of the door until only the wheels 44 are left in the ambulance. One of the technicians then presses the switch 58 (see FIGS. 6-13), and the terrain engaging portion 12 is automatically lowered to the ground. Thus, the EMS technicians need not lift the stretcher and the patient to the ground. Further, when the patient transport device is being loaded into an ambulance from the raised position, the wheels 44 are placed on the ambulance floor and the patient supporting portion 16 is supported by the EMS technicians. The technician then depress the switch 58, which causes the terrain engaging portion 12 to be lifted towards toward the patient supporting portion 12. The device can then be rolled onto the ambulance. For mobility, the terrain engaging portion 12 includes a plurality of omni-directional wheels 28.
This arrangement of the lift-assisting means also enables the patient transport device to be moved between its lowest and highest positions without requiring a large longitudinal movement of the telescoping members 18 and 20 relative to one another. Typically, for the patient supporting portion to go from its lowest to its highest positions it must travel a vertical distance of about two feet. However, within this range of movement the two telescoping members 18 and 20 of the undercarriage only move about eight inches relative to one another. Therefore, the lift assisting device 22 need not provide a large degree of translational movement to be effective.
The lift assisting device 22 is preferably implemented by means of a pneumatic cylinder. This type of device is preferred because it is powered by compressed gas, which is readily available in most EMS environments. More particularly, emergency medical technicians generally have compressed oxygen with them on emergency calls. The tank of oxygen can be easily connected to the pneumatic cylinder 22, and a suitable valve on the tank can be opened and closed to assist in raising and lowering the patient transport device during use.
It will be readily appreciated, however, that other devices can be used to implement the lift assisting means. For example, as seen in FIGS. 12A (raised position), 12B (top view), and 12C (lowered position) a lead screw 90 that is driven by an electric motor 92 can provide the necessary translational movement to assist in lifting and lowering the patient transport device. With this implementation, a portable battery 94 is preferably mounted on the undercarriage 12 to provide the necessary power to drive the motor. Control of the motor can be provided by means of a suitable switch 58 mounted at a convenient location on the patient supporting portion of the device. Additional switches can be placed on the front, rear and other side of the patient supporting device for easy access by the EMS technicians. The switches could be powered either by the battery 94 (in the hydraulic embodiments) or by separate small batteries (not shown).
It is not necessary that the lift assisting mechanism be a motor, however. For example, it would be feasible and within the general objective of the present invention to place tension springs between the opposed ends of the tubular members 1 and 20 which would tend to pull these two members together. This arrangement would cause the device to normally assume its raised position, and would drastically reduce the manual effort required to raise and lower the patient supporting portion when a patient is placed upon it.
Referring to FIG. 3, the patient supporting portion 16 includes a plurality of sections 31, 32, 34 which are pivotally interconnected at pivot points 36. The sections 31, 32, 34 may be maintained in an in-line configuration C such as that illustrated in FIGS. 1 and 2. Also, the sections 31 and 34 may be moved by actuation of pneumatic cylinders 22a, 22b, respectively, between the in-line configuration C and a configuration D such as that illustrated in FIG. 3 in which the section 31, which generally supports a patient's upper body portion, is raised, and in which the section 34, which generally supports a patient's legs, is lowered. The section 32, which generally supports a patient's hips, remains in the horizontal position of FIGS. 1 and 2. The sections 31 and 34 are adjustable independently of each other and independently of the section 32 through suitable control of their respective actuators 22a and 22b, for example by means of valves connecting each to a source of compressed gas. Also, the sections 31 and 34 are adjustable independent of the height adjustment of the patient supporting portion 16 relative to the terrain engaging portion 12.
Further, the sections 31 and 34 are adjustable to a plurality of dotted line positions E intermediate of the in-line configuration C of FIGS. 1 and 2 and the configuration D of FIG. 3. A collapsible side rail 37 and a foot rest 38 can be included in the frame-work of the patient supporting portion 16. Also, a cushion 40 is typically provided on the patient supporting portion 16 to improve patient comfort. As stated above, to facilitate loading the patient transport device into an ambulance or the like, a slide bar 42 having loading wheels 44 (FIG. 2) can be provided on the underside of the patient supporting portion 16.
FIGS. 6A, 6B and 6C illustrate an embodiment of the present invention which include two pneumatic cylinders 56 disposed on the terrain engaging portion 12. Pneumatic cylinders 56 are operated by a compressed air tank 50 which includes a regulator (not shown) and remote controlled valves 54. Supply lines 52 connect the compressed air tank 50 to the pneumatic cylinders 56. A remote control switch 58 is provided on the patient supporting portion 16 for operating the control valves 54. The switch, or switches as discussed above, operate to open and close the valves 54 through wires (not shown) connected to a solenoid (not shown) or some other means of activating electrically controlled valves. Thus, merely by depressing the switch 58, the EMS technician can cause the patient supporting portion, or the terrain engaging portion, to be raised or lowered automatically. No manual effort for lifting or lowering the patient supporting portion is required, other than the depression of the switch.
FIGS. 7A, 7B and 7C show respectively raised and lowered positions of the patient transport device according to the present invention including hydraulic cylinders 56' provided on the undercarriage 12. FIG. 7B illustrates a top view of the terrain engaging portion 12, taken along the line B--B shown in FIG. 7A. The hydraulic cylinders 56' are operated by a hydraulic pump 50' which includes a reservoir (not shown). Supply lines 52' connects the hydraulic pump 50' to the hydraulic cylinders 56'. A battery power source 62 is provided to operate the hydraulic pump 50'. An electric switch 58 is provided to operate the battery source 62 to supply power to the pump 50' in the manner described above with respect to FIGS. 6A-6C.
FIGS. 8A, 8B and 8C illustrate an embodiment of the present invention which includes a pneumatic cylinder 70 connected vertically between the patient supporting portion 16 and the terrain engaging portion 12 of the patient transport device. FIGS. 9A and 9B illustrate a similar embodiment which includes a hydraulic cylinder 70' disposed vertically between the patient supporting portion 16 and the terrain engaging portion 12. In these two embodiments, the vertical cylinder 70, 70' is composed of a telescoping lifting rod to enable the rod to extend to the fullest height necessary in order to transport the patient in the raised position. The rod is connected to cross bars 71 disposed on the patient supporting portion 16 and the terrain engaging portion 12. The remainder of the driving means for driving the cylinders 70, 70' are similar to those described in the embodiment shown in FIGS. 7A, 7B and 7C and 6A, 6B and 6C.
FIGS. 10A, 10B and 10C illustrate an embodiment of the present invention which includes a pneumatic cylinder 80 which is disposed at an angle relative to vertical. A cross rod 82 is provided between the two legs 24. Another embodiment of the angled cylinder 80' is shown in FIG. 11A, 11B and 11C which illustrate a hydraulic cylinder similar to that shown in FIGS. 7A, 7B and 7C and 9A, 9B and 9C.
FIG. 13A, 13B and 13C illustrate another embodiment of the present invention which includes a pneumatic bag 100 connected between the patient supporting portion 16 and the terrain engaging portion 12 of the patient transport device. The pneumatic bag 100 consists of a collapsible air bag cylinder connected through the supply line 104 to a compressed air source 102. The compressed air source 102 includes an air tank, regulator (not shown) and remote controlled valves (not shown). These valves are operated by the electric switch 58 to inflate and deflate the collapsible air bag 100. A low pressure air bag is used which would allow smooth movements between the upper and the lower positions of the patient transport device. Springs 106 are provided inside the tubular members 20 to provide a biasing force against which the air bag 100 works. In the raised position of the device, the springs 106 are compressed, while in the lowered position, the springs 106 are in their non-tensioned state. The springs 106 are placed or fixed between the end of the inner tubular member 20 and the opposite end of the outer tubular member 20. In one possible embodiment, 300 lb. springs can be used.
Although not shown in FIGS. 6A, 6B and 6C through 13A, 13B and 13C, the patient supporting portion of these embodiments may consist of three sections, as shown in FIG. 3.
The foregoing has described a lift-assisted, mobile, field-use patient transport device which enables an EMS crew to avoid much of the lifting involved in moving the patient between the raised and lowered positions on the stretcher. Such structure can reduce the load lifted by the crew in the previously described example by as much as 1000 lbs. Further, when a powered device is used as the lift assisting mechanism, the height of the stretcher can be set at any incremental position between the lowest and highest positions, rather than be limited to a few, fixed number of positions as in conventional, manually operated stretchers. | A mobile device for transporting patients in the field is power adjustable and includes a frame having a terrain engaging portion connected to a patient supporting portion. The patient supporting portion is height adjustable between a first position adjacent the terrain engaging portion and a second position remote from the terrain engaging portion. A self-contained power device is connected to the frame for adjusting the height of the patient supporting portion relative to the terrain engaging portion. An actuator is operably connected for actuating the self contained power device whereby manual adjustment of the patient supporting portion relative to the terrain engaging portion is avoided. The patient supporting portion has a plurality of sections adjustable relative to each other. The self-contained power device provides adjustment for the sections independently of each other and independently of the height adjustment. | 0 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] Non-Provisional Application based on Provisional Application No. 60/830,614 filed Jul. 14, 2006
[0002] This Application claims the benefit of U.S. Provisional Application No. 60/830,614 filed Jul. 14, 2006.
BACKGROUND OF THE INVENTION
[0003] The present invention relates to the membrane separation of higher boiling point components from mixtures with a wide range of boiling points. In particular, the present invention is a membrane and process to separate aromatics from gasoline, or similar wide-boiling mixtures, such as petroleum naphtha.
[0004] Pervaporation is a well-known membrane process. Pervaporation has been and is being considered for recovery of aromatics from refinery streams. A multicomponent liquid feed may be separated based on a selective solution-diffusion mechanism, with the permeate removed as a vapor. A vacuum is typically maintained on the permeate side of the membrane to facilitate permeation. Pervaporation is an endothermic process. Heat input is required to maintain the pervaporation process. Typically, the feed to the pervaporation process is preheated to temperature selected for efficient permeation of the select portion of the feed into the membrane, and at a pressure sufficient to maintain the feed in liquid phase. The desired operating temperature and flux are maintained by heating the membrane and/or by reheating the feed. Adiabatic operation in conventional membrane separation systems can result in a significant drop in temperature and loss of permeate flux. Interstage reheating of the retentate/feed is conventionally used to maintain temperature. Adiabatic operation is very desirable, and most desirable without a significant drop in temperature.
[0005] Gasoline is a complex mixture of aliphatic and aromatic hydrocarbons having a wide boiling range. Aromatics may be separated from gasoline by pervaporation to obtain higher-octane fuel. However, the wide boiling range, variable composition and volatility of market gasolines make separation with simple pervaporation membrane systems difficult and inefficient. The lower boiling, lower octane aliphatic components in gasoline permeate competitively with the higher boiling higher-octane aromatics, thereby limiting the permeation of the aromatic content. The competitive permeation of aliphatic compounds also limits membrane selectivity, thereby reducing aromatic selectivity. High yields of aromatic permeate require considerable energy, which reduces the overall efficiency of the membrane system. Prior art membrane systems have also employed pre-distillation steps to remove lower boiling aliphatics from gasoline, thereby concentrating aromatics in the higher boiling liquid. Complex systems using pre-fractionation, multi-stage membrane processing, and/or recycle with post-fractionation, to address these issues are generally not desirable for efficient membrane systems.
[0006] The present invention enables considerable simplifications to the pervaporation process, when separating wide boiling range feeds such as gasoline for example. These simplifications can lead to the reduced cost, weight and volume and system complexity required for increased efficiency to enable commercialization of this application.
SUMMARY OF THE INVENTION
[0007] Processes for the segregation of aromatics from gasoline cuts by use of a pervaporation membrane system typically involve liquid feed operation. When a liquid feed approach is applied to wide range boiling streams, e.g marketable gasolines, a relatively deep vacuum is required to achieve concentrations of aromatics in the permeate. This is because the C6 and lower boiling point constituents of the gasoline, typically relatively low in aromatics, permeate the membrane preferentially unless the backpressure on the membrane is low enough to mitigate the effect of the high vapor pressure of these compounds on permeation rate.
[0008] In the present invention, the competitive permeation of low boiling aliphatics can be largely avoided allowing effective performance with enhanced aromatics selectivity at only moderate membrane backpressures. The present invention includes feeding the gasoline or naphtha in a mixed vapor/liquid phase state, at a controlled extent of vaporization and then operating the membrane module in an essentially adiabatic mode. This eliminates the need for any predistillation. The heavier aromatic rich portion of the vapor preferentially condenses onto the membrane, enhancing aromatics permeation, and the heat of condensation of this portion of the vapor provides the heat needed to vaporize the permeate on the back side of the membrane. As the aromatics permeate the membrane (depleting aromatic content of the liquid contacting the membrane) they are replenished by the continual preferential condensation of the higher boiling aromatics contained in the vapor portion of the feed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates a simple embodiment of the present invention.
[0010] FIG. 2 shows a schematic of the apparatus used for Improved Membrane Separation using mixed vapor-liquid feed.
[0011] FIG. 3 shows a schematic of alternative apparatus for improved membrane separation using mixed vapor-liquid feed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] Separations of aromatics from gasoline, or similar wide-boiling mixtures, such as petroleum naphtha, are improved by means of a pervaporation membrane process employing a mixed phase vapor-liquid feed. The extent of feed vaporization is controlled, as detailed hereinafter, a consequence of which aromatic selectivity of the permeate is increased. Higher permeate yields of aromatics are also made possible in adiabatic operations. Simplified system configurations are enabled with the present invention.
[0013] Partial vaporization of gasoline feed concentrates the higher boiling fraction of the feed which is rich in aromatic components in the liquid fraction. Preferential wetting of the membrane surface by this liquid phase results in higher aromatic concentrations contacting the membrane, thereby improving flux and selectivity when compared to processing the full boiling range gasoline as a liquid. Lower boiling aliphatic components of the gasoline preferentially remain in the vapor phase, thereby reducing competitive permeation through the membrane.
[0014] Furthermore, adiabatic operation of the pervaporation membrane separation process is improved by employing mixed phase vapor-liquid feed. Progressive condensation of the vapor phase, provides heat to the membrane thereby minimizing the temperature change of the membrane resulting from the endothermic pervaporation process. Significant permeate yield gains are made possible from near adiabatic operation using mixed-phase feed. Consequently, the membrane area required can be reduced. Pervaporation of mixed-phase vapor/liquid feed enables considerable simplifications to the process scheme, i.e. predistillation of lower boiling components in the feed can be avoided, along with the associated pumps and controls. Interstage and/or internal heat exchangers to maintain pervaporation temperature can be reduced or eliminated.
[0015] Referring to FIG. 1 , there is shown a very simplified schematic illustration of the membrane separation system of the present invention. A feed reservoir contains the wide boiling range material ( 1 ) that is intended for membrane separation, such as conventional gasoline or naphtha, for example. The term “wide boiling range” in the context of gasoline or naphtha means a boiling range of greater than about 50° C. and preferably great than 150° C. from the initial boiling point to the final boiling point as determined by ASTM MethodD86-05. Gasoline boiling ranges from 30° to 200° C. are typical based on this method. Aromatic constituents are found in fractions boiling above about 80° C. Pump means ( 2 ) is used to feed and pressurize the feed material to the membrane apparatus ( 5 ). The desired feed rate is controlled by a flow control valve ( 3 ). The desired feed pressure is controlled by back pressure regulating means ( 8 ) operating on the retentate ( 7 ) selected based on the composition of the feed and desired operating temperature of the membrane. Heater means ( 4 ) is used to control the temperature of the feed to the membrane apparatus ( 5 ). In a preferred embodiment, the feed pressure P f and membrane temperature T f are controlled to provide an optimal vapor liquid mixture to the membrane. By optimal, we mean a vapor liquid mixture whereby the aromatic components in the feed are concentrated in the liquid portion contacting at least a portion of the membrane. Conversely, the lower boiling point aliphatics are concentrated in the vapor. In a preferred embodiment, the aromatics in the liquid portion of the vapor liquid mixture fed to the membrane are concentrated by greater than about 10%, more preferably greater than about 25%, and most preferably greater than about 50%. The end result of which is to condense a liquid layer onto the membrane that is rich in the constituents of the feed that comprise the preferred permeate while maintaining the remaining feed in a vapor state. The term “preferred permeate” means the constituents of the feed that the invention's user wish to separate, as permeate, from the feed. The term “preferred retentate” means the constituents of the feed that the invention's user wish to separate as retentate and which, if in liquid form at the separation membrane, would compete with the preferred permeate. In this embodiment, the preferred retentate contains aliphatic constituents of the feed that have a lower boiling range than the preferred permeate.
[0016] Feed material is partially vaporized to maintain dual feed states, liquid ( 1 a ) and vapor ( 1 b ). The term “partially vaporized” means there is sufficient vaporization to provide the optimal vapor liquid mixture to the membrane as described in paragraph [ 0013 ]. As illustrated in the figure, the liquid ( 1 a ) contacts and wets the pervaporation membrane ( 5 a ). As previously described, liquid ( 1 a) has an increased content of the preferred permeate (relative to the feed), while the vapor ( 1 b ) phase has an increased content of the preferred retentate.
[0017] The pervaporation membrane ( 5 a ) is a selective membrane, selected to preferentially permeate the preferred permeate. In a preferred embodiment where feed ( 1 ) comprises gasoline or naphtha, for example, and the preferred permeate is aromatics rich hydrocarbons, pervaporation membrane ( 5 a ) is an aromatic selective membrane such as described in U.S. Pat. No. 5,670,052 for example. The selective pervaporation membrane ( 5 a ) may include a physical porous support means (not shown) such as Gortex™, for example, capable of providing physical support of the selective pervaporation membrane ( 5 a ) under the temperature, pressure, and materials conditions described herein. Alternative supports include sintered metal or ceramic porous media. A preferred support means includes an asymmetric porous media such as a porous ceramic tube or monolith having a microporous surface material, such as described in co-pending application U.S. Ser. No. 60/836,319.
[0018] In a preferred embodiment, selective pervaporation membrane ( 5 a ) comprises a cross-linked polyimide-polyadipate membrane polymer supported on a porous ceramic support means.
[0019] A feature of the present invention is the substantially adiabatic operation of the pervaporation membrane ( 5 a ). The pervaporation process is endothermic. As previously described, the feed material is maintained partially vaporized. Progressive condensation of the higher boiling temperature constituents of the vapor phase feed onto the pervaporation membrane supplies heat to the membrane, offsetting the heat lost to the endothermic pervaporation process.
[0020] Yet another feature of the present invention is the liquid layer ( 1 a ) that contacts the separation membrane ( 5 a ). The membrane temperature T f and the pressure on the membrane feed side P f are maintained to condense a relatively thin layer of preferred permeate rich condensate on the membrane surface. Though not intending to be bound by any particular theory, in a preferred embodiment the liquid layer ( 1 a ) is maintained as a relatively thin layer to facilitate achieving and maintaining both thermal and compositional equilibrium between vapor, liquid and membrane. In the embodiment where feed comprises conventional gasoline or naphtha and the preferred permeate is the aromatic constituents of the feed, the liquid layer is maintained by control of T m and P f such that the condensation rate of aromatic-rich constituents is about equal to the permeate rate of such constituents.
[0021] Permeate ( 6 ), having increased concentration of the preferred permeate, is condensed and collected by conventional means illustrated by pump means ( 9 ).
[0022] Retentate ( 7 ) is collected by conventional means.
[0023] The examples presented below illustrate and exemplify the subject matter for this invention.
EXAMPLE 1
Pervaporation Membrane
[0024] An aromatic selective membrane of the type described in U.S. Pat. No. 5,670,052 was used to concentrate aromatics from the gasoline in the permeate. The polyimide-polyadipate membrane used was crosslinked with diepoxidecyclooctane (DECO). The polyimide hard segment contains pyromellitic dianhydride (PMDA) and 4,4′-methylene bis(2-chloroaniline) (MOCA). The soft segment polyadipate had a molecular weight of about 2000.
[0025] The PEI-DECO polymer was coated on a 0.1 micron porosity Gortex support to a thickness of about 40 microns. The polymer film was protected by an additional layer of 0.05 micron porosity Gortex overlayer, thereby creating a sandwich structure with a total membrane thickness of about 150 microns. Spiral-wound membrane elements of 0.9 m 2 active area each were fabricated from the coated sheets and used for the separations as described in Examples 3 and 4.
[0026] A plate-frame (wafer cassette) module design with internal heating was also used as noted in the examples. Polymer coating thickness was 7 microns. Two sheets were layered together, front to back, for a nominal total PEI-DECO polymer thickness of 14 microns, followed by an additional 0.05 micron porosity Gortex overlayer. Several sheets were used flat and sealed by means of viton o-rings to obtain 0.2 m 2 area.
EXAMPLE 2
[0027] A simplified process schematic of the apparatus used in this example is provided in FIG. 2 . A conventional gasoline feed ( 20 ) was pressurized by pump ( 21 ) to obtain the desired feed pressure. Feed flow was controlled by a mass flow control valve ( 22 ). The feed was heated to the desired temperature by means of a heat exchanger ( 23 ) by contacting against a circulating hot ethylene glycol-water mixture, for this example, typically maintained at 120° C. Alternatively, a silicone oil bath was used to obtain gasoline feed temperatures up to about 160° C. The preheated feed is substantially vapor upon delivery into the membrane module ( 24 ). Backpressure on the membrane was controlled by means of a pressure regulator ( 25 ) operating on the retentate stream ( 28 ) thereby providing the desired operating pressure P f . The permeate ( 26 ) was recovered under vacuum provided by a vacuum pump ( 32 ). The permeate vapor was cooled by means of heat exchanger ( 27 ) to about 30° C. The “heavy” permeate condensate ( 26 a ) was separated, by means of the gas/liquid vacuum separator ( 30 ), from the remaining permeate vapor ( 26 b), and recovered by means of a liquid pump ( 29 ) then stored in gasoline reservoir ( 31 ) which, in this example, is a high octane fuel reservoir. The remaining permeate vapor ( 26 b ) was compressed by the vacuum pump ( 32 ) and cooled to about 30° C. by heat exchanger ( 33 ) to obtain additional “light” liquid permeate ( 26 c ) from the vacuum exhaust. Alternatively, the entire permeate ( 26 ) was cooled by heat exchanger ( 27 ) and compressed by vacuum pump ( 32 ) to obtain the high octane fuel. Hot retentate ( 28 ) was cooled to about the ambient temperature of 20° C. by means of forced air-fin heat exchanger ( 37 ) and stored in reservoir ( 39 ) which serves in this example as a low octane gasoline reservoir. In some examples, a portion of the hot retentate ( 28 ) was recycled by means of pump ( 36 ) to mix with the membrane feed ( 20 ) prior to heating with heat exchanger ( 23 ).
EXAMPLE 3
[0028] For this embodiment, a polymer coated ceramic monolith was constructed in the following manner:
[0029] A solution of poly(ethylene adipate) “PEA,” pyromellitic dianhydride “PMOA,” 4,4′-methylene bis(2 chloroaniline) and 1,2,5,6-diepoxycyclo octane “DECO” was mixed with equal amounts of DMF and acetone to create an approximate 2.0 wt % polymer solution. The final molar ratios of the components were nominally 1-PEA2000/2-PMDA/1-MOCA/2-DECO. The solution was maintained at room temperature or lower after adding DECO. The solution was used to coat a porous ceramic monolith by drawing the liquid polymer into the porous surface of the monolith. The coated monolith was caused to form a polymer film of the composition described in U.S. Pat. No. 5,670,052 on the surfaces, including the interior surfaces, of the porous monolith, forming a polymer coating substantially free of voids and holes, having a surface area of about 0.1 m 2 .
[0030] The membrane was used in the simplified process and apparatus depicted in FIG. 2 . A conventional gasoline comprising Japanese regular unleaded winter grade gasoline was used as feed ( 21 ). The feed gasoline was tested to determine its octane rating and composition, having about 90.3 RON, about 33.9 wt % aromatics, and about 23.1 wt % C5 minus light aliphatic hydrocarbons. The process illustrated in FIG. 2 was operated under two sets of conditions, the first to produce a liquid phase feed to the membrane system, the second to produce a mixed liquid/vapor feed in accordance with the present invention. Liquid phase feed conditions were obtained by operating at a membrane feed pressure P f of about 960 kPa (absolute), and a membrane outlet pressure of about 950 kPa (absolute). Membrane feed temperature was maintained at about 140° C. These pressures are substantially above the bubble point pressure of the gasoline feed at 140° C., whereby the membrane feed is maintained in a liquid state.
[0031] The same apparatus was used under a second set of process conditions to produce a mixed liquid/vapor phase feed. Accordingly, the membrane inlet pressure was maintained at about 465 kPa (absolute) measured after control valve ( 22 ), and membrane outlet at about 445 kPa (absolute) measured at the back pressure regulator ( 25 ). Membrane feed temperature was maintained at about 140° C., measured at the inlet distributor to the membrane element after heat exchanger ( 23 ). Under these conditions, feed to the membrane was estimated to be about 45 wt % liquid and 55 wt % vapor. Outlet temperatures were measured in the retentate stream exiting the membrane element. In both the liquid phase case and the mixed liquid/vapor case, vacuum was maintained on the cooled permeate by means of an eductor pump ( 32 ). Table 1 below compares permeate rate, permeate octane number, permeate density, permeate aromatics, and permeate aliphatics for both liquid and mixed liquid/vapor feed. Operating with liquid phase conditions resulted in a permeate rate of 0.11 g/s. The adiabatic temperature drop resulting from the pervaporation process was 21° C. The permeate pressure obtained by condensing and pumping away the permeate was 40.7 kPa. The permeate obtained with liquid phase feed had increased aromatic content, but a substantial increase in C5Minus light hydrocarbon content. The light hydrocarbons resulted in a higher vapor pressure permeate and consequently higher permeate pressure. It should be noted that an effect of use of the eductor ( 32 ) is that the permeate pressure is affected by the permeate stream control and is not independently set by the user. The octane number increased corresponding to the increased aromatic content.
[0032] Mixed phase vapor/liquid feed to the membrane in accordance with the present invention, produced improved membrane separation performance. Permeate rate increased to 0.17 g/s. The adiabatic temperature drop was less at 11° C., a consequence of vapor condensation in the membrane feed channels balancing the heat loss associated with the endothermic pervaporation process. Vacuum improved with the permeate pressure at 23 kPa and a corresponding decrease in the volatile C5Minus hydrocarbons in the permeate. The aromatic content of the permeate increased substantially to 52.5%. The permeate octane rating increased to 97.8 RON corresponding to the increased aromatics content and reduced C5Minus content.
[0000]
TABLE 1
Phase
Feed
Liquid
Mixed
Feed Rate, g/s
1.0
1.0
Temperature at Inlet, ° C.
139.2
139.1
Pressure at Inlet, kPa
960
465
Temperature at Outlet, ° C.
117.8
128.3
Pressure at Outlet, kPa
950
445
Permeate Rate, g/s
0.11
0.17
Permeate Pressure, kPa
40.7
23.3
Permeate Octane Number, RON
90.3
96.1
97.8
Permeate Density g/cc at 20° C.
0.7253
0.7285
0.7668
Permeate Aromatic, wt/%
33.9
37.5
52.5
Permeate C5Minus HC, wt %
23.1
31.9
17.2
EXAMPLE 4
[0033] The embodiment of the present invention illustrated in FIG. 2 may be extended to a two stage membrane system, as illustrated in FIG. 3 .
[0034] Similar to example 2, a conventional gasoline 40 was pressurized by pump ( 41 ) to obtain the desired feed pressure. Feed flow was controlled by a mass control valve, not shown. The feed was heated to the desired temperature by heat exchanger ( 43 a ). The pre-heated feed is substantially vapor upon delivery to first membrane module ( 44 a ). The feed pressure P f and temperature T f were maintained to provide an estimated optimal vapor-liquid mixture to the membrane whereby a relatively thin layer of liquid is maintained in contact with the membrane to contact the membrane with aromatics rich liquid. The temperature T f and pressure P f are controlled such that the condensation rate of aromatic rich feed constituents is about equal to the permeation rate of such constituents.
[0035] The retentate ( 45 ) from the first membrane module ( 44 a ) is re-heated by heat exchanger ( 43 b ) and fed to second membrane module ( 44 b ), operated in substantially the same manner as described for first membrane module ( 44 a ). Aromatics-rich permeate ( 46 a ) and 46 b ) from the first and second membrane modules are collected and cooled by heat exchange ( 47 ), separated by separator means ( 50 ) and stored in the high RON reservoir ( 51 ). Retentate ( 49 ) from the second membrane module ( 46 b ) is either cooled by heat exchanger ( 57 ) and stored in low RON reservoir ( 59 ), or recycled to supplement fresh feed ( 40 ). | The present invention pertains to a process for the separation of aromatics from a feed stream, including aromatics and non-aromatics by selectively permeating the aromatics through a membrane comprising feeding a mixed phase vapor-liquid feed to a membrane wherein said liquid phase preferentially wets the surface of the membrane. | 1 |
This application is a continuation-in-part of application Ser. No. 976,438, filed Nov. 13, 1992, now U.S. Pat. No. 5,269,756.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to suction catheters, and more particularly to a method and apparatus for keeping them clear so that effective suctioning can be maintained.
2. Description of the Prior Art
In the use of endotracheal tubes, regardless of whether passed through the mouth or through a tracheotomy, there are times when lung secretions are too thick and sticky to be easily extracted through a suction catheter. Dilution helps thin the secretions and irrigate the catheter lumen so good vacuum flow is maintained, thereby promoting removal of lung secretions which must be removed from the lung.
The current practice of irrigation uses syringes or compressible vials as means of instilling the irrigation solution into the lung along the exterior of the catheter or through a lumen inside the wall of the catheter in order to promote dilution. This practice requires more than two hands or the interruption of the suction flow in order to instill the irrigating fluid into the system. A break in the suction flow may cause the secretion pool to be incompletely removed. Also, there is the possibility that the volume of irrigation fluid from the single loaded syringe or vial may not be adequate and will require a reload effort.
SUMMARY OF THE INVENTION
Described briefly, according to a typical embodiment of the present invention, a thumb or finger operable pump is located near the patient end of the suctioning catheter assembly. This pump receives the irrigation fluid from a comparatively large reservoir and can withdraw the fluid from the reservoir and pump it into an irrigation supply channel in the suction catheter on an as-needed basis during suctioning. Thus, the one hand of the administrator can both stabilize the junction piece at the patient end of the suction catheter and operate the irrigator while the other hand controls vacuum flow and catheter location as needed for the suctioning function. Alternatively, the irrigation pump may be placed on the same member which carries the vacuum flow control so that both devices may be operated by the same hand.
BRIEF DESCRIPTION OF THE DRAWING
The single FIGURE of drawing is a schematic illustration of a cased suction catheter situated for use through a tracheotomy and employing irrigation according to the method and apparatus of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
For the purposes of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated device, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
Referring now to the drawing, a cased suction catheter assembly 11 of the general type shown in my U.S. Pat. No. 5,125,893, issued Jun. 30, 1992, is provided with a four-way junction or cross piece 12 at the patient end (where the tee piece 17 FIG. 1 of that patent was located in the patent) and to which is connected an endotracheal tube 13 entering the trachea (not shown) through a tracheotomy 14 in the neck 16 of the patient. The flexible sheath 17 is connected and sealed to a sleeve 21 received on the end of the cross piece opposite the endotracheal tube. The distal end of the sheath is connected and sealed to the manifold 18.
A catheter tube 19 is fixed in the manifold 18 but slidably received in the sleeve 21 which may have a valve in it (such as valve 23 shown in FIG. 1 in the above-mentioned patents). The catheter tube 19 has an internal lumen 22 which is like and has the same purpose as the lumen 29 in the catheter tube 20 of the aforementioned patent. The patient end of the catheter tube is open at 23 and the lumen 22 opens in the side of the catheter at the patient end at opening 24 from which irrigation fluid can be discharged into the lung around the catheter.
The lumen 22 communicates with the irrigation fluid supply tube 26 connected to the manifold 18. A suction tube 28 is connected to the manifold 18 and through it to the catheter tube 19. However, this suction line is independent of and isolated from the lumen 22 and associated tube 26. A manually operable vacuum control valve 29 is associated with the vacuum line 28 at the manifold. The valve is normally closed but can be opened by the thumb 31 of the administrator. The line 28 is connected to a suction source 32.
An air/oxygen ventilating machine 33 is connected through hose 34 to the bottom stem 36 of the cross fitting.12. According to the illustrated embodiment of the present invention, a self-priming pump assembly 37 is connected to the top stem 38 of the cross fitting. The intake port 39 of the pump is connected to a comparatively large reservoir such as an IV infusion bag 41 which can be hung on arm 42A of an IV stand 42 by means of the eyelet 41E at the top of the bag. The outlet line 43 of the bag is connected to the inlet port 39 of the pump assembly 37. The discharge port 44 of the pump is connected through the tube 46 to a Y-connector 47 which is, in turn, connected to the tube 26. A needle pierceable cap 48 is provided at the upper end of the other branch of the Y-fitting 47 for addition of material to the irrigation system from a syringe if, and when, desired. An overcap 49 on a flexible hinge 51 is provided on the upper end fitting of tube 26 to close that tube if the Y-connector 47 is removed from it. Similarly, hinged overcap 50 is provided at the upper end of the tube 27.
Two one-way valves shown schematically at 45A and 45B are provided between the inlet and outlet ports 39 and 44 of the pump assembly 37. Thus, irrigating fluid can be drawn from line 43 through valve 45A into the pump bellows, and squeezed out by pressure from the thumb of one hand of the administrator and through the one-way valve 45B into the line 46 and thereby through the tube 26 and lumen 22 and out through the opening 24 when in the patient's lung 52, as indicated by the dotted line in the drawing.
OPERATION
As one hand 53 stabilizes the cross fitting 12 and is in position for operation of the pump with the thumb 54 when irrigation is needed, the catheter tube 19 is pushed down into the lung by advancing the other hand 56 forward in the direction of arrow 57. Suctioning can be increased or decreased by decreasing or increasing the opening in vacuum inlet valve 29 by operating the thumb 31. Irrigation is applied as needed by operating the pump 37 by pushing and releasing the upper end of the bellows with the thumb 54.
The pump, being securely attached to the patient end of the cased suction catheter assembly at the cross piece 12, allows the hand that stabilizes the cross piece to also activate the pump which refills automatically, thus permitting fluid irrigation as long as is needed. The other hand controls the vacuum flow as needed to complete the treatment.
Although the-above-described and illustrated pump system lines 46, 26 communicate with an in-the-wall lumen 22 in the catheter, the pump system and line 46 may be connected to line 27 for down-the-catheter lumen purge of the catheter 19 itself in those types of cased catheters which irrigate the interior of the catheter tube itself rather than irrigating at the tip of the catheter. Alternatively or in addition, the irrigation line 46 can be at the patient connector for external wash of the catheter itself. An example would be connection to port 55 of the catheter assembly shown in the U.S. Pat. No. 3,991,762 issued Nov. 16, 1976 to Radford.
If there is any concern about possible confusion between IV lines and bottles with the irrigation system lines and bottles, the apparatus may be sized and/or color coded, and the spike for entering the fluid bag would not have a drip chamber. Similarly, the distal fitting that enters the irrigation sites can be sized or keyed to prevent connection with an intravenous needle or IV lines.
The pump bellows illustrated, or cylinder if a piston pump is used, can be filled from the bag many times by simply releasing thumb pressure from the valve button and without letting go of the catheter system at all. If a piston/cylinder pump is used, the piston pressure of the pump can be changed by the amount of thumb pressure on it. For different situations where nominal thumb pressure might be needed to produce more or less pressure, the amount applied by a given amount of force on the thumb can be determined by selection of appropriate piston diameter. Since it is preferred that the pump be self-priming, the reservoir need not be an elevated bag, but can simply be a bag or other container resting on a surface in the patient area. In an alternative embodiment of the present invention, the self-priming pump assembly 37 may be connected to the exterior of the manifold 18. Such a configuration allows for operation of the pump assembly 37 by a digit of the hand 56.
While the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiment has been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected. | A cased suctioning catheter assembly with a protective flexible sheath around the catheter tube, has a thumb or finger operable pump located near the patient end of the catheter assembly. This pump receives irrigation fluid from a bag hanging on an IV stand and, when operated, pumps it into an irrigation lumen in the suction catheter on an as-needed basis during suctioning. Thereby one hand of the administrator can both stabilize the cross piece at the patient end of the suction catheter assembly and operate the irrigator, while the other hand controls vacuum flow as needed for the suctioning function. | 0 |
FIELD OF THE INVENTION
[0001] This invention relates generally to deuterium-enriched olanzapine, pharmaceutical compositions containing the same, and methods of using the same.
BACKGROUND OF THE INVENTION
[0002] Olanzapine, shown below, is a well known thienobenzodiazepine.
[0000]
[0000] Since olanzapine is a known and useful pharmaceutical, it is desirable to discover novel derivatives thereof. Olanzapine is described in U.S. Pat. No. 5,229,382; the contents of which are incorporated herein by reference.
SUMMARY OF THE INVENTION
[0003] Accordingly, one object of the present invention is to provide deuterium-enriched olanzapine or a pharmaceutically acceptable salt thereof.
[0004] It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the deuterium-enriched compounds of the present invention or a pharmaceutically acceptable salt thereof.
[0005] It is another object of the present invention to provide a method for treating schizophrenia, bipolar disorder, and/or psychotic depression, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the deuterium-enriched compounds of the present invention or a pharmaceutically acceptable salt thereof.
[0006] It is another object of the present invention to provide a novel deuterium-enriched olanzapine or a pharmaceutically acceptable salt thereof for use in therapy.
[0007] It is another object of the present invention to provide the use of a novel deuterium-enriched olanzapine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament (e.g., for the treatment of schizophrenia, bipolar disorder, and/or psychotic depression,).
[0008] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery of the presently claimed deuterium-enriched olanzapine.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0009] Deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1 H (hydrogen or protium), D (2H or deuterium), and T (3H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art recognizes that in all chemical compounds with a H atom, the H atom actually represents a mixture of H and D, with about 0.015% being D. Thus, compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015%, should be considered unnatural and, as a result, novel over their non-enriched counterparts.
[0010] All percentages given for the amount of deuterium present are mole percentages.
[0011] It can be quite difficult in the laboratory to achieve 100% deuteration at any one site of a lab scale amount of compound (e.g., milligram or greater). When 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium-enriched can be achieved by either exchanging protons with deuterium or by synthesizing the molecule with enriched starting materials.
[0012] The present invention provides deuterium-enriched olanzapine or a pharmaceutically acceptable salt thereof. There are twenty hydrogen atoms in the olanzapine portion of olanzapine as show by variables R 1 -R 20 in formula I below.
[0000]
[0013] The hydrogens present on olanzapine have different capacities for exchange with deuterium. Hydrogen atom R 1 is easily exchangeable under physiological conditions and, if replaced by a deuterium atom, it is expected that it will readily exchange for a proton after administration to a patient. Treatment of olanzapine with a deuterated acid such as D 2 SO 4 /D 2 O will cause the exchange of certain protons for deuterium atoms. Among the compounds expected, depending on the contact time and temperature of the exchange reaction, are olanzapine with R 17 =D, olanzapine with R 17 and R 3 -R 4 =D, and olanzapine with R 17 and R 2 -R 5 =D. The remaining hydrogen atoms are not easily exchangeable and may be incorporated by the use of deuterated starting materials or intermediates during the construction of olanzapine. Olanzapine with R 14 -R 16 =D is known (Iyer, et al., J. Chrom. Sci. 2004, 42, 383-387) and has been used for mass spectroscopic (not therapeutic) studies.
[0014] The present invention is based on increasing the amount of deuterium present in olanzapine above its natural abundance. This increasing is called enrichment or deuterium-enrichment. If not specifically noted, the percentage of enrichment refers to the percentage of deuterium present in the compound, mixture of compounds, or composition. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Since there are 20 hydrogens in olanzapine, replacement of a single hydrogen atom with deuterium would result in a molecule with about 5% deuterium enrichment. In order to achieve enrichment less than about 5%, but above the natural abundance, only partial deuteration of one site is required. Thus, less than about 5% enrichment would still refer to deuterium-enriched olanzapine.
[0015] With the natural abundance of deuterium being 0.015%, one would expect that for approximately every 6,667 molecules of olanzapine (1/0.00015=6,667), there is one naturally occurring molecule with one deuterium present. Since olanzapine has 20 positions, one would roughly expect that for approximately every 133,340 molecules of olanzapine (20×6,667), all 20 different, naturally occurring, mono-deuterated olanzapines would be present. This approximation is a rough estimate as it doesn't take into account the different exchange rates of the hydrogen atoms on olanzapine. For naturally occurring molecules with more than one deuterium, the numbers become vastly larger. In view of this natural abundance, the present invention, in an embodiment, relates to an amount of an deuterium enriched compound, whereby the enrichment recited will be more than naturally occurring deuterated molecules.
[0016] In view of the natural abundance of deuterium-enriched olanzapine, the present invention also relates to isolated or purified deuterium-enriched olanzapine. The isolated or purified deuterium-enriched olanzapine is a group of molecules whose deuterium levels are above the naturally occurring levels (e.g., 5%). The isolated or purified deuterium-enriched olanzapine can be obtained by techniques known to those of skill in the art (e.g., see the syntheses described below).
[0017] The present invention also relates to compositions comprising deuterium-enriched olanzapine. The compositions require the presence of deuterium-enriched olanzapine which is greater than its natural abundance. For example, the compositions of the present invention can comprise (a) a μg of a deuterium-enriched olanzapine; (b) a mg of a deuterium-enriched olanzapine; and, (c) a gram of a deuterium-enriched olanzapine.
[0018] In an embodiment, the present invention provides an amount of a novel deuterium-enriched olanzapine.
[0019] Examples of amounts include, but are not limited to (a) at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, to 1 mole, (b) at least 0.1 moles, and (c) at least 1 mole of the compound. The present amounts also cover lab-scale (e.g., gram scale), kilo-lab scale (e.g., kilogram scale), and industrial or commercial scale (e.g., multi-kilogram or above scale) quantities as these will be more useful in the actual manufacture of a pharmaceutical. Industrial/commercial scale refers to the amount of product that would be produced in a batch that was designed for clinical testing, formulation, sale/distribution to the public, etc.
[0020] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof.
[0000]
[0000] wherein R 1 -R 20 are independently selected from H and D; and the abundance of deuterium in R 1 -R 20 is at least 5%, provided that if R 14 -R 16 are D, then at least one of R is D. The abundance can also be (a) at least 10%, (b) at least 15%, (c) at least 20%, (d) at least 25%, (e) at least 30%, (f) at least 35%, (g) at least 40%, (h) at least 45%, (i) at least 50%, (j) at least 55%, (k) at least 60%, (l) at least 65%, (m) at least 70%, (n) at least 75%, (o) at least 80%, (p) at least 85%, (q) at least 90%, (r) at least 95%, and (s) 100%.
[0021] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 1 is at least 100%.
[0022] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 2 -R 5 is at least 25%. The abundance can also be (a) at least 50%, (b) at least 75%, and (c) 100%.
[0023] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 6 -R 13 is at least 13%. The abundance can also be (a) at least 25%, (b) at least 38%, (c) at least 50%, (d) at least 63%, (e) at least 75%, (f) at least 88%, and (g) 100%.
[0024] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 17 is at least 100%.
[0025] In another embodiment, the present invention provides a novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 18 -R 20 is at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.
[0026] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof.
[0000]
[0027] wherein R 1 -R 20 are independently selected from H and D; and the abundance of deuterium in R 1 -R 20 is at least 5%, provided that if R 14 -R 16 are D, then at least one of R is D. The abundance can also be (a) at least 10%, (b) at least 15%, (c) at least 20%, (d) at least 25%, (e) at least 30%, (f) at least 35%, (g) at least 40%, (h) at least 45%, (i) at least 50%, (j) at least 55%, (k) at least 60%, (l) at least 65%, (m) at least 70%, (n) at least 75%, (O) at least 80%, (p) at least 85%, (q) at least 90%, (r) at least 95%, and (s) 100%.
[0028] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 1 is at least 100%.
[0029] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 2 -R 5 is at least 25%. The abundance can also be (a) at least 50%, (b) at least 75%, and (c) 100%.
[0030] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 6 -R 13 is at least 13%. The abundance can also be (a) at least 25%, (b) at least 38%, (c) at least 50%, (d) at least 63%, (e) at least 75%, (f) at least 88%, and (g) 100%.
[0031] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 17 is at least 100%.
[0032] In another embodiment, the present invention provides an isolated novel, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 18 -R 20 is at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.
[0033] In another embodiment, the present invention provides novel mixture of deuterium enriched compounds of formula I or a pharmaceutically acceptable salt thereof.
[0000]
[0000] wherein R 1 -R 20 are independently selected from H and D; and the abundance of deuterium in R 1 -R 20 is at least 5%, provided that if R 14 -R 16 are D, then at least one of R is D. The abundance can also be (a) at least 10%, (b) at least 15%, (c) at least 20%, (d) at least 25%, (e) at least 30%, (f) at least 35%, (g) at least 40%, (h) at least 45%, (i) at least 50%, (j) at least 55%, (k) at least 60%, (l) at least 65%, (m) at least 70%, (n) at least 75%, (o) at least 80%, (p) at least 85%, (q) at least 90%, (r) at least 95%, and (s) 100%.
[0034] In another embodiment, the present invention provides a novel mixture of, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 1 is at least 100%.
[0035] In another embodiment, the present invention provides a novel mixture of, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 2 -R 5 is at least 25%. The abundance can also be (a) at least 50%, (b) at least 75%, and (c) 100%.
[0036] In another embodiment, the present invention provides a novel mixture of, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 6 -R 13 is at least 13%. The abundance can also be (a) at least 25%, (b) at least 38%, (c) at least 50%, (d) at least 63%, (e) at least 75%, (f) at least 88%, and (g) 100%.
[0037] In another embodiment, the present invention provides a novel mixture of, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 17 is at least 100%.
[0038] In another embodiment, the present invention provides a novel mixture of, deuterium enriched compound of formula I or a pharmaceutically acceptable salt thereof, wherein the abundance of deuterium in R 18 -R 20 is at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.
[0039] In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a deuterium-enriched compound of the present invention.
[0040] In another embodiment, the present invention provides a novel method for treating a disease selected from schizophrenia, bipolar disorder, and/or psychotic depression, comprising: administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of the present invention.
[0041] In another embodiment, the present invention provides an amount of a deuterium-enriched compound of the present invention as described above for use in therapy.
[0042] In another embodiment, the present invention provides the use of an amount of a deuterium-enriched compound of the present invention for the manufacture of a medicament (e.g., for the treatment of schizophrenia, bipolar disorder, and/or psychotic depression,).
[0043] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is intended to be taken individually as its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
Definitions
[0044] The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.
[0045] The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.
[0046] “Host” preferably refers to a human. It also includes other mammals including the equine, porcine, bovine, feline, and canine families.
[0047] “Treating” or “treatment” covers the treatment of a disease-state in a mammal, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting it development; and/or (c) relieving the disease-state, e.g., causing regression of the disease state until a desired endpoint is reached. Treating also includes the amelioration of a symptom of a disease (e.g., lessen the pain or discomfort), wherein such amelioration may or may not be directly affecting the disease (e.g., cause, transmission, expression, etc.).
[0048] “Therapeutically effective amount” includes an amount of a compound of the present invention that is effective when administered alone or in combination to treat the desired condition or disorder. “Therapeutically effective amount” includes an amount of the combination of compounds claimed that is effective to treat the desired condition or disorder. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
[0049] “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. The pharmaceutically acceptable salts include the conventional quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lacetic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
Synthesis
[0050] Scheme 1 shows a route to olanzapine (Chakrabarti, et al., U.S. Pat. No. 5,229,382; Calligaro, et al., Bioorg. Med. Chem. Lett. 1997, 7, 25-30).
[0000]
[0051] Scheme 2 shows how various deuterated starting materials and intermediates can be used in the chemistry of Scheme 1 to make deuterated olanzapine analogs. A person skilled in the art of organic synthesis will recognize that these materials may be used in various combinations to access a variety of other deuterated olanzapines. Bromination of olanzapine should produce the tribromide 6, which can be reduced to 7 as shown in equation (1) of Scheme 2. Compound 7 is olanzapine with R 17 and R 3 -R 4 =D. Various deuterated forms of compound 1 from Scheme 1 are known and are shown as 8-10 in Scheme 2. If 8 is used in the chemistry of Scheme 1, olanzapine with R 2 -R 5 =D will ultimately result. If 9 is used in the chemistry of Scheme 1, olanzapine with R 2 and R 4 =D will ultimately result. If 10 is used in the chemistry of Scheme 1, olanzapine with R 4 =D will ultimately result. The thiophene 2 from Scheme 1 can be synthesized from malononitrile and propanal in the presence of sulfur (c.f. Z. Wang, PCT 2004094390). If perdeuteriopropanal 11 is used, the thiophene 12 results, as shown in equation (2) of Scheme 2. If 12 is used in the chemistry of Scheme 1, olanzapine with R 17 -R 20 is afforded. Various deuterated forms of N-methylpiperazine are known (13-15) or commercially available (16). If 13 is used in the chemistry of Scheme 1, olanzapine with R 14 -R 16 =D will ultimately result. This compound is known (vide supra), but a person skilled in the art of organic synthesis will recognize that 13 is useful in the formation of other olanzapines where R 14 -R 16 as well as other R groups are replaced by deuterium atoms according to the other processes described herein. If 14 is used in the chemistry of Scheme 1, olanzapine with R 6 -R 16 =D will ultimately result. If 15 is used in the chemistry of Scheme 1, olanzapine with R 6 -R 13 =D will ultimately result. If 16 is used in the chemistry of Scheme 1, olanzapine with R 6 -R 9 =D will ultimately result.
[0000]
EXAMPLES
[0052] Table 1 provides compounds that are representative examples of the present invention. When one of R 1 -R 20 is present, it is selected from H or D.
[0000]
1
2
3
4
5
6
[0053] Table 2 provides compounds that are representative examples of the present invention. Where H is shown, it represents naturally abundant hydrogen.
[0000]
7
8
9
10
11
12
[0054] Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. | The present application describes deuterium-enriched olanzapine, pharmaceutically acceptable salt forms thereof, and methods of treating using the same. | 2 |
BACKGROUND OF THE INVENTION
This invention pertains to caulking guns for dispensing mastic compounds. More particularly, it pertains to a caulking gun capable of using disposable caulk tubes of different diameters, in the same caulking gun.
Caulking guns are used to apply sealants and adhesives, hereafter referred to as mastic compounds, when installing windows and doing general caulking and bonding on buildings. Caulking guns used by tradesmen to apply mastic compound fall into one of two general types. The first type is a bulk dispensing gun which is a complete unit unto itself, comprising a closed refillable cylindrical chamber containing a spout, a plunger within the cylinder and an actuating means to move the plunger forward to dispense the mastic compound from the cylinder.
The second type of caulking gun found in today's market place, is one that has an open frame structure to support a single disposable caulking tube and an actuating mechanism designed to move a push rod assembly for dispensing the mastic compound contained in the disposable caulking tube. The push rod assembly consists of a single push rod with a single thrust disk attached to one end of the push rod. The current common open frame caulk tube gun, hereafter referred to as the “C-gun”. Each C-gun is currently designed hold one specific size disposable caulk tube having a plastic spout on one end and a movable plunger on the opposite end. The present invention is concerned with the C-gun, and in the following discussion the term “caulking gun” should be understood as referring to a C-gun type caulking gun.
Currently only two C-gun type sizes are commercially available. One C-gun has a nominal cradle length of 23 cm (9 inches) and is sized to receive a 0.35 liter (12.8 fluid ounce) caulk tube with an inside diameter of approximately 4.6 cm. (1 13/16 inches). This tube size is referred to hereafter as “size A” tube. The second C-gun with a nominal cradle length of 13 inches is sized to receive a 0.95 liter (32 fluid ounce) disposable caulk tube which has an inside diameter of approximately 6.2 cm (2 7/16 inches). This tube size is referred to hereafter as “size B” tube. The length of each conventional C-gun is designed to receive only one specific size disposable caulk tube; either a “size A” caulk tube or a “size B” caulk tube. Also, the diameter of the thrust disk on each conventional C-gun is intentionally designed to be used exclusively with the plunger in either a “size A” caulk tube or “size B” caulk tube. To the inventors' knowledge no one offers a C-gun having a single thrust disk capable of fitting into the inside diameter of plungers for a “size A” and a “size B” disposable caulk tube. Also no one offers a C-gun capable of using disposable caulk tubes with different outside diameters within the same C-gun cradle.
Since the introduction of disposable caulking tubes (1920's), there have been only two standard size disposable caulk tubes available in general commerce, a small size (size A) and a large size (size B). The small size has a body length of 20.3 to 21.6 cm. (8.0 to 8.5 inches), and has an outer diameter of 4.4 to 5.1 cm (0.1.75 to 2.0 inches), and has a net content of approximately 0.31 liters (10.5 fluid ounces) of mastic compound (the 0.38 liter (12.8 fluid ounce gross capacity of the caulk tube is not completely filled with mastic). The large size has a body length of 31 to 31.8 cm (12.25 to 12.50 inches), and has an outer diameter of 6 to 6.7 cm (2.38 to 2.63 inches), and has a net content of approximately 0.9 liter (30 fluid ounces) of mastic compound. These two disposable caulk tubes are currently the only disposable caulk tube sizes produced for use in C-guns sold to the general public and tradesmen using mastic compounds. However, the inventors have developed a new novel size disposable caulk tube that has the diameter of the “size B” disposable caulk tube and the body length of the “size A” disposable caulk tube. This novel sized caulking tube, which is the subject of pending application Ser. No. 10/886,178, is referred to hereafter as a “size C” caulk tube.
Because size A disposable caulk tubes are being sold and size C disposable caulk tubes will soon be on the market, there is a need for having single C-gun capable of receiving either a size A and a size C caulk tube. The C-gun of this invention is designed to receive only one tube at a time, and is easily adept at receiving either a size A or a size C disposable caulk tube (as selected by the user). In its simplest embodiment, this novel C-gun accepts either a size A or C caulk tube with no adjustments being required. The benefits of having a multi-purpose C-gun capable of holding a single tube of either “size A” or “size C” caulk tubes is realized in the economics of manufacturing (one gun serving two purposes) and in the broader utility embodied in a single multi-purpose C-gun that is compatible with multiple sizes of disposable caulk tubes, which will benefit workmen applying mastic compound.
It is an object of the present invention to embody within one multi-purpose C-gun the capability of dispensing mastic compounds from either a standard “size A” disposable caulk tube or the novel “size C” disposable caulk tube.
SUMMARY OF THE INVENTION
The multi-purpose C-gun of the present invention is designed to dispense mastic compounds from disposable caulk tubes with body lengths of 20.3 to 21.6 cm, (8.0 to 8.5 inches) and caulk tubes which have variable outer diameters, ranging from 4.4 to 6.7 cm (1.75 to 2.63 inches). This multi-purpose C-gun has a conventional structure including a cradle for receiving disposable caulk tubes, a forward end plate with a slot for retaining and centering the spout of the caulk tube, a push rod assembly with an attached thrust disk means on one end, and an activating mechanism to move the push rod forward, causing the thrust disk means to contact and move the tube plunger to dispense mastic compound from the caulk tube. The dual-purpose C-gun differs from conventional designs in that the forward end plate can be modified to hold either size A or size C caulk tubes, and that there may be multiple thrust disks.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS
FIG. 1 a is a perspective view of a size A disposable caulk tube.
FIG. 1 b is a perspective view of a size B disposable caulk tube.
FIG. 1 c is a perspective view of a size C disposable caulk tube.
FIG. 2 is a perspective view of the multi-purpose C-gun in its simplest embodiment according to this invention.
FIG. 3 is a perspective view of the push rod with a fixed thrust disk and a floating thrust disk on the same push rod and raised retainer on front plate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a multi-purpose C-gun that may modify and share features with a number of conventional C-guns. To provide a basis for the design of the multi-purpose C-gun, the caulk tubes with which it is used will be described. FIG. 1 a shows the conventional size A disposable caulk tube. It has a cylindrical body 10 a a stationary front end 20 a from which a spout 30 a protrudes, a plunger 40 a that is movable within the cylindrical body when subject to external force. The cylindrical body has a front rim 15 a that extends slightly beyond the front end 20 a so that the front disk is slightly recessed. FIGS. 1 b and 1 c show conventional size B and novel size C caulk tubes. The size B caulk tube has a larger diameter and is longer that the size A caulk tube. The novel size C caulk tube has the same diameter as size B and the same length as size A.
FIG. 2 , shows a representative C-gun that is suitable for the present invention. There is an open framework cradle too for receiving a disposable caulk cartridge. At the front of the cradle, there a front end plate 1 that acts as a stop and that has a receiving slot 2 for receiving the spout 30 a or 30 c of a disposable caulk tube. As shown in FIG. 2 and FIG. 3 , the front end plate is circular with an outer diameter sized to be capable of receiving a caulk tube with a diameter in the range of 4.4 to 6.7 cm (1.75 to 2.63 inches). At the rear of the cradle there is a rear end plate 7 that is attached to a stock that holds push rod 6 , and actuating mechanism 9 , which is frequently a trigger. Receiving slot 2 keeps the caulk tube in approximately the same line as the push rod and serves to hold the caulk tube in a manner to reduce its lateral motion within the cradle during use. The rear end plate contains a central hole 8 through which the push rod moves longitudinally. When activated the push rod moves forward so that thrust disk 4 attached to an end of the push rod applies pressure to the plunger( 40 a or 40 c ) of the cartridge, and moves the plunger forward causing mastic compound to be expelled from the spout. The open structure half cylinder cradle 100 of the representative embodiment may be formed by welding longitudinal metal strips 5 to end plates 1 and 7 and welding semi-circular metal straps 11 , laterally between longitudinal metal strips 5 to form cradle 100 in which the disposable caulk tube is placed. The cradle of the caulking gun of the present invention is designed to receive a variety of disposable caulk tubes with a body length between 20.3 to 21.6 (8.0 and 8.5 inches) and with an outer diameter between 4.4 to 6.7 cm (1.75 to 2.63 inches). Other cradle designs are also envisioned such as half cylinders, optionally with perforations or slots of various sizes to reduce the weight of the gun.
In the embodiment shown in FIG. 2 , there maybe a circular retainer groove 3 in the inner surface of the front end plate. This retainer groove can be sized to hold the rim 15 a or 15 c in place and may be stamped or recessed into the front end plate. An alternate embodiment is shown in FIG. 3 . That embodiment has two changes from the embodiment shown in FIG. 2 . First there is a circular raised retainer disk 21 integral to the inner surface of front end plate 1 . The diameter of the circular raised retainer disk is small enough that it can fit within the front rim 15 a of a size A caulk tube or within the front rim 15 c of a size C caulk tube. The raised retainer surface would contact the front end of the caulk tube to help center and hold the caulk tube in position. The raised retainer can be can be molded, welded, or stamped in place. It can be stepped so the step with a smaller diameter would retain a size A caulk tube while the step with the larger diameter would retain a size C caulk tube.
The second change is the addition of a second thrust disk 42 . Thrust disk 4 , which is attached securely to an end of push rod 6 is designed to fit into plunger 40 a of a size A caulk tube. Thrust disk 42 is designed to fit exclusively into plunger 40 c of a size C caulk tube. It is situated directly behind thrust disk 4 and is designed to slide along the length of the push rod unless locked in place by a mechanical means, such as a dowel pin, a pressure place that bites into the push rod, a notch, a screw, or a locking collar. The locking means shown in FIG. 3 is a dowel pin 22 penetrating push rod 6 and a corresponding mating slot 23 cut into sliding thrust disk 42 . The size of the slot is slightly larger than the size of the dowel pin so that the sliding thrust disk can be moved from one side to the other side of the dowel pin when the slot is aligned with the dowel pin. To lock the sliding disk in place next to fixed thrust disk 4 , sliding thrust disk 42 is rotated so that slot 23 is not aligned with dowel pin 22 . When locked in place through rotation, the sliding thrust disk is in position to engage the plunger of a size C caulk tube. When the multi-purpose C-gun is used with a size A caulk tube, sliding thrust disk 42 is not locked in place, fixed thrust disk 4 becomes the working disk and thrust disk 42 slides along the push rod as the push rod penetrates deeper in the caulk disk.
The exemplified features are not meant to be limiting. For instance, the cradle can be made of solid sheets, strips of metal, perforated sheets to reduce bulk. The C-gun need not even be made of metal as described. Plastics and composite components are all within the scope and the advantages and disadvantages of each material will be obvious to one skilled in the art. It is within the scope of this invention to incorporate ergonomic handles, drip-less or quick pressure release features, and retaining edges on the front plate, all which have been previously disclosed as improvements over the traditional caulk gun | A C-gun type caulk gun capable of accepting disposable caulk tubes having different outside diameters within a similar caulk tube body length. | 1 |
This application is a continuation of application Ser. No. 159,092, filed Feb. 23, 1988 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an organic solvent-based ink for use in an ink-jet printer.
2. Prior Art
Several systems have been proposed for ink-jet recording; electric field controlled jet that is ejected under an electrostatic attractive force; drop-on-demand ink (impulse jet) that is ejected under the oscillating pressure created by a piezoelectric transducer; and thermal ink jet that is ejected under the pressure created by air bubbles formed and grown with heat. These and other known methods of ink-jet recording are capable of producing an image with a very high degree of resolution.
Inks used in ink-jet printer are generally of two types: water-based inks which employ water as the principal solvent, and organic solvent-based inks which employ organic solvents as the principal solvent. Images printed with water-based inks are usually low in water resistance whereas organic solvent-based inks are capable of providing printed image with improved water resistance and the prints produced have excellent quality.
Whichever type of inks are used in ink-jet printer, abnormal ink ejection frequently occurs for various reasons such as nozzle clogging, filter clogging and time-dependent changes in ink properties. Since this has been a major cause of limited application of ink-jet recording systems, it is very important to develop inks, particularly organic solvent-based inks for ink-jet printer, that can be ejected in a more consistent way and many proposals have been put forth to meet this need. For example, with a view to stabilizing the dissolution or dispersion of coloring materials used in inks, Japanese Patent Publication No. 344/1982 and Japanese Patent Application (OPI) Nos. 78050/1980, 3871/1982, 3873/1982 and 36381/1986 (a term "OPI" herein means unexamined Japanese Patent Publication) have proposed improvements centering on the solvents to be incorporated in organic solvent-based inks. However, the experiments conducted by the present inventors have shown that these prior art organic solvent-based inks cannot always be ejected in a consistent way.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an organic solvent-based ink that can be ejected consistently to produce printed images of good quality.
The object of the present invention can be attained by an organic solvent-based ink in which at least one compound selected from the group consisting of aromatic sulfonamides and hydroxybenzoic acid esters and an oil-soluble dye are dissolved in an organic solvent.
According to the present invention, there is to provide an organic solvent-based ink for ink-jet printing which comprises at least one compound selected from the group consisting of an aromatic sulfonamide and a hydroxybenzoic acid ester and oil-soluble dye dissolved in an organic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The organic solvent-based ink of the present invention assures highly stable ink ejection over a prolonged period of time for an ink-jet printer. In addition, the ink can be left to stand at the nozzle orifice for a prolonged period of time without deterioration in its properties. Furthermore, printed images of good quality can be produced using the ink of the present invention.
In order to produce stable ink ejection, the present inventors prepared organic solvent-based inks for an ink-jet printer by combining various kinds of oil-soluble dyes and organic solvents and investigated the quality of printed characters and the consistency of ink ejection over prolonged printing with three types of printers, i.e., electric field controlled ink-jet printer, drop-on-demand printer and thermal ink-jet printer. As a result, it was found that combinations of dyes and ordinary organic solvents alone were insufficient to ensure stable ink ejection and the ability of inks to be left at the nozzle orifice over a prolonged period of time without deterioration in their properties. In particular, the stability of ink ejection was very low in a system that additionally employed an air stream to increase the driving frequency and hence the speed of flight of ink droplets. Microscopic observation of these phenomena revealed that when the solvent evaporated by a very small amount at the nozzle orifice, dye is crystalized out of the solution at the nozzle orifice in spite of the presence of a sufficient amount of solvent to dissolve the dye and that this led to abnormal ink ejection from the orifice. It was also found that dye crystallization at the nozzle orifice was particularly heavy when the dye had a great tendency to crystallize.
On the basis of these findings, the present inventors conducted intensive studies on an effective method for preventing dye crystallization a the nozzle orifice so as to ensure consistent ink ejection. As a result, the present inventors found that the objection could effectively be attained by incorporating an aromatic sulfonamide or a hydroxybenzoic acid ester in organic solvent-based inks.
It is not completely clear why an addition of these compounds contributes to improved stability of ink ejection. A plausible explanation will be as follows: the polar moiety of the molecules of an aromatic sulfonamide or hydroxybenzoic acid ester is strongly oriented toward the polar moiety of the dye molecule so as to mask the polar point; at the same time, the distance between dye molecules is increased to facilitate their movement and the affinity of the dye for the solvent is sufficiently increased to prevent its crystallization.
Illustrative aromatic sulfonamides that can be used in the present invention include p-toluenesulfonamide, N-ethyl-p-toluenesulfonamide, N-butyl-p-toluenesulfonamide and N-cyclohexyl-p-toluenesulfonamide. These aromatic sulfonamides are preferably incorporated in the organic solvent-based ink of the present invention in amounts of 0.1-40 wt%.
Illustrative hydroxybenzoic acid esters that can be used in the present invention include 2-ethylhexyl p-hydroxybenzoate and n-nonyl p-hydroxybenzoate. These hydroxybenzoic acid esters are preferably incorporated in the organic solvent-based ink of the present invention in amounts of 0.1-40 wt%.
These aromatic sulfonamides and hydroxybenzdic acid esters have so large polarity that they may be able to prevent dye crystallization in a very effective manner.
Any dye being soluble in organic solvents or the aforementioned aromatic sulfonamides or hydroxybenzoic acid esters can be used in the present invention. Typically useful dyes, include azo dyes, metal complex salt dyes, naphthol dyes, anthraquinone dyes, indigo dyes,carbonium dyes, quinoimine dyes, cyanine dyes, quinoline dyes, nitro dyes, nitroso dyes, benzoquinone dyes, naphthoquinone dyes, naphthalimide dyes, perinone dyes, and phthalocyanine dyes. These dyes may be used either independently or in combination. The dyes are preferably incorporated in the organic solvent-based ink of the present invention in amounts of 0.1-10 wt%, with the range of 0.5-5 wt% is more preferred.
The type of organic solvents to be used in the present invention depends, to some extent, on dyes but since most dyes are polar, highly polar solvents will act as good solvents and less polar solvents act as poor solvents Therefore, less polar solvents which have a small ability to dissolve dyes are not favorable for the purpose of dissolving dyes. However, even such solvents can be used if they are mixed with the aforementioned aromatic sulfonamides or hydroxybenzoic acid esters. If desired, less polar solvents may be combined with highly polar solvents. Specific examples of the organic solvents that can be used in the present invention include: aliphatic hydrocarbons; naphthenic hydrocarbons; aromatic hydrocarbons such as mono- or di-substituted alkylnaphthalenes, alkyl derivatives of biphenyls, xylylethane and phenethylcumene; glycols; mono- or di-alkyl ethers of glycols and esters of glycols; aliphatic acids and esters thereof; nitrogenous compounds such as amide and pyrrolidone compounds. It should, however, be noted that these are not the sole examples of the organic solvents that can be used in the present invention.
The higher their boiling points, the more advantageous the solvents are from the viewpoint of reduced evaporation and drying speed. However, solvents having a higher boiling temperatures have a tendency to produce viscous inks that are difficult to eject in a smooth way. On the other hand, solvents having lower boiling points produce inks that will dry too quickly at the nozzle orifice. Therefore, a suitable solvent having the desired viscosity and boiling point should be selected in consideration of the measure adopted by the print head to prevent ink drying.
The following examples are provided for the purpose of further illustrating the present invention but are in no way to be taken as limiting. In the Examples, a percent shows based on weight.
EXAMPLE 1
______________________________________Oil-soluble black dye (nigrosine dye) 4.0%Phenethylcumene 56.0%Diglyme 20.0%2-Ethylhexyl p-hydroxybenzoate 20.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to make an organic solvent-based ink. Continuous jet formation with this ink on a field-controlled ink-jet printer produced stable ink ejection even after 500 hours. The ink remained stable in solution even after it was left to stand for 6 months at room temperature and it was successfully ejected in a consistent manner. The printer was left for a month with no cap on the nozzle, and yet the ink was successfully ejected again in jet form without clogging the nozzle orifice. In all instances, the print was clean and produced image of good quality.
EXAMPLE 2
______________________________________Oil-soluble black dye 3.0%(chromium premetalized dye)Diisopropylnaphthalene 64.0%Carbitol 18.0%N-Ethyl-p-toluenesulfonamide 15.0%______________________________________
The above-listed ingredients were mixed and -0 stirred well at room temperature to form a complete membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. Continuous jet formation with this ink on a thermal ink-jet printer produced stable ink ejection even after 500 hours. The ink remained stable in solution even after it was left to stand for 6 months at room temperature and it was successfully ejected in a continuous manner. The printer was left for a month with no cap on the nozzle and yet the ink was successfully ejected again in jet form without clogging the nozzle orifice. In all instances, the print was clean and produced image of good quality.
EXAMPLE 3
______________________________________Oil-soluble cyan dye (copper phthalocyanine dye) 3.5%Phenethylcumene 80.5%Diethylene glycol hexyl ether 15.0%N-butyl-p-toluenesulfonamide 1.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. Continuous jet formation with this ink on a field-controlled ink-jet printer produced stable ink ejection eve after 500 hours. The ink remained stable in solution even after it was left to stand for 6 months at room temperature and it was successfully ejected in a consistent manner. The printer was left for a month with no cap on the nozzle and yet the ink was successfully ejected again in jet form without clogging the nozzle orifice. In all instances, the print was clean and produced image of good quality.
EXAMPLE 4
______________________________________Oil-soluble magenta dye (rhodamine dye) 4.0%Isopropylnaphthalene 76.0%Carbitol 15.0%N-Cyclohexyl-p-toluenesulfonamide 5.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. Continuous jet formation with this ink on a drop-on-demand ink-jet printer produced stable ink ejection even after 500 hours. The ink remained stable in solution even after it was left to stand for 6 months at room temperature and it was successfully ejected in a consistent manner. The printer was left for a month with no cap on the nozzle, and yet the ink was successfully ejected again in jet form without clogging the nozzle orifice. In all instances, the print was clean and produced images of good quality.
EXAMPLE 5
______________________________________Oil-soluble yellow dye (quinoline dye) 2.0%Methylnaphthalene 67.0%Diglyme 16.0%n-Nonyl p-hydroxybenzoate 15.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. Continuous jet formation with this ink on a drop-on-demand ink-jet printer produced stable ink ejection even after 500 hours. The ink remained stable in solution even after it was left to stand for for 6 months at room temperature and it was successfully ejected in a continuous manner. The printer was left to stand for a month with no cap on the nozzle and yet the ink was successfully ejected again in jet form without clogging the nozzle orifice. In all instances, the print was clean and produced image of good quality.
COMPARATIVE EXAMPLE 1
______________________________________Oil-soluble black dye 4.0%(same as used in Example 1)Phenethylcumene 56.0%Triethylene glycol monomethyl ether 20.0%Diglyme 20.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. In a continuous jet formation test conducted with a field-controlled ink-jet printer, the ink started to be ejected abnormally in 50 hours. The print lacked some degree of sharpness and the image produced was somewhat inferior to that attained in Example 1.
COMPARATIVE EXAMPLE 2
______________________________________Oil-soluble black dye 3.0%(same as used in Example 2)Diisopropylnaphthalene 64.0%Carbitol 33.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. In a continuous jet formation test on a thermal ink-jet printer, the ink started to be ejected abnormally in 10 hours. The print lacked some degree of sharpness and the image it produced was somewhat inferior to that attained in Example 2.
COMPARATIVE EXAMPLE 3
______________________________________Oil-soluble cyan dye 3.5%(same as used in Example 3)Phenethylcumene 80.5%Diethyleneglycol hexylether 16.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. In a continuous jet formation on a field-controlled ink-jet printer, the ink started to be ejected abnormally in 10 hours. The print lacked some degree of sharpness and the image produced was somewhat inferior to that attained in Example 3.
COMPARATIVE EXAMPLE 4
______________________________________Oil-soluble magenta dye 4.0%(same as used in Example 4)Isopropylnaphthalene 76.0%Carbitol 20.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. In a continuous jet formation on a drop-on-demand ink-jet printer, the ink started to be ejected abnormally in 20 hours. The print lacked some degree of sharpness and the image produced was somewhat inferior to that attained in Example 4.
COMPARATIVE EXAMPLE 5
______________________________________Oil-soluble yellow dye 2.0%(same as used in Example 5)Methylnaphthalene 67.0%Diglyme 21.0%N-Methyl-2-pyrrolidone 10.0%______________________________________
The above-listed ingredients were mixed and stirred well at room temperature to form a complete solution. The solution was filtered through a membrane filter (0.45 μm in pore size) to form an organic solvent-based ink. In a continuous jet formation test on a drop-on-demand ink-jet printer, the ink started to be ejected abnormally in 30 hours. The print lacked some degree of sharpness and the image produced was somewhat inferior to that attained in Example 5.
The organic solvent-based ink of the present invention which is intended to be used in ink-jet printer produces printed image of good quality and ensures very stable ink ejection over a prolonged period of recording with an ink-jet printer. The organic solvent-based ink of the present invention also provides record of high quality and reliability even when it is used with a mechanical recording system such as a pen plotter.
While the invention has been described in detail and with reference to specific embodiment thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit- and scope thereof. | An organic solvent-based ink for ink-jet printer comprises at least one compound selected from the group consisting of an aromatic sulfonamide and a hydroxybenzoic acid ester and an oil-soluble dye dissolved in an organic solvent. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a power transfer apparatus for secondary or coupled driving wheels of a four-wheel drive vehicle.
2. Description of the Related Art
In conventional four-wheel drive vehicles, in turning a corner of a small turning radius at low or middle speed in a four-wheel driving mode, there is caused a difference in wheel speed between front and rear wheels which is attributed to a difference in turning radius between the front and rear wheels, resulting in the occurrence of a tight corner braking phenomenon.
Front and rear wheels driving systems disclosed in JP-B-7-61779 and JP-B-7-64219 are known as related arts for solving the problem of tight corner braking phenomenon.
In the front and rear wheels driving systems disclosed in the Japanese Examined Patent Publications, an average wheel speed of secondary driving wheels relative to an average wheel speed of primary driving wheels is adjusted by providing a transfer (a speed increasing system) between the primary and secondary driving wheels.
In this transmission, by switching on and off a direct connective clutch and a transmission clutch, there occurs a switch between a direct connecting mode in which the average wheel speed of the primary driving wheels and the average wheel speed of the secondary driving wheels are almost equalized and a speed increasing mode in which the average wheel speed of the secondary driving wheels is made larger than the average wheel speed of the primary driving wheels.
In this front and rear wheels driving system, when turning a small corner in the four-wheel driving mode, the occurrence of tight corner braking phenomenon is prevented by bringing the secondary driving wheels in the speed increasing mode by the transmission.
Incidentally, in the aforesaid transfer (the speed increasing apparatus) for four-wheel drive vehicles, at least two hydraulic or electromagnetic actuators are required as a power source for operating the direct connective clutch and the transmission clutch, and this leads to a problem that the transmission itself is made larger in size and hence heavier in weight.
Furthermore, in this transmission, since constituent components are assembled piece by piece in the assembling processes of the transmission, the number of processes is increased and hence the productivity is deteriorated. In addition, since there are many items needing adjustments such as clearance and spring load, the productivity is also deteriorated.
SUMMARY OF THE INVENTION
Consequently, an object of the present invention is to provide power transfer apparatus that can be made smaller in size and lighter in weight overall.
According to the first aspect of the present invention, there is provided a power transfer apparatus provided between an input shaft and an output shaft for selectively changing the speed of the output shaft relative to the speed of the input shaft.
The power transfer apparatus system includes a clutch for directly connecting the input shaft to the output shaft, a transmission brake serially disposed in an axial direction of the clutch, an actuator serially disposed in an axial direction of the transmission brake for disengaging the clutch at the same time of activating the transmission brake and a planetary carrier sub-assembly serially disposed in the axial direction of the clutch.
The clutch has a clutch inner hub fixed to the input shaft, a clutch guide, a plurality of clutch discs attached to the clutch inner hub, a plurality of clutch plates attached to the clutch guide so as to be disposed alternately with the clutch discs, a clutch piston and a biasing unit for biasing the clutch piston in a direction in which the clutch discs engage with the clutch plates.
The transmission brake has a brake inner hub coupled with the clutch piston at one end thereof, a plurality of brake discs attached to the brake inner hub and a plurality of brake plates attached to the casing so as to be disposed alternately with the brake discs.
The planetary carrier sub-assembly has a planetary carrier rotatably disposed around the input shaft and the output shaft and coupled with the clutch guide, a first pinion gear rotatably carried on the planetary carrier, a second pinion gear having the number of teeth which is different from that of the first pinion gear, a first sun gear fixed to the input shaft and meshing with the first pinion gear and a second sun gear fixed to the output shaft and meshing with the second pinion gear.
According to the power transfer apparatus of the first aspect of the present invention, since the single actuator can be used to disengage the clutch at the same time of activating the transmission brake, it is possible to provide a power transfer apparatus which is made smaller in size and light in weight. In addition, since the clutch and the transmission brake are serially disposed in the axial direction, the outside diameter of the power transfer apparatus can be made small.
Furthermore, when the actuator is activated, since the engagement of the clutch is gradually released while the transmission brake is gradually activated, the transfer of power from the input shaft to the output shaft is never interrupted, and the occurrence of a gearshift shock can be prevented.
Note that in the above mentioned power transfer apparatus, the first and second pinion gears may be formed integrally.
According to the second aspect of the present invention, the power transfer apparatus wherein the clutch further has a one-way clutch interposed between the clutch inner hub and the clutch guide.
Thus, since the one-way clutch is interposed between the clutch inner hub and the clutch guide, a load generated when the input shaft is connected to the output shaft can be partly borne by the one-way clutch, and therefore the load capacity of the clutch can be reduced.
According to the third aspect of the present invention, there is provided a power transfer apparatus as set forth in the first aspect of the present invention, wherein the clutch piston is disposed within a space defined between the clutch guide and a radial outer side of the clutch plates so as to be extend axially.
According to the construction, even if a power transfer member such as the clutch inner hub is disposed on the inner diameter side, the (on and off) control of the clutch can be implemented on the outside diameter side.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of a power train of a four-wheel drive vehicle which is suitable for application of a power transfer apparatus according to the present invention;
FIG. 2 is a cross-sectional view of the power transfer apparatus (transmission) and a rear differential according to an embodiment of the present invention;
FIG. 3 is an enlarged cross-sectional view of the power transfer apparatus according to the embodiment of the present invention;
FIG. 4 is a front view of a clutch guide;
FIG. 5 is a cross-sectional view taken along the line 5 — 5 in FIG. 4 ;
FIG. 6 is a rear view of the clutch guide;
FIG. 7 is a front view of a clutch piston;
FIG. 8 is a cross-sectional view taken long the line 8 — 8 in FIG. 7 ;
FIG. 9 is a front view of a one-way clutch;
FIG. 10 is a cross-sectional view taken along the line 10 — 10 in FIG. 9 showing a state in which the one-way clutch is mounted on a clutch inner hub;
FIG. 11 is a cross-sectional view taken along the line 11 — 11 in FIG. 3 ;
FIG. 12 is a cross-sectional view taken along the line 12 — 12 in FIG. 3 ;
FIG. 13 is a front view of the brake inner hub;
FIG. 14 is a cross-sectional view taken along the line 14 — 14 in FIG. 13 ;
FIG. 15 is a cross-sectional view showing a process for assembly of an oil pump driving pin;
FIG. 16 is a cross-sectional view showing a process for assembly of an oil pump sub-assembly;
FIG. 17 is a cross-sectional view showing a process for assembly of a planetary carrier sub-assembly;
FIG. 18 is a cross-sectional view showing a process for assembly of a direct connective clutch sub-assembly;
FIG. 19 is a cross-sectional view showing processes for inserting an input shaft and measuring N 1 , N 2 ;
FIG. 20 is a cross-sectional view showing a process for measuring dimensions S 1 , S 2 of a front case sub-assembly;
FIG. 21 is a cross-sectional view showing a process for assembly of the front case sub-assembly;
FIG. 22 is a cross-sectional view showing a process for assembly of a companion flange; and
FIG. 23 is an explanatory view showing a state in which a four-wheel drive vehicle is turning left.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIG. 1 , there is shown a schematic view of a power train for a wheel-drive vehicle built based on a front-engine, front-drive (FF) vehicle to which a speed increasing apparatus (a power transfer apparatus) according to the present invention.
What should be noticed here is that the present invention is not limited to a four-wheel drive vehicle which is built based on the FF vehicle but may be applied to a four-wheel drive vehicle built based on a rear-engine, rear-drive (RR) vehicle or a front-engine, rear-drive (FR) vehicle.
As shown in FIG. 1 , a power train according to an embodiment according to the present invention mainly includes a front differential 6 and a rear differential 12 and a power transfer apparatus of the present invention. The power or drive from an engine 2 disposed at the front of the vehicle is transmitted from an output shaft 4 a of a transmission 4 to the front differential 6 . A power transfer apparatus or a speed increasing apparatus (a transmission) 10 according to the present invention to which the power so transmitted to the front differential 6 is then transmitted via a propeller shaft 8 . The power from the speed increasing apparatus is 10 transmitted to the rear differential 12 .
The front differential 6 has a conventionally known construction in which power from the output shaft 4 a of the transmission 4 is transmitted to left and right front drive axles 20 , 22 via a plurality of gears 14 within a differential case 6 a and output shafts 16 , 18 , whereby left and right front wheels are driven, respectively.
As will be described later on, the rear differential 12 includes a pair of planetary gear sets and a pair of electromagnetic actuators adapted for controlling the application of multi-plate brake mechanisms respectively, and left and right rear wheels are driven by virtue of power transmitted to left and rear wheel drive axles 24 , 26 by controlling the electromagnetic actuators.
FIG. 2 shows a cross-sectional view of the speed increasing apparatus 10 of the present invention and the rear differential 12 disposed on a downstream side of the speed increasing apparatus 10 . The speed increasing apparatus 10 includes an input shaft 30 rotatably mounted in a casing 28 and an output shaft (hypoid pinion shaft) 32 .
The speed increasing apparatus 10 includes further an oil pump sub-assembly 34 , a planetary carrier sub-assembly 38 , a (directly connective) clutch sub-assembly 40 , and a transmission brake 42 .
The rear differential 12 disposed on the downstream side of the transmission 10 has a hypoid pinion gear 44 formed on a distal end of the hypoid pinion shaft 32 .
The hypoid pinion gear 44 meshes with a hypoid ring gear 48 , and power from the hypoid ring gear 48 is inputted into ring gears of a pair of left and right planetary gear sets 50 A, 50 B.
Sun gears of the planetary gear sets 50 A, 50 B are rotatably mounted around the left rear axle 24 and the right rear axle 26 , respectively. Planetary carriers of the planetary gear sets 50 A, 50 B are fixed to the left rear axle 24 , and the right rear axle 26 , respectively. A planet gear carried on the planetary carrier meshes with the sun gear and the ring gear.
The left and right planetary gear sets 50 A, 50 B are connected, respectively, to brake mechanisms 51 each provided for variably controlling the torque of the sun gear. The brake mechanism 51 includes a wet multi-plate brake 52 and an electromagnetic actuator 56 for actuating the multi-plate brake 52 .
Brake plates of the wet multi-plate brake 52 are fixed to a casing 54 , and brake discs thereof are fixed to the sun gear of the planetary gear set 50 A, 50 B.
The electromagnetic actuator 56 is made up of a core (yoke) 58 , an electromagnetic coil 60 inserted into the core 58 , an armature 62 and a piston 64 connected to the armature 62 .
When current is applied to the electromagnetic coil 60 , the armature 62 is attracted to the core 58 by the coil 60 to thereby generate a thrust. The piston 64 integrally connected to the armature 62 is caused to press against the multi-plate brake 52 by virtue of the thrust so generated, whereby a brake torque is generated.
As this occurs, the sun gears of the planetary gear sets 50 A, 50 B are fixed relative to the casing 54 , respectively, and a driving force of the hypoid pinion shaft 32 is transmitted to the left and right rear axles 24 , 26 via the ring gears, planet gears and planetary carriers of the planetary gear sets 50 A, 50 B.
Output torques to the left and right rear axles 24 , 26 can be variably controlled by varying current applied to the electromagnetic coil 60 .
Next, referring to FIG. 3 , the construction of the speed increasing apparatus 10 will be described in detail. The casing 28 of the speed increasing apparatus 10 is fixed to the casing 54 of the rear differential 12 with a bolt 66 .
The oil pump sub-assembly 34 includes a base 68 , an oil pump body 70 and a cover 72 . The cover 72 is fixed to the oil pump body 70 with a bolt 76 . The oil pump sub-assembly 34 is fixed to the casing 54 of the rear differential 12 with a bolt 74 .
The oil pump sub-assembly 34 is made up of a trochoidal pump, and the oil pump body 70 has an outer rotor having internal teeth and an inner rotor having external teeth. An oil pump driving pin 36 is fitted in the inner rotor.
The planetary carrier sub-assembly 38 includes a planetary carrier 78 rotatably mounted around the input shaft 30 and the output shaft 32 via bearings 80 .
The planetary carrier 78 has a shaft 82 , and a small-diameter pinion gear (a first pinion gear) 84 and a large-diameter pinion gear (a second pinion gear) 86 which are both integrally formed around the shaft 82 are rotatably mounted on the planetary carrier 78 .
The small-diameter pinion gear 84 meshes with a first sun gear 88 which is fixed to the input shaft 30 with splines 90 , 92 , whereas the large-diameter pinion gear 86 meshes with a second sun gear 94 which is fixed to the output shaft 32 with splines 96 , 98 .
The direct connective clutch sub-assembly 40 includes a clutch guide 104 which is fixed to the planetary carrier 78 with splines 100 , 102 . FIG. 4 is a front view of the clutch guide 104 , FIG. 5 is a cross-sectional view taken along the line 5 — 5 in FIG. 4 , and FIG. 6 is a rear view of the clutch guide 104 .
As shown best in FIG. 5 , the clutch guide 104 has an outer circumferential clutch guide 104 a , a ring 104 b welded to the outer circumferential clutch guide 104 a and an inner circumferential clutch guide 104 c fixed to the outer circumferential clutch guide 104 a . The inner circumferential clutch guide 104 c has splines 102 .
As shown best in FIG. 6 , the clutch guide 104 has six protruding portions 122 which protrude in radial direction. Recesses 124 are disposed between the protruding portions 122 and the ring 104 b.
Referring to FIG. 3 again, the direct connective clutch sub-assembly 40 has a clutch inner hub 106 that is fixed to the input shaft 30 with splines 108 , 110 . A plurality of clutch discs 112 are mounted on an outer circumferential portion of the clutch inner hub 106 so as not to rotate relative to the clutch inner hub 106 but to move in an axial direction of the same.
Furthermore, a plurality of clutch plates 114 are mounted on the clutch guide 104 so as not to rotate but to move in the axial direction, and are disposed such that the clutch plates 114 alternate with the clutch discs 112 .
A clutch piston 116 is disposed within a space defined between the clutch guide 104 and a radial out side of the clutch discs 112 so as to be extended in the axial direction. As shown in FIGS. 7 and 8 , the clutch piston 116 has six protruding portions 116 a each of which extends in the axial direction.
Each protruding portion 116 a has a shoulder 117 on each side of the protruding portion 116 in the vicinity of a distal end thereof. A coil spring 118 is interposed between the clutch guide 104 and the clutch piston 116 for biasing the clutch piston 116 in a direction in which the clutch discs 112 and the clutch plates 114 are brought into engagement with each other.
A one-way clutch 120 is interposed between the clutch inner hub 106 and the clutch guide 104 of the direct connective clutch sub-assembly 40 . FIG. 9 is a front view of the one-way clutch 120 , and FIG. 10 is a cross-sectional view taken along the line 10 — 10 in FIG. 9 .
An outer ring 126 of the one-way clutch 120 is fixed to the clutch guide 104 , and an inner ring 128 thereof is fixed to the clutch inner hub 106 .
As shown in FIG. 9 , the outer ring 126 of the one-way clutch 120 has a plurality of projections 130 , and a recess 132 is imposed between a pair of adjacent projections 130 .
The one-way clutch 120 is such as to transmit a torque in one direction when the rotational speed of the input shaft 30 is equal to or larger than the rotational speed of the clutch guide 104 which is located on the output side.
Referring to FIG. 11 , a cross-sectional view taken along the line 11 — 11 in FIG. 3 is shown. The axially protruding portions 116 a of the clutch piston 116 are inserted into between the clutch guide 104 and the outer ring 126 of the one-way clutch 120 .
Furthermore, the protruding portions 122 of the clutch guide 104 fit in between the pairs of projections 130 on the outer ring 126 of the one-way clutch 120 , respectively, and torque is transmitted from the outer ring 126 of the one-way clutch 120 to the clutch guide 104 at these fitting portions.
Referring to FIG. 12 , a cross-sectional view taken along the line 12 — 12 in FIG. 3 is shown. The axially protruding portions 116 a of the clutch piston 116 are inserted into between the clutch plates 114 and the clutch guide 104 .
The clutch plate 114 has a plurality of projections 114 a which are formed on an outer circumferential side thereof, and the protruding portions 122 of the clutch guide 104 fit in between pairs of adjacent projections 114 a , respectively, whereby the clutch plate 114 is mounted on the clutch guide 104 so as not to rotate but to move in the axial direction.
Referring back to FIG. 3 , again, reference numeral 42 denotes a transmission brake, and an end of a brake inner hub 136 of the transmission brake 42 is in engagement with the clutch piston 116 . FIG. 13 shows a front view of the brake inner hub 136 , and FIG. 14 shows a cross-sectional view of the brake inner hub 136 taken along the line 14 — 14 in FIG. 13 .
As shown in FIG. 13 , the brake inner hub 136 has six holes 136 a which are spaced apart from each other in a circumferential direction. The axially protruding portions 116 a of the clutch piston 116 shown in FIG. 8 are inserted into the holes 136 a of the brake inner hub 136 , respectively, whereby the brake inner hub 136 is restricted from moving in an axially rightward direction when the brake inner hub 136 is brought into abutment with the shoulders 117 of the clutch piston 116 .
A plurality of brake discs 138 are mounted on the brake inner hub 136 so as not to rotate relative to the clutch inner hub 136 but to move in the axial direction of the same. Furthermore, a plurality of brake plates 140 are mounted on the casing 28 so as not to rotate but to move in the axial direction and are disposed such that the brake plates 140 alternate with the brake discs 138 . An end plate 144 is interposed between the brake inner hub 136 and the rightmost brake disc 138 .
Reference numeral 148 denotes a hydraulic piston functioning as an actuator, which activates the transmission brake 42 when moved rightward by virtue of an oil pressure introduced into an oil pressure chamber 152 . The oil pressure so introduced into the oil pressure chamber 152 is supplied from the oil pump sub-assembly 34 . The hydraulic piston 148 is normally biased by a coil spring 150 in a direction in which the application of the transmission brake 42 is released.
A companion flange 154 is fixed to the input shaft 30 by means of splines 156 , 158 . The companion flange 154 is coupled with the propeller shaft 8 shown in FIG. 1 .
Next, referring to FIGS. 15 to 22 , an assembling procedure of the speed increasing apparatus 10 according to the present invention which has been described heretofore will be described. Firstly, as shown in FIG. 15 , the oil pump driving pin 36 is assembled to the hypoid pinion shaft (the output shaft) 32 of the rear differential 12 , which has not yet been assembled into the casing 54 .
Next, as shown in FIG. 16 , the oil pump sub-assembly 34 is assembled to the rear differential 12 , and the bolt 74 is tightened. As this occurs, the oil pump driving pin 36 fits in the inner rotor which is incorporated in the oil pump main body 70 .
Thus, the function of the oil pump itself can be verified by constituting a primary complete body in which the base 68 , the oil pump body 70 and the cover 72 are assembled and installed together with the other associated components to be incorporated as the oil pump sub-assembly 34 . In addition, since the assembled state of the oil pump is maintained during a transportation, the oil pump sub-assembly 34 so assembled as the primary complete body is also effective when assembling oil pumps at a location which is far away from the final assembly line.
Next, as shown in FIG. 17 , the planetary carrier sub-assembly 38 is assembled to a bearing supporting portion 73 (refer to FIG. 16 ) disposed on the oil pump cover 72 . As this occurs, the splines 98 of the second sun gear 94 and the splines 96 of the hypoid pinion gear shaft 32 come to fit together.
Thus, the components to be incorporated such as the pinion gears 82 , 86 , the sun gears 88 , 94 and the bearings 80 are fixed by a circlip 81 after the components have been assembled in place onto the planetary carrier 78 , whereby the planetary carrier sub-assembly 38 can be completed as the primary complete body.
Consequently, the meshing conditions between the pinion gears 84 , 86 and the sun gears 88 , 94 and the thrust clearance can be verified on the planetary carrier sub-assembly 38 . In addition, since the assembled condition of the planetary carrier sub-assembly 38 is maintained during transportation, the planetary carrier sub-assembly 38 thus assembled as the primary complete body is also effective when assembling oil pumps at a location which is far away from the final assembly line.
Next, as shown in FIG. 18 , the direct connective clutch sub-assembly 40 is assembled to splines 100 (refer to FIG. 17 ) of the planetary carrier 78 . Furthermore, the transmission brake 42 is assembled to the direct connective clutch sub-assembly 40 .
Namely, the brake inner hub 136 of the transmission brake 42 is brought into engagement with the piston 116 of the direct connective clutch sub-assembly 40 , and the brake discs and the brake plates are mounted on the brake inner hub 136 in such a manner that the discs and the plates alternate with each other.
The clutch torque (which is determined by a set load of the coil spring 118 ) of the (direct connective) clutch 40 needs to be controlled at a certain value. To make this happen, while the clutch discs 112 and the clutch plates 114 need to be installed by selecting thicknesses thereof, performing this process during assembling processes of the whole rear differential 12 leads to a deterioration in working efficiency of the total assembly operation.
However, in this embodiment, since the clutch discs 112 and the clutch plates 114 are assembled as a part of the direct connective clutch sub-assembly 40 , the aforesaid process can be separated from the assembling processes of the whole rear differential 12 . In addition, since the assembled condition of the direct connective clutch sub-assembly 40 can be maintained during transportation, this arrangement is also effective when attempting to assemble rear differentials at a location which is far away from the final assembly line.
Next, as shown in FIG. 19 , the input shaft 30 is inserted. As this occurs, the input shaft 30 fits in place in the first sun gear 88 at the splines 90 , 92 . In addition, the input shaft 30 also fits in place in the clutch inner hub 106 of the direct connective clutch sub-assembly 40 at the splines 108 , 110 .
In this condition, heights N 1 , N 2 in FIG. 19 are measured. Namely, the height N 1 from the casing 54 to a shim 142 of the rear differential 12 and the height N 2 to the brake plate 140 at the uppermost end of the transmission brake 42 are measured.
Next, as shown in FIG. 20 , dimensions S 1 , S 2 of two locations of a front case sub-assembly 27 which is assembled in a separate process are measured. The front case sub-assembly 27 includes a casing 28 , bearings 146 which rotatably bear the input shaft 30 , the hydraulic piston 148 of the transmission brake 42 and the coil spring 150 .
Thickness are selected for the shim 142 and the brake end plate 144 with a view to set a specified clearance from a difference between N 1 and N 2 which were measured in the previous process.
The transmission hydraulic piston 148 is incorporated in the front case sub-assembly 27 , and in order to set the clearance of the transmission brake, the dimension S 2 from a mating surface between the casing 28 of the transfer apparatus 10 and the casing 54 of the rear differential 12 to an end surface of the hydraulic piston 148 needs to be measured.
Performing this measuring process during the assembling processes of the whole rear differential 12 leads to the deterioration in working efficiency of the total assembly operation. However, since the front case sub-assembly according to the embodiment is not affected by dimensions of the peripheral components, this measuring process can be separated from the assembling processes of the whole rear differential 12 .
Next, as shown in FIG. 21 , the front case sub-assembly 27 is assembled. An inner race of the bearing 146 is press fitted over the input shaft 30 , and the casing 28 is fastened to the casing 54 of the rear differential 12 with screws 66 . As this occurs, the brake clearance of the transmission brake 42 and the axial clearance of the respective components incorporated in the casing 28 become specified values.
Lastly, as shown in FIG. 22 , the companion flange 154 is assembled onto the input shaft 30 . Namely, the companion flange 154 is fixed onto the input shaft 30 by fitting the splines 156 , 158 together.
The operation of the speed increasing apparatus 10 and the rear differential 12 according to the embodiment that have been described heretofore will be described below.
The transmission brake 42 is in an OFF mode in which no oil pressure is introduced to the oil chamber 152 of the hydraulic piston 148 , the direct connective clutch 40 is engaged by virtue of the biasing force of the coil spring 118 .
Thus, the input shaft 30 and the planetary carrier 78 are connected together via the direct connective clutch 40 and the one-way clutch 120 , whereby the planetary carrier 78 encompassing the pinion gears 84 , 86 and the first and second sun gears 88 , 94 rotate together. Namely, these constituent components rotate as a block or unit.
As this occurs, the pinion gears 84 , 86 do not rotate on their axes but rotate together with the input shaft 30 and the output shaft 32 . Namely, power inputted from the companion flange 154 is outputted to the output shaft (hypoid pinion shaft) 32 as it is.
In the event that the left and right electromagnetic coils 60 of the rear differential 12 are switched off in this direct connecting mode, since the respective brake mechanisms 51 are not activated, the respective sun gears of the planetary gear sets 50 A, 50 B idly rotate around the left and right rear axles 24 , 26 .
Consequently, the driving force (torque) of the hypoid pinion gear 32 is not transmitted to the left and right rear axles 24 , 26 at all. In this case, the rear wheels spin, and all the driving force is directed to the front wheels, whereby the vehicle operates as a two-wheel drive vehicle.
In the event that a predetermined amount of current is conducted to the left and right electromagnetic coils 60 so that the left and right multi-plate brakes 52 are fully applied via the pistons 64 , the sun gears of the planetary gear sets 50 A, 50 B are fixed to the casing 54 , respectively.
Thus, the driving force of the hypoid pinion shaft 32 is transmitted to the left and right rear axles 24 , 26 via the ring gears of the planetary gear sets 50 A, 50 B, the planet gears and the planet carriers.
Consequently, the driving force of the input shaft 30 is equally divided and is then transmitted to the left and right rear axles 24 , 26 . As a result, the four-wheel drive vehicle is put in the four-wheel drive mode to thereby be allowed to drive straight ahead.
On the other hand, when turning a corner having a small turning radius in the four-wheel drive mode in low and middle speed ranges, an oil pressure is introduced to the oil chamber 152 of the transmission brake 42 so as to push the hydraulic piston 148 in the rightward direction to thereby activate the transmission brake 42 .
At the same time as this occurs, the brake inner hub 136 of the transmission brake 42 pushes the clutch piston 116 of the direct connective clutch 40 in the rightward direction against the biasing force of the coil spring 118 , so that the engagement of the direct connective clutch 40 is released.
By this operation, the clutch guide 104 is fixed to the casing 28 via the transmission brake 42 , and the planetary carrier 78 coupled with the clutch guide 104 is then fixed to the casing 28 .
Even with the planetary carrier 78 being fixed to the casing 28 , the small-diameter pinion gear 84 and the large-diameter pinion gear 86 which are held within the planetary carrier 78 can still rotate, and in this condition, the planetary carrier sub-assembly 38 part becomes a gear train having a certain gear ratio, whereby a change in speed is established between the input shaft 30 and the output shaft (hypoid pinion shaft) 32 .
Here, setting the number of teeth (N 1 ) of the sun gear 88 , the number of teeth (N 2 ) of the small-diameter pinion gear 84 , the number of teeth (N 3 ) of the large-diameter pinion gear 86 and the number of teeth (N 4 ) of the sun gear 94 to establish the following relationship among them, an increase in speed is established between the input shaft 30 and the output shaft 32 .
N1 N2 · N3 N4 > 1.0 [ Equation No . 1 ]
In this embodiment, the numbers of teeth of the respective pinion gears 84 , 86 and the first and second sun gears 88 , 94 are set so that an increased speed ratio becomes 1.07.
Assume that the vehicle turns left as shown in FIG. 23 in a state in which the rotational speed of the output shaft (the hypoid pinion shaft) 32 is made larger than that of the input shaft 30 . As this occurs, more current is conducted to the right-hand side electromagnetic coil 60 than to the left-hand side electromagnetic coil 60 in the rear differential, so that the right-hand side brake mechanism 51 is applied more strongly than the left-hand side brake mechanism 51 .
This allows the driving force of the hypoid pinion shaft 32 to be distributed more to the right rear axle 26 , and since this allows, in turn, the driving torque of the rear outer wheel of the turning vehicle to become larger than the driving torque of the rear inner wheel thereof, as indicated by an arrow 4 in FIG. 23 , the turning performance in, for example, the low to middle speed ranges can be enhanced.
In addition, on the contrary, the driving torque of the rear inner wheel of the turning vehicle is allowed to be made larger than the driving force of the rear outer wheel thereof, whereby a required running stability can be obtained in a high speed range.
Thus, by controlling the values of current conducted to the left and right electromagnetic coils 60 , the driving force of the input shaft 30 can arbitrarily be distributed to the left and right rear axles 24 , 26 in the direct connecting mode or by increasing the rotational speed thereof by the speed increasing apparatus 10 , whereby an optimum turning control and/or easy escape from a trap in the muddy road can be attained.
A switch from the direct connecting mode to the speed increasing mode will be controlled as below. A threshold for the steering effort or steering angle is set relative to the vehicle speed, and the speed increasing apparatus 10 is controlled so as to be put in the speed increasing mode when the steering effort or steering angle exceeds the threshold so set.
In addition, the rear differential 12 will be controlled as below. Values of current that is conducted to the electromagnetic coils 60 relative to the steering effort or steering angle are set in advance as a map.
By using this, the values of current that is conducted to the left and right electromagnetic coils 60 are controlled based on the turning angle and the steering effort or steering angle, the driving torque of the rear outer wheel of the turning vehicle is controlled so as to become larger than the driving torque of the rear inner wheel thereof.
While there has been described in connection with the preferred embodiments of the present invention, it will be obvious to those skilled in the art that various changes and modifications may be made therein without departing from the present invention, and it is aimed, therefore, to cover in the appended claims all such changes and modifications as fall within the true spirit and scope of the present invention.
According to the first aspect of the present invention, since only the single actuator can be used to disengage the clutch while activating the transmission brake in a simultaneous fashion, it is possible to provide the power transfer apparatus that is smaller in size and lighter in weight. In addition, since the clutch and the transmission brake are serially disposed in the axial direction, the outside diameter of the power transfer apparatus can be made small.
Furthermore, since when the actuator is activated, the engagement of the clutch is gradually released while the transmission brake is gradually applied, there is caused no interruption in transmitting power from the input shaft to the output shaft, thereby making it possible to prevent the occurrence of a shock when a change in speed takes place.
According to the second aspect of the present invention, since the one-way clutch is interposed between the clutch inner hub and the clutch guide, the load generated when the input shaft and the output shaft are directly connected to each other can be partially borne by the one-way clutch, thereby making it possible to reduce the load capacity of the clutch.
According to the third aspect of the present invention, even if the power transmission member such as the clutch inner hub is disposed on the inner diameter side, the control (On/Off) of the clutch can be implemented on the outside diameter side. | A power transfer apparatus including a clutch having a biasing device for biasing the clutch piston in a direction in which the clutch discs engage with the clutch plates, a transmission brake disposed in line in an axial direction of the clutch, an actuator disposed in line in an axial direction of the transmission brake for disengaging the clutch at the same time of applying the transmission brake, and a planetary carrier sub-assembly disposed in line in the axial direction of the clutch, wherein the power transfer apparatus provided between an input shaft and an output shaft which are accommodated within a casing for selectively changing the speed of the output shaft. | 1 |
BACKGROUND OF THE INVENTION
The invention relates generally to the field of footgear: dress shoes, athletic boots, sneakers, orthopedic shoes and the like, and more particularly to an improved means for quick, easy, inexpensive and therapeutic individual custom fitting by mechanical means within said footgear.
Walking is a complicated bio-mechanical process. As the heel strikes, the Talus and attached Calcaneous (heel) bone, which make up the Sub Taler joint, move downwardly and medially, acting as a shock absorber. The range of said movement is called pronation. The degree of pronation is a direct factor that determines the efficiency of the foot and leg as well as all related parts of the body above the foot, as well as the parts of the foot distal to these bones.
Abnormal degrees of pronation can cause incorrect positioning of all the directly and indirectly connected bones which in turn causes strain on all the directly and indirectly connected joints, ligaments, nerves, blood vessels and muscles. This strain may be felt any where throughout the body as aches, pains, fatigue, cramping, pulled muscles, fasciitis, tendenitis, etc. If left untreated the condition may worsen and cause chronic “bad knees”, “bad backs”, neuromas, stress fractures of bones, etc.
The degrees of pronation are also influenced by the kind of footgear and the fit of said footgear.
PRIOR ART
The problems arising from excessive pronation have been treated by devices worn in footgear to minimize the degree of pronation. Such “supports” are lumped together as “Arch Supports” and “Foot Orthotics”. “Arch Supports” are relatively inexpensive- twenty, thirty dollars- and are sold over the counter, usually by shoe size. “Foot Orthotics” are custom built over plaster casts- or the like- of the individual foot and may cost four and five hundred dollars. The devices may be constructed and formed of leather, metals and plastics of varying degrees of rigidity. While the main benefits of such “supports” derive from the support under the Sub Taler joint, the “supports” mimic the shape of the bottom of the foot and often have built up edges to maintain the foot in position relative to the Sub Taler supported area.
All such devices have many faults in common. They take up space within the footgear. Their fit and efficiency is effected by the shape of the sole of the footgear. As they are constantly worn they pick up odors from the feet. The breakdown of the shoe with wear will change the efficiency of the devices. The condition of the person wearing said devices may change. Changing shoes, the wearer may forget to include the devices. They may be lost. Because of their cost a person may choose not to buy them and so allow his condition to worsen. A less expensive device may not be correct for the condition treated.
Adjustments of said devices are costly. It requires the services of persons trained in the art, who have the necessary machinery and materials. Adjustments also require the investment of travel time to and from the business or offices of the adjuster for one or more times.
It is therefore among the objects of the present invention to provide means for adjusting the interior of footgear to meet the needs of the individual foot, in which the advantages of the above are substantially retained, and the disadvantages substantially eliminated.
Another object of the invention lies in the provision of mechanical means to achieve the initial custom support, as well as subsequent adjustments, quickly, easily and inexpensively. Another object is to provide means by which an individual can adjust the shoe himself when necessary. The relatively small cost and ease of use may attract its use for even small problems and thus, in the long run, prevent many of the complications arising from neglect of treating small problems.
U.S. Pat. No. 5,285,584 granted to this inventor uses a similar screw means to raise the inner aspect of the heel. The devices of this Patent consists of two distinct parts. One part controls the Sub Taler joint (heel) area of the foot. The other part controls the forward ball of the foot (metatarsal) area. However, it has been found that the raising of the small area under the Sub Taler joint area puts a painful and unwearable pressure on that small area. A semi rigid extension extending under most of medial side of the foot can distribute this excessive pressure and make it bearable and wearable. However, such a semi rigid extension cannot be used with the aforementioned patent because such an extension would then extend over and impinge the mechanism for controlling the forward metatarsal area and interfere with the working of that part of the invention. Ref lexly, it would also interfere with the working of the Sub Taler (heel) part of that invention.
It is an object of the present invention to overcome the foregoing problem.
These objects and advantages will be apparent in the drawings.
SUMMARY OF THE INVENTION
In accordance with the present invention, a semi rigid piece along the long arch area, extends from the heel area to the ball of the foot area and is disposed over the inner sole of the shoe. This semi rigid piece may be of steel or plastic. The foot is maintained in position by the sides of the shoes.
The device is provided with lifting means to raise or lower the semi rigid piece. In the preferred embodiment, the lifting means is a screw that penetrates the shoe upwardly through the sole.
In another embodiment, a rigid supportive piece raises from a slit in the sole of the shoe in the Sub Taler joint heel area. This supportive piece is activated by a spring that causes it to revolve into a vertical position or as close to a vertical as the overriding semi rigid piece pressed against the foot will allow. A screw, penetrating from the side of the heel area goes through a bore in said supportive piece and acts as its axle. Tightening of this screw forces the supportive piece tightly against side flanged attachments to the wall of the slot to maintain its position.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 . is a longitudinal section of a shoe illustrating the semi rigid piece and the underlying screw mechanism penetrating up through the sole/heel;
FIG. 2 . is a longitudinal section of a shoe illustrating another embodiment of an underlying mechanism with a controlling screw penetrating the side of the heel;
FIG. 3 . is a plan view of the shoe sole shown in FIG. 1 illustrating the through bore of the heel;
FIG. 4 . is a plan view of a shoe sole illustrating yet another means of raising and lowering the semi rigid piece controlled by a screw penetrating the side of the heel; and
FIG. 5 . is a sectional view taken along line A—A of FIG. 4, illustrating another means of raising and lowering the semi rigid piece controlled by a screw penetrating the side of the heel.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention fits conventional shoes made for men or women. Such shoes generally comprise a upper, a outer sole, a heel, a internal sole and a sock lining.
The invention, as seen in FIG. 1, provides a semi rigid piece 1 , for supporting the arch of the foot, and an underlying flanged Tee Nut 2 set into the top of through bore 4 of the heel 13 . Said Tee Nut 2 contains inner threads to mesh with the threads of screw 3 . Screw 3 penetrates the bore 4 of the heel and contacts the bottom of the semi rigid piece 1 in the area of its heel end. Screw 3 has a notch 5 at its lower end to facilitate the use a screw driver to turn said screw 3 to raise or lower said semi rigid piece 1 . The sock lining 11 is of a material that helps dissipate the pressure of the semi rigid piece 1 . The semi rigid piece 1 is secured to the sock lining 11 directly by the use of adhesives or adhesive tapes.
With the foot in the footgear, the screw 3 is turned until the wearer feels the semi rigid piece 1 contact the medial area of the foot. Then, walking determines if the amount of raise is comfortable. If the wearer of the shoe is seeking relief from some particular pain or ache, some days or weeks trials are indicated. If there is no relief, piece 1 can be raised for other trials. If other areas of discomfort appear, the semi rigid piece 1 can then be lowered back to its comfortable position.
In another embodiment of the invention as shown in FIGS. 2-4, said semi rigid piece 1 overlies a slot 6 in the sole area 15 of the heel 13 . The slot 6 contains a supporting piece 9 and flanged pieces 7 and 8 attached to opposing walls of said slot 6 (FIG. 4 ). Operation of handle 16 provides counter clockwise rotation of screw 12 at the side of the heel 13 releasing the friction pressure holding said supporting piece 9 in place between flanged pieces 7 and 8 . This frees piece 9 so it can respond to the urging of spring 10 and rotate up to and force up semi rigid piece 1 as much as it can until it is stopped by the pressure of the foot above it. Then screw 12 is turned via handle 16 clockwise within its nut 14 to bring said support piece 9 and the flanged pieces 7 and 8 tightly together to maintain support piece 9 and semi rigid piece 1 in position. Flanged pieces 7 and 8 are adhered to the walls of slot 6 by their flange parts. The sides of support piece 9 and the flange pieces 7 and 8 are roughened to provide additional friction to maintain support piece 9 in position.
In another embodiment of the invention as shown in FIGS. 2-5, the semi rigid piece 1 overlies a slot 6 in the sole area 15 of the heel 13 . The slot 6 contains a supporting piece 9 and flanged pieces 7 and 8 attached to opposing walls of said slot 6 (FIG. 4 ). Operation of handle 16 provides counter clockwise rotation of screw 12 at the side of the heel 13 releasing the friction pressure holding said supporting piece 9 in place between flanged pieces 7 and 8 . This frees piece 9 so it can respond to the urging of spring 10 and rotate up to and force up semi rigid piece 1 as much as it can until it is stopped by the pressure of the foot above it. Then screw 12 is turned via handle 16 clockwise within its nut 14 to bring said support piece 9 and the flanged pieces 7 and 8 tightly together to maintain support piece 9 and semi rigid piece 1 in position. Flanged pieces 7 and 8 are adhered to the walls of slot 6 by their flange parts. The sides of support piece 9 and the flange pieces 7 and 8 are roughened to provide additional friction to maintain piece 9 in position.
The semi rigid piece 1 forming the foot support can be made from a single member of flexible plastic or several layers or leaves of plastic, leather or the like.
With the foregoing and other objects in view, the invention resides in the novel arrangement and combination of parts and in the details of construction hereinafter described and claimed, it being understood that changes in the precise embodiments of the invention herein disclosed may be within the scope of what is claimed without departing from the spirit of the invention. | In a shoe, an apparatus for the support of a foot, comprising a semi rigid piece of metal or plastic extending from the heel to the ball of the foot, disposed over the inner sole of the shoe, and a screw penetrating upward to raise or lower the semi rigid piece. | 0 |
BACKGROUND
[0001] The invention relates to a secondary assembly drive of an internal combustion engine and to a method for operating this drive. The secondary assembly drive comprises two parallel drive planes and:
a first crankshaft wheel that can be rotationally connected to a crankshaft of the internal combustion engine and is arranged in the first drive plane, a second crankshaft wheel that can be rotationally connected to the crankshaft and is arranged coaxial to the first crankshaft wheel in the second drive plane, an electric machine that can be operated selectively as a generator or as a motor with a machine shaft, a first machine shaft wheel that can be rotationally connected to the machine shaft and is arranged in the first drive plane, in order to be driven by the crankshaft in the generator mode of the electric machine, a second machine shaft wheel that can be rotationally connected to the machine shaft and is arranged coaxial to the first machine shaft wheel in the second drive plane, in order to drive the crankshaft in the motor mode of the electric machine, an endlessly rotating first traction mechanism that wraps around the wheels arranged in the first drive plane, an endlessly rotating second traction mechanism that wraps around the wheels arranged in the second drive plane, a first coupling that is arranged in the first drive plane and allows the machine shaft to be taken over relative to the crankshaft, and a second coupling that is arranged in the second drive plane and allows the crankshaft to be taken over relative to the machine shaft.
[0011] A dual belt drive according to the class for driving ancillary drives of an internal combustion engine emerges from US 2006/0145643 A1. The individual drives in the two drive planes, called ancillary drive and starter drive below, are configured with different transmission ratios from the crankshaft to the machine shaft so that, when the belts of the internal combustion engine start up, the highest possible starting torque is transferred from the electric machine to the crankshaft. Here, both couplings, of which the first coupling allows the machine shaft to be taken over relative to the crankshaft and, in contrast, the second allows the crankshaft to be taken over relative to the machine shaft, are formed as clamping roller freewheels and are arranged in the drive sense between the machine shaft and the two machine shaft wheels, i.e., on the side of the electric machine.
SUMMARY
[0012] The invention is based on the objective of improving the design of an ancillary drive of the type mentioned above and disclosing a method for operating such an ancillary drive.
[0013] This objective is met, in terms of the device and in terms of the method, according to the invention. Advantageous constructions of the invention can be taken from the description and claims below.
[0014] Accordingly, the second coupling is a freewheel coupling that is arranged, in the drive sense, between the second crankshaft wheel and the crankshaft and allows the crankshaft to be taken over relative to the second crankshaft wheel. One essential advantage of this structural design according to the invention is based on the fact that the available installation space for the freewheel coupling on the side of the crankshaft is significantly larger than on the side of the machine shaft and results in the fact that the highly loaded contact surfaces during the starting process of the internal combustion engine can be dimensioned in the freewheel coupling in sufficient number and size corresponding to the starting torque to be transferred.
[0015] The freewheel coupling is advantageously a clamping roller freewheel whose inner ring rotates with the second crankshaft wheel and whose outer ring rotates with the crankshaft, wherein the spring-mounted clamping rollers are opposite ramp-shaped recesses in the outer ring. This known construction of the freewheel coupling that lifts as a function of centrifugal force for the benefit of lower contact friction at higher rotational speeds is called an external star freewheel below.
[0016] The first coupling is a freewheel coupling that is arranged in the drive sense between the first machine shaft wheel and the machine shaft and allows, in the rotational direction of the generator mode, the machine shaft to be taken over relative to the first machine shaft wheel. This freewheel coupling is advantageously also a clamping roller freewheel whose inner ring, however, rotates with the machine shaft and whose outer ring rotates with the first machine shaft wheel, wherein the spring-mounted clamping rollers are opposite ramp-shaped recesses in the inner ring. This known design of the freewheel coupling, especially in the form of generator freewheels, blocks essentially without influencing the rotational speed and is called an inner star freewheel below.
[0017] As an alternative to such a freewheel, on the side of the electric machine, a spring decoupling can also be provided with two-sided stops or basically also a rigid connection between the first machine shaft wheel and the machine shaft, wherein, however, the ancillary drive must then be equipped with an (actively) switchable freewheel.
[0018] In addition, in the drive sense between the first crankshaft wheel and the crankshaft there can be a controllable third coupling for the operative disconnection of the first drive plane from the crankshaft. When the third coupling is open, on one hand, when the internal combustion engine is running, the ancillary drive can be stopped, in order to minimize its operative friction losses. On the other hand, when the internal combustion engine is stopped, air conditioning can be provided when the vehicle is parked. For this purpose, another motor mode of the electric machine with the rotational direction opposite that for the generator mode and an air-conditioning system compressor can be provided that is formed for a compressor operation in both rotational directions. A compressor wheel that can be rotationally connected to a compressor shaft of the air-conditioning system compressor is arranged in the ancillary drive, in order to drive the air-conditioning system compressor in the generator mode, i.e., in one direction when the internal combustion engine is running, and in the additional motor mode, i.e., in the other direction when the internal combustion engine is stopped. In the additional motor mode, the rotational direction in the opposite direction relative to that in the generator mode prevents a drive-dependent change of the taut section and slack section in the ancillary drive, so that a tensioning device for pre-tensioning the first traction mechanism is arranged in the slack section, i.e., always functionally optimized both when the internal combustion engine is running (generator mode and normal air-conditioning mode) and also when the internal combustion engine is stopped (mode for air conditioning when the vehicle is parked).
[0019] Relative to a freewheel coupling, the third coupling should be actively switchable, for which, in particular, electrically controllable magnetic couplings are available. This also applies to a controllable fourth coupling that should be arranged, for the operative disconnection of the second drive plane from the machine shaft, in the drive sense between the second machine shaft wheel and the machine shaft. An opening of the fourth coupling after the internal combustion engine starts up has the effect that the starter drive runs down after the startup process of the internal combustion engine and stops when the internal combustion engine is running.
[0020] A tensioning device arranged in the slack section can be used for the pre-tensioning of the traction mechanism of the ancillary drive and the starter drive.
[0021] For the operation of the ancillary drive according to the invention, at least three operating modes are provided:
a start mode in which the electric machine is operated as a motor and drives the crankshaft until the internal combustion engine starts up, a normal operating mode in which the electric machine is operated as a generator and is driven by the crankshaft, and a boost mode in which the electric machine is operated as a motor and supports the driving of the crankshaft when the internal combustion engine is running.
[0025] According to the construction of the ancillary drive, the following operating modes are optionally possible:
a switch-off mode in which the third coupling is open and the first drive plane, i.e., the ancillary drive, is operatively disconnected from the crankshaft, a mode for air conditioning when the vehicle is parked in which the third coupling is open and the electric machine is operated in another motor mode in the rotational direction opposite that of the generator mode and drives the air-conditioning system compressor, and an expanded normal operating mode in which the fourth coupling is open and the second drive plane, i.e., the starter drive, is operatively disconnected from the machine shaft.
[0029] As preferred traction mechanisms there are, on the side of the ancillary drive, a non-positive fit poly-V belt and, on the side of the starter drive, a positive fit toothed belt. An ancillary drive according to the invention can nevertheless also be a chain-chain drive or a belt-chain drive. Other ancillary drives, optionally also in other drive planes, can also be provided. This relates, in particular, to a coolant pump that is arranged in the ancillary drive for cooling the internal combustion engine and is also formed for a pumping operation in both operative rotational directions. According to the construction of the coolant pump, its reversal of rotational direction does not lead to a change of the suction and pressure sides, but can be associated with pumping rates of different magnitudes. Analogous to air conditioning when the vehicle is parked or cooling of the vehicle interior, coolant that is heated during operation and is circulated when the internal combustion engine is stopped can be used for heating the vehicle interior (heating when the vehicle is parked).
[0030] The control/regulation of the individual operating modes is realized with the help of state parameters of the internal combustion engine, optionally the temperature of the vehicle interior, and, if provided, the switching state of the controllable couplings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Additional features of the invention are also given from the following description and from the drawings that show schematically an ancillary drive according to the invention for a motor vehicle internal combustion engine. Shown are:
[0032] FIG. 1 the layout of the ancillary drive in a perspective view,
[0033] FIG. 2 the ancillary drive (first drive plane) in a schematic view,
[0034] FIG. 3 the starter drive (second drive plane) in a schematic view.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0035] FIG. 1 discloses the crankshaft drive of an internal combustion engine with an ancillary drive that is arranged on the free end of the crankshaft 1 and is constructed as a double belt drive in two parallel drive planes. The ancillary drive 2 running in the first drive plane comprises a first crankshaft wheel 3 that is arranged on the crankshaft 1 , a first machine shaft wheel 4 that is arranged on the machine shaft 5 of an electric machine 6 , a compressor wheel 7 that is arranged on the compressor shaft 8 of an air-conditioning system compressor 9 , a first traction mechanism wrapping around the first wheels 3 , 4 , 7 in the form of an endlessly rotating poly-V belt 10 , and a first tensioning device in the form of a known spring-loaded belt tensioner 11 between the first crankshaft wheel 3 and the first machine shaft wheel 4 .
[0036] The starter drive 12 in the second drive plane comprises a second crankshaft wheel 13 that is arranged on the crankshaft 1 coaxial to the first crankshaft wheel 3 , a second machine shaft wheel 14 that is arranged on the machine shaft 5 coaxial to the first machine shaft wheel 4 , a second traction mechanism wrapping around the second wheels 13 , 14 in the form of an endlessly rotating toothed belt 15 , and a second tensioning device also in the form of a known belt tensioner 16 between the second crankshaft wheel 13 and the second machine shaft wheel 14 .
[0037] The electric machine 6 is a starter generator that drives the machine shaft 5 in the starter mode and in the motor mode and is driven by the machine shaft 5 in the generator mode.
[0038] The air-conditioning system compressor 9 is a wobble plate compressor that is formed for a compressor operation in both rotational directions and is inserted into the coolant circuit of the vehicle air-conditioning system independent of the rotational direction accordingly.
[0039] The drive-specific interconnection of the ancillary drive is given from the schematically shown individual drives, wherein FIG. 2 shows the ancillary drive 2 and FIG. 3 shows the starter drive 12 . The operative rotational direction of the crankshaft 1 , which is also called CR here, corresponds to the rotational direction drawn with a plus sign. The rotational direction of the machine shaft 5 also drawn with AL/M is positive when the electric machine 6 is in generator mode AL and is driven by the crankshaft 1 and also when the electric machine 6 is in the motor mode M-CR and drives the crankshaft 1 . The rotational direction of the machine shaft 5 has a minus sign when the electric machine 6 is in an additional motor mode M-A/C and drives the air-conditioning system compressor 8 , which is also called A/C here, in the air-conditioning system compressor 9 in a correspondingly reverse rotational direction when the internal combustion engine is stopped.
[0040] In the ancillary drive 2 , the rotational connection of the first machine shaft wheel 4 to the machine shaft 5 is realized by means of a first coupling 17 in the form of a clamping roller freewheel that is constructed as an inner star freewheel and allows, in the positive rotational direction, the machine shaft 5 to be taken over relative to the first machine shaft wheel 4 and thus relative to the crankshaft 1 and blocks in the correspondingly opposite, negative rotational direction. The clamping roller freewheel 17 is constructed as a generator freewheel with the known decoupling function of the generator, wherein its inner ring rotates with the machine shaft 5 and wherein its outer ring rotates with the first machine shaft wheel 4 .
[0041] In the starter drive 12 , the rotational connection of the second crankshaft wheel 13 to the crankshaft 1 is realized by means of a second coupling 18 in the form of a clamping roller freewheel that is constructed as an outer star freewheel and allows, in the positive rotational direction, the crankshaft 1 to be taken over relative to the second crankshaft wheel 13 and thus relative to the machine shaft 5 and is blocks in the correspondingly opposite rotational direction. The clamping roller freewheel 18 is arranged structurally so that its inner ring rotates with the second crankshaft wheel 13 and its outer ring rotates with the crankshaft 1 .
[0042] The first crankshaft wheel 3 is rotationally connected to the crankshaft 1 by means of a third coupling 19 in the form of an electrically controllable magnetic coupling (this can be either open when de-energized or closed when de-energized). In the open state, the magnetic coupling 19 is used for the operative disconnection of the ancillary drive 2 from the crankshaft 1 .
[0043] The second machine shaft wheel 14 is rotationally connected to the machine shaft 5 by means of a fourth coupling 20 also in the form of an electrically controllable magnetic coupling (this can be either open when de-energized or closed when de-energized). In the open state, the magnetic coupling 20 is used for the operative disconnection of the starter drive 12 from the machine shaft 5 .
[0044] The compressor wheel 7 can be rotationally connected to the compressor shaft 8 optionally with a controllable (not shown) magnetic coupling.
[0045] The following ratio of the transmission ratios TR 1 and TR 2 applies, namely TR 1 >TR 2 , if TR 1 is the rotational speed ratio between the first crankshaft wheel 3 and the first machine shaft wheel 4 and if TR 2 is the rotational speed ratio between the second crankshaft wheel 13 and the second machine shaft wheel 14 .
[0046] The following operating modes for the ancillary drive are provided:
a) a start mode in which the electric machine 6 drives the crankshaft 1 from a standstill until the internal combustion engine starts:
the electric machine 6 is in the motor mode M-CR with positive rotational direction, the magnetic coupling 19 is closed (but could also be open), the magnetic coupling 20 is closed, the crankshaft 1 is driven by means of the starter drive 12 and drives the ancillary drive 2 by means of the closed magnetic coupling 19 and the first crankshaft wheel 3 : due to the previously mentioned transmission ratios TR 1 and TR 2 , the first coupling 17 is in the freewheel position and the second coupling 18 is in the blocking position, the internal combustion engine starts and when the internal combustion engine is running, the first coupling 17 is in the blocking position and the second coupling 18 is in the freewheel position, the magnetic coupling 20 is open and the starter drive 12 disconnected operatively from the machine shaft 5 comes to a stop, the first belt tensioner 11 also called BT 1 and the second belt tensioned 16 called BT 2 are always in the slack section of the respective belt drive 2 or 12 optimally in terms of function, i.e., both before and also after the startup process of the internal combustion engine;
b) a normal operating mode in which the electric machine 6 is driven by the crankshaft 1 of the running internal combustion engine:
the electric machine 6 is in the generator mode AL with positive rotational direction, the magnetic coupling 20 is open and the starter drive 12 is stopped (expanded normal operating mode), the magnetic coupling 19 is closed and the crankshaft 1 drives the ancillary drive 2 by means of the first crankshaft wheel 3 , the first coupling 17 is in the clamping position and the electric machine 6 is in the generator mode AL with positive rotational direction, the compressor wheel 7 is driven in the positive rotational direction, the first belt tensioner 11 is in the slack section of the ancillary drive 2 ;
c) a boost mode in which, when the internal combustion engine is running, the electric machine 6 assists in the driving of the crankshaft 1 :
the electric machine 6 is in the motor mode M-CR with positive rotational direction, the magnetic coupling 19 is closed (but could also be open), the magnetic coupling 20 is closed, the rotating crankshaft 1 of the running internal combustion engine is driven by means of the starter drive 12 and drives the ancillary drive 2 by means of the closed magnetic coupling 19 and the first crankshaft wheel 3 : due to the previously mentioned transmission ratios TR 1 and TR 2 , the first coupling 17 is in the freewheel position and the second coupling 18 is in the blocking position, the end of the boost mode: the electric machine 6 changes from the driving motor mode M-CR to the driven generator mode AL that sets in when reaching the same rotational speeds of the first machine shaft wheel 4 and the machine shaft 5 , the magnetic coupling 20 is open and the starter drive 12 operatively disconnected from the machine shaft 5 comes to a stop, as in the start mode, the belt tensioners 11 and 16 are always in the slack section of the respective belt drive 2 or 12 optimally in terms of function.
d) a switch-off mode in which the magnetic coupling 19 is open and the ancillary drive 2 is operatively disconnected from the crankshaft 1 ;
the internal combustion engine is running, the ancillary drive 2 is stopped, the starter drive 12 is stopped or in boost mode, the connection of the ancillary drive 2 is realized by closing the magnetic coupling 19 . For reducing transient load spikes during the rotational synchronization of the crankshaft 1 and ancillary drive 2 , it can be useful to accelerate the electric machine 6 to a rotational speed above the connecting generator mode AL before the connection and/or to close the magnetic coupling 19 within the synchronization phase so that the drive torque that can be transferred by the magnetic coupling 19 is always less than a limiting torque that, if exceeded, would lead to a slippage of the poly-V belt 10 to an undesirable degree.
e) a mode for air conditioning when the vehicle is parked in which the electric machine 6 drives the air-conditioning system compressor 9 when the internal combustion engine is stopped:
the magnetic coupling 19 is open, the electric machine 6 is in an additional motor mode M-A/C with a rotational direction opposite that in the generator mode, the first coupling 17 is in the clamping position and the compressor wheel 7 is driven in the negative direction, the magnetic coupling 20 is closed (but could also be open) and the starter drive 12 is driven against the shown positive rotational direction, the second coupling 18 is in the freewheel position, the first belt tensioner 11 is in the slack section of the ancillary drive 2 , the starting of the internal combustion engine from the mode for air conditioning when the vehicle is parked is realized by changing the rotational direction of the electric machine 6 from the (negative) additional motor mode M-A/C to the (positive) motor mode M-CR. Here, the first coupling 17 changes from the clamping position to the freewheel position and the ancillary drive 2 rotating “backward” comes to a stop. The second coupling 18 changes from the freewheel position to the clamping position and the crankshaft 1 is driven from the stopped state until the internal combustion engine starts—continues in the start mode under a).
LIST OF REFERENCE NUMBERS
[0083] 1 Crankshaft
[0084] 2 Ancillary drive
[0085] 3 First crankshaft wheel
[0086] 4 First machine shaft wheel
[0087] 5 Machine shaft
[0088] 6 Electric machine
[0089] 7 Compressor wheel
[0090] 8 Compressor shaft
[0091] 9 Air-conditioning system compressor
[0092] 10 First traction mechanism, poly-V belt
[0093] 11 First tensioning device, first belt tensioner
[0094] 112 Starter drive
[0095] 13 Second crankshaft wheel
[0096] 14 Second machine shaft wheel
[0097] 15 Second traction mechanism, toothed belt
[0098] 16 Second tensioning device, second belt tensioner
[0099] 17 First coupling, clamping roller freewheel
[0100] 18 Second coupling, clamping roller freewheel
[0101] 19 Third coupling, magnetic coupling
[0102] 20 Fourth coupling, magnetic coupling | A secondary assembly drive of an internal combustion engine and a method for operating same are provided. The secondary assembly drive includes, in two drive planes, an assembly drive ( 2 ) and a starter drive ( 12 ) and permits, in addition to a normal operating mode, the following operating modes:—starting of the internal combustion engine,—boosting of the internal combustion engine,—air-conditioning, and—deactivation of the assembly drive ( 2 ). | 1 |
FIELD OF THE INVENTION
[0001] This invention relates generally to an electronic reprographic printing system, and more particularly concerns feeder apparatus process for improving feeding of compilations of recording sheets that often accompanies this general method of reproduction and printing.
BACKGROUND OF THE INVENTION
[0002] In the process of electrostatographic reproduction, a light image of an original to be copied or printed is typically recorded in the form of a latent electrostatic image upon a photosensitive member, with a subsequent rendering of the latent image visible by the application of electroscopic marking particles, commonly referred to as toner. The visual toner image can be either fixed directly upon the photosensitive member or transferred from the member to another support medium, such as a sheet of plain paper. To render this toner image permanent, the image must be “fixed” or “fused” to the paper, generally by the application of heat and pressure.
[0003] With the advent of high speed xerography reproduction machines wherein copiers or printers can produce at a rate in excess of three thousand copies per hour, the need for sheet handling system to, for example, feed paper or other media through each process station in a rapid succession in a reliable and dependable manner in order to utilize the full capabilities of the reproduction machine. These sheet handling systems must operate flawlessly to virtually eliminate risk of damaging the recording sheets and generate minimum machine shutdowns due to misfeeds or multifeeds. It is in the initial separation of the individual sheets from the media stack where the greatest number of problems occur which, in some cases, can be due to up curl and down curl in sheets which generally occur randomly in the document stack.
[0004] Applicant has found that previous approaches incorporated a venturi fluffer (U.S. Pat. No. 6,264,188 to Taylor et al.) to break apart the sheets on the stack. That patent discloses a venturi fluffer utilizing internal and external flaps in order to maintain a relatively constant throat cross section and pressure to achieve sheet separation. The venturi fluffer provided satisfactory performance in uncoated papers up to 200 gsm, slightly lower with coated stocks due to an observed lack of sufficient air pressure to break up the sheet pairs inherent in coated stocks, even with heat. The venturi fluffer provided a wide throat cross section that delivered sufficient air volume to maintain sheet separation, once achieved, but at an insufficient pressure necessary to break up sheet pairings observed during testing. Various combinations of fluffer pressure settings and configurations provided little relief across the wide range of media types prescribed.
[0005] Other high pressure fluffing systems use multiple blower pressure settings to provide the correct air flow rate and pressure into the side of a stack. All of the systems have pressure losses due to air flowing above the stack.
SUMMARY OF THE INVENTION
[0006] There is provided a sheet feeding apparatus for feeding a stack of sheets in a direction of movement to a process station, comprising: a sheet tray for holding said stack of sheets; an air plenum, positioned above said stack of sheets, for picking up a sheet from said stack of sheets when a vacuum force in said air plenum; a paper fluffer for blowing a constant volume of air at pressure between individual sheets in said stack to produce a fluffed stack of sheets, said paper fluffer having means for adjusting air pressure between individual sheets.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] [0007]FIG. 1 is a schematic elevational view of an illustrative electrophotographic printing having the features of the present invention therein.
[0008] FIGS. 2 - 4 is a schematic of an air plenum of a media feeder employed with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0009] While the present invention will hereinafter be described in connection with preferred embodiments, it will be understood that it is not intended to limit the invention to a particular embodiment.
[0010] For a general understanding of the features of the present invention, reference is made to the drawings. In the drawings, like reference numerals have been used throughout to designate like elements. It will become evident from the following discussion that the present invention and the various embodiments set forth herein are suited for use in a wide variety of printing and copying systems, and are not necessarily limited in its application to the particular systems shown herein.
[0011] By way of a general explanation, FIG. 1 is a schematic elevational view showing an electrophotographic printing machine which incorporates features of the present invention therein. It will become evident from the following discussion that the present invention is equally well suited for use in a wide variety of copying and printing systems, and is not necessarily limited in its application to the particular system shown herein. As shown in FIG. 1, during operation of the printing system, a color or black/white original document 38 is positioned on a raster input scanner (RIS), indicated generally by the reference numeral 10 . The RIS contains document illumination lamps, optics, a mechanical scanning drive, and a charge coupled device (CCD array). The RIS captures the entire image from original document 38 and converts it to a series of raster scan lines and moreover measures a set of primary color densities, i.e. red, green and blue densities, at each point of the original document. This information is transmitted as electrical signals to an image processing system (IPS), indicated generally by the reference numeral 12 . IPS 12 converts the set of red, green and blue density signals to a set of colorimetric coordinates.
[0012] IPS 12 contains control electronics which prepare and manage the image data flow to a raster output scanner (ROS), indicated generally by the reference numeral 16 . A user interface (UI), indicated generally by the reference numeral 14 , is in communication with IPS 12 . UI 14 enables an operator to control the various operator adjustable functions. The operator actuates the appropriate keys of UI 14 to adjust the parameters of the copy. UI 14 may be a touch screen, or any other suitable control panel, providing an operator interface with the system. The output signal from UI 14 is transmitted to IPS 12 . IPS 12 then transmits signals corresponding to the desired image to ROS 16 , which creates the output copy image. ROS 16 includes a laser with rotating polygon mirror blocks. Preferably, a nine facet polygon is used. ROS 16 illuminates, via mirror 37 , the charged portion of a photoconductive belt 20 of a printer or marking engine, indicated generally by the reference numeral 18 , at a rate of about 400 pixels per inch, to achieve a set of subtractive primary latent images. ROS 16 will expose the photoconductive belt 20 to record three latent images which correspond to the signals transmitted from IPS 12 . One latent image is developed with cyan developer material. Another latent image is developed with magenta developer material and the third latent image is developed with yellow developer material. These developed images are transferred to a copy sheet in superimposed registration with one another to form a multicolored image on the copy sheet. This multicolored image is then fused to the copy sheet forming a color copy.
[0013] With continued reference to FIG. 1, printer or marking engine 18 is an electrophotographic printing machine. Photoconductive belt 20 of marking engine 18 is preferably made from a polychromatic photoconductive material. The photoconductive belt 20 moves in the direction of arrow 22 to advance successive portions of the photoconductive surface sequentially through the various processing stations disposed about the path of movement thereof. Photoconductive belt 20 is entrained about transfer rollers 24 and 26 , tensioning roller 28 , and drive roller 30 . Drive roller 30 is rotated by a motor 32 coupled thereto by suitable means such as a belt drive. As roller 30 rotates, it advances belt 20 in the direction of arrow 22 .
[0014] Initially, a portion of photoconductive belt 20 passes through a charging station, indicated generally by the reference numeral 33 . At charging station 33 , a corona generating device 34 charges photoconductive belt 20 to a relatively high, substantially uniform potential.
[0015] Next, the charged photoconductive surface is rotated to an exposure station, indicated generally by the reference numeral 35 . Exposure station 35 receives a modulated light beam corresponding to information derived by RIS 10 having multicolored original document 38 positioned thereat. The modulated light beam impinges on the surface of photoconductive belt 20 . The beam illuminates the charged portion of the photoconductive belt to form an electrostatic latent image. The photoconductive belt 20 is exposed three times to record three latent images thereon.
[0016] After the electrostatic latent images have been recorded on photoconductive belt 20 , the belt advances such latent images to a development station, indicated generally by the reference numeral 39 . The development station includes four individual developer units indicated by reference numerals 40 , 42 , 44 , and 46 . The developer units are of a type generally referred to in the art as “magnetic brush development units.” Typically, a magnetic brush development system employs a magnetizable developer material including magnetic carrier granules having toner particles adhering triboelectrically thereto. The developer material is continually brought through a directional flux field to form a brush of developer material. The developer material is constantly moving so as to continually provide the brush with fresh developer material. Development is achieved by bringing the brush of developer material into contact with the photoconductive surface. Developer units 40 , 42 , and 44 , respectively, apply toner particles of a specific color which corresponds to the compliment of the specific color separated electrostatic latent image recorded on the photoconductive surface.
[0017] The color of each of the toner particles is adapted to absorb light within a preselected spectral region of the electromagnetic wave spectrum. For example, an electrostatic latent image formed by discharging the portions of charge on the photoconductive belt 20 corresponding to the green regions of the original document will record the red and blue portions as areas of relatively high charge density on photoconductive belt 20 , while the green areas will be reduced to a voltage level ineffective for development. The charged areas are then made visible by having developer unit 40 apply green absorbing (magenta) toner particles onto the electrostatic latent image recorded on photoconductive belt 20 . Similarly, a blue separation is developed by developer unit 42 with blue absorbing (yellow) toner particles, while the red separation is developed by developer unit 44 with red absorbing (cyan) toner particles. Developer unit 46 contains black toner particles and may be used to develop the electrostatic latent image formed from a black and white original document. Each of the developer units is moved into and out of an operative position. In the operative position, the magnetic brush is substantially adjacent the photoconductive belt, while in the nonoperative position, the magnetic brush is spaced therefrom. (In FIG. 1, each developer unit 40 , 42 , 44 , and 46 is shown in the operative position.) During development of each electrostatic latent image, only one developer unit is in the operative position, while the remaining developer units are in the nonoperative position. This ensures that each electrostatic latent image is developed with toner particles of the appropriate color without commingling.
[0018] After development, the toner image is moved to a transfer station, indicated generally by the reference numeral 65 . Transfer station 65 includes a transfer zone, generally indicated by reference numeral 64 . In transfer zone 64 , the toner image is transferred to a sheet of support material, such as plain paper amongst others. At transfer station 65 , a sheet transport apparatus, indicated generally by the reference numeral 48 , moves the sheet into contact with photoconductive belt 20 . Sheet transport 48 has a pair of spaced belts 54 entrained about a pair of substantially cylindrical rollers 50 and 52 . A sheet gripper (not shown in FIG. 1) extends between belts 54 and moves in unison therewith. A sheet is advanced from a stack of sheets 56 disposed on a tray. A feeder 58 according to the present invention advances the uppermost sheet from stack 56 onto a pre-transfer transport 60 . Transport 60 advances a sheet (not shown in FIG. 1) to sheet transport 48 . The sheet is advanced by transport 60 in synchronism with the movement of the sheet gripper. In this way, the leading edge of the sheet arrives at a preselected position, i.e. a loading zone. As belts 54 move in the direction of arrow 62 , the sheet moves into contact with the photoconductive belt 20 , in synchronism with the toner image developed thereon. In transfer zone 64 , a corona generating device 66 charges the backside of the sheet to the proper magnitude and polarity for attracting the toner image from photoconductive belt 20 thereto. In this way, three different color toner images are transferred to the sheet in superimposed registration with one another.
[0019] One skilled in the art will appreciate that the sheet may move in a recirculating path for four cycles when under color black removal is used. Each of the electrostatic latent images recorded on the photoconductive surface is developed with the appropriately colored toner and transferred, in superimposed registration with one another, to the sheet to form the multicolor copy of the colored original document.
[0020] After the last transfer operation, the sheet transport system directs the sheet to a vacuum conveyor 68 . Vacuum conveyor 68 transports the sheet, in the direction of arrow 70 , to a fusing station, indicated generally by the reference numeral 71 , where the transferred toner image is permanently fused to the sheet. The fusing station includes a heated fuser roller 74 and a pressure roller 72 . The sheet passes through the nip defined by fuser roller 74 and pressure roller 72 . The toner image contacts fuser roller 74 so as to be affixed to the sheet. Thereafter, the sheet is advanced by a pair of rollers 76 to a catch tray 78 for subsequent removal therefrom by the machine operator.
[0021] The final processing station in the direction of movement of photoconductive belt 20 , as indicated by arrow 22 , is a photoreceptor cleaning station.
[0022] The sequence of operation of the sheet feeder of the present invention is as follows. A stack of paper 56 is placed into the elevator paper tray 120 .
[0023] Fluffer has air opening 1 . Fluffer 200 is arranged such that it may inject air between sheets in the stack and on top surface of the sheet to be fed. The air pressure between sheets helps separate sheets, i.e. puff the sheets up. The air on top of the surface of the sheet to be fed, on the other hand, due to the Venturi effect, creates a vacuum to help pull the sheet to the feeder head. The combined effects improve the speed of the sheet acquisition speed and ensure a single sheet feed.
[0024] Fluffer and orifice utilizing an air opening port 1 having a predefined cross section combined with a hinged nozzle dam 2 . Papers of varying basis weight and coating behave differently in the fluff air. The lightweight sheets tend to fluff very high covering the entire cross section of the orifice while heavyweight sheets will not, often leaving a gap between the top of the stack and the top of the orifice opening. This results in a loss of valuable fluffer pressure and air volume. In the present invention, the nozzle dam will drop down in front of the orifice opening to retard a great percentage of this lost air and redirecting it back into the stack. Nozzle dam is hinged to allow it to move with the stack from a low position and blocked from moving above the upper opening of the orifice thus limited the stack fluff height.
[0025] [0025]FIG. 3 illustrates the fluffing of lightweight sheets tend to fluff very high covering the entire cross section of air opening port 1 , these sheets tend to over fluff over a desire fluff position 70 . Nozzle dam is hinged to move with the stack from a low position and blocked from moving above the upper opening of the orifice reducing air pressure on the stack thus limited the stack fluff height to desired fluff position.
[0026] [0026]FIG. 2 illustrates the fluffing of heavyweight sheets tend to fluff low only covering lower cross section of air opening port 1 . At fluffer set with nozzle dam down, the air pressure is set to allow heavy weight sheets to fluff to a desired fluff position 70 .
[0027] The nozzle dam 2 is constructed of a molded ABS plastic material. It is designed to mount on top of the nozzle assembly 300 using an integral hinge pin. The top surface of the nozzle dam 2 rest normally upon the top surface of the nozzle assembly 300 with the face of the component dropping down over the orifice opening thus blocking a portion of the opening. There is mounted to the face of nozzle dam 2 , a small tab 5 that rests upon the top sheet of the stack when in its proper position. The purpose of the tab 5 is to allow the nozzle dam to move up and down within its prescribed limit with the paper as it is fluffed. The length of the tab 5 allows the nozzle dam 2 to ride with the paper regardless of the relative lateral distance between of the edge of the stack and the fluffer while within its prescribed specification.
[0028] The nozzle assembly 200 consists of the nozzle body orifice nozzle dam, and pivot (not shown). The fluffer nozzle is an open face design that is positioned at some distance from the side of the paper supply stack. Air is thus directed into the side of the stack for the purpose of creating an air gap between individual sheets at the top of the paper supply stack and to provide sufficient air volume to allow the upper sheets to maintain separation until acquired and fed by the shuttle feed head. Various orifice shapes may be applied to achieve certain performance characteristics dependent upon the size of the shuttle feed head, vacuum system, relative position of the orifice to the feed head, papers size and characteristic, fluffer air pressure, air velocity and volume, feed rates, and total number of fluffer systems required and their locations around the paper supply stack.
[0029] The stack fluff height, when exposed to a constant air pressure and volume, will vary dependent upon the basis weight of the paper and the coating chemistry. Other factors affecting the height of fluff may include manufacturing and packaging process, temperature, humidity and storage methods which may contribute waviness or curl to the sheets.
[0030] Under normal conditions the lightweight sheets tend to fluff up to and above the top of the fluffer orifice while the heaviest papers may only fluff to half the height of the orifice or less. The opening at the top of the orifice provides a large leakage path for fluff air thus reducing the pressure and volume impressed into the stack to promote separation. In addition, some papers appear to form pairs, especially in heavyweight coated papers, that are difficult to separate, even with the application of heat, with a reduced fluff pressure and more difficult to maintain separation under reduced air flow.
[0031] The nozzle dam provides a method of controlling air loss from open orifice type fluffer systems especially where singular air supplies are shared between multiple fluffer and fluffer/air knife systems. The device provides better control of the fluff and reduce the need for more powerful and expensive blower systems to overcome system losses due to manufacturing tolerance and paper performance.
[0032] Referring to FIG. 3, feeder plenum 58 is located above the stack 56 . The feeder plenum 58 includes a cavity which may be evacuated thereby forming a pressure differential. The difference in pressure between the inside of the feeder plenum 58 and the outside of the feeder plenum 58 draws the supply paper towards the lower paper contact surface of the feeder plenum 58 by vacuum.
[0033] Drive assembly 600 is, attached to air plenum 58 for translating the acquired sheet's leading edge 57 into feed rollers. Then, drive assembly translates air plenum in a direction of movement towards the feed rollers 55 so that a lead edge of the acquired sheet is lifted above and forward of the flange 121 and into the feed rollers 58 .
[0034] Other embodiments and modifications of the present invention may occur to those skilled in the art subsequent to a review of the information presented herein; these embodiments and modifications, as well as equivalents thereof, are also included within the scope of this invention. | A sheet feeding apparatus for feeding a stack of sheets in a direction of movement to a process station, including: a sheet tray for holding the stack of sheets; an air plenum, positioned above the stack of sheets, for picking up a sheet from the stack of sheets when a vacuum force in the air plenum; a paper fluffer for blowing air between individual sheets in the stack, the paper fluffer having means for adjusting air flow between individual sheets. | 1 |
REFERENCE TO RELATED APPLICATION
This application is a continuation of application Ser. No. 08/299,583, filed Sep. 1, 1994, which was a continuation-in-part of U.S. Ser. No. 07/836,711, filed Feb. 19, 1992, now U.S. Pat. No. 5,372,580, which was a continuation-in-part of U.S. Ser. No. 07/551,807, filed Jul. 12, 1990, which is now U.S. Pat. No. 5,090,955.
BACKGROUND OF THE INVENTION
This invention relates generally to a method for producing a polyethylene oxide implant and, in particular, to a method for producing a biocompatible crosslinked polyethylene oxide gel which can be injected into the human body for tissue replacement and augmentation.
It is well known that hydrogels have been used in many biomedical applications, as they can be made non-toxic and compatible with tissue. U.S. Pat. Nos. 4,983,181 and 4,994,081, which issued in 1991 to Civerchia, teach a method of polymerizing a hydrogel in the presence of a crosslinking agent to form a three dimensional polymeric meshwork having controlled spacings between the molecules thereof to anchor the macromolecules which have a known size and to insure that the micromolecules will be substantially uniformly interspersed within the polymeric meshwork of the polymerized hydrophilic monomer. The step of forming the crosslinking of the hydrogel can be performed with a crosslinking agent which may be external, such as ultraviolet radiation, or a crosslinking agent added to the hydrogel clear viscous monomer solution, which crosslinking agent may be, for example, ethyleneglycol dimethacrylate. The hydrogel taught in these patents is a transparent collagen hydrogel which is capable of promoting epithelial cell growth.
Some of the drawbacks of using collagen gels are that they typically biodegrade in three to six months, and are well known for their infectious and immunologic reactions. In addition, collagen implants are, in time, colonized by the recipient cells and vessels.
Another type of substance commonly used in biomedical applications is a silicone gel. However, silicone gels are also known to cause immunologic reactions, and tend to migrate away from the implantation site. In addition, silicone implants become encapsulated by dense fibrous tissues created by cellular reactions to a foreign substance implanted into the tissue. Finally, while silicone gels do allow for efficient oxygen diffusion, there is insufficient transportation of nutrients across the space that the implants occupy.
SUMMARY OF THE PRESENT INVENTION
It is therefore an object of the present invention to provide a process for producing a gel implant which is biocompatible with and nonerodible in the body.
Another object of the present invention is to provide an implant which can be easily removed from the body if desired.
It is also an object of the present invention to provide a biocompatible gel which is injectable into the body and does not cause infectious, inflammatory, or immunologic reactions following implantation.
It is a further object of the present invention to provide an injectable biocompatible gel which does not migrate away from the site of the injection, and allows for both oxygen and nutrient support.
It is a still further object of the present invention to provide a polyethylene oxide gel which can be cracked after gelation but before entering the body or during the actual injection process.
These and other objects are accomplished in the present instance by using a novel process for creating a polyethylene oxide (PEO) gel which can be injected into the body as an implant. Using gamma radiation crosslinking, a PEO gel in deoxygenated saline solution is synthesized for use as permanent soft implants for tissue replacement and augmentation, which is useful in plastic and reconstructive surgery, ophthalmic procedures such as refractive corneal surgery, retinal detachment surgery, and oculoplastics.
Using this novel process, the PEO gel is biocompatible and its characteristics can be engineered by modulating PEO-water concentration and radiation dosage (to control its transparency and hardness) and by modulating electrolyte concentration (to control volume expansion and final water content) to fit a specific medical requirement. The gel is injectable through small gauge (e.g. 25 ga) needles, and is found biocompatible intrastromally and subcutaneously. The gel is not colonized by cells and vessels, and is therefore easily removable by flushing using saline solutions (preferably hypertonic). The shape of implants composed of this PEO gel is moldable by digital massage of the tissue surrounding the implant.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates pictorially a single PEO molecule;
FIG. 2 is a graphic representation showing the influence of molecular weight on gelification dose.
FIG. 3 is a graphic representation showing the percentage of light transmission through both a human cornea and a PEO gel implant prepared by a the present process to the wavelength of light.
FIGS. 4A and 4B illustrate pictorially the reflection of light from an implant within a cornea.
FIG. 5 is a graphic representation showing the percentage of light reflection from a cornea with an implant in relation to the refractive index of the implant; and
FIG. 6 is a diagrammatic view of the cornea, illustrating both the transverse and radial directions in which the modulus of elasticity is measured.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Polyethylene oxide (PEO) and polyethylene glycol (PEG) are fabricated by two different methods, but generally refer to the same polymeric synthetic product having the formula:
--(--CH.sub.2 --CH.sub.2 --O--).sub.n --
The difference between these two polymers resides in their respective molecular weight usage. PEGs have molecular weight below a few thousand daltons, whereas PEOs have molecular weights starting from several thousands to several million daltons.
PEO is soluble in benzene, freon, chloroform, and tetrohydrofurane, and is also soluble in water at all temperatures except near the boiling point. PEO is also soluble in salt solutions.
As the PEO polymer is highly soluble in water, to use it as a biocompatible material, it is necessary to decrease its solubility. This can be done by creating an insoluble crosslinked network, as can be seen in FIG. 1. Each crosslink is indicated by a junction, as shown at 1 in FIG. 1. This network has the advantage to be hydrophilic, and, consequently, it will swell in water.
One method for producing crosslinked PEO is by endlinking the network with a chemical reaction by using, for example, hexamethylene diisocyanate as the crosslinking agent and a branching agent such as mannitol, pentaerythrytol or 1,2,6-hexametriol. However, because toxic chemical reagents (in the same concentration range as PEO) are used during the crosslinking, an additional purification step must be employed to eliminate any remaining trace of the reagents.
Another way to create this network is to expose the PEO to gamma radiation. However, while pure PEO can be gamma ray crosslinked without water, the process requires a very high radiation dosage (greater than 100 Mrad), making it impractical. By using a PEO-water solution, the crosslinking can be accomplished using a much smaller radiation dosage (about 1 Mrad). This crosslinking is indirect and involves water molecules: ##STR1##
The radicals produced react on the PEO polymer chain to yield: ##STR2##
The crosslinked PEO chain has a much higher molecular weight than the base PEO used in the reaction. If a single link occurs between two 200,000 dalton chains a 400,000 dalton molecule is obtained. A link can occur between any two carbon moieties of any two different PEO molecules as shown in the above formula. Gelation occurs when there is at least one crosslink per polymer chain initially present.
Gelation depends on several parameters: the PEO concentration, the molecular weight, and the radiation dose. The influence can be represented in the chart shown in FIG. 2 showing the radiation dose vs. the PEO concentration in aqueous solution for different molecular weights, where MW1>MW2>MW3>MW4. As can be seen in FIG. 2, at a given concentration, the higher the molecular weight, the lower the radiation dose necessary to form a gel. However, gelation may not occur, as oxygen dissolved in the solution acts as a scavenger of gamma rays and thus will quench the crosslinking process.
To prevent this, the PEO solution should be carefully degassed. The solution is pulled under vacuum until no more bubbles of gas appear in the solution, then the vacuum is replaced by argon or another inert gas. This procedure may be repeated several times in order to decrease the residual amount of oxygen remaining in the solution.
In the preferred embodiment, a 0.8% to 8% PEO solution by weight was prepared by dissolving a PEO preparation (e.g. 200,000 daltons) in a saline solution. The solution used, a Balanced Salt Solution (BSS), was selected as it is best suited for the intended medical application. Other solutions may be used, depending on the intended use of the gel. The BSS composition, which may be obtained from Alcon, Inc., is listed below in Table I.
TABLE I______________________________________Solute Percentage (by weight)______________________________________Sodium Chloride 0.64Potassium Chloride 0.075Calcium Chloride 0.048Magnesium Chloride 0.03Sodium Acetate 0.039Sodium Citrate Dihydrate 0.17______________________________________
Free oxygen was then removed from the solution by placing the solution in a sealed container which was evacuated using vacuum and then filled with pure Argon gas (>99.999%) to prevent gaseous contamination from the surrounding atmosphere. The canister was then irradiated by exposing it to a gamma ray source (Cobalt 60) for a dosage of between 2.5 and 25 Mrads to crosslink the PEO. To obtain a uniform gel (Isotrope) the solution can be continuously agitated, even during radiation (using a rocking platform oscillatory shaker). Aseptic and contamination-free transfer of the PEO gel to sterile syringes was performed in a laminar flow-hood presterilized with UV radiation for use in experimental procedures which will be discussed.
It was observed that the PEO hydrogel of a specific electrolyte concentration, will swell when immersed in a saline solution with a lower electrolyte content, while it will shrink if immersed in a saline solution with a higher electrolyte concentration. Therefore, implanting a PEO gel crosslinked in a saline solution having a different electrolyte concentration than surrounding tissue will result in a postoperative change of the implant's volume. While this phenomenon may result in postoperative complications in certain medical applications, it can be advantageous in applications such as vitreous substitution with polymers and retinal detachment surgery where controlled tissue-to-tissue compression is required.
For a given PEO solute concentration, the higher the irradiation dosage, the higher the crosslink density. Using a 0.8% PEO solution, the irradiation dosage was varied from 0.8 Mrads to over 13 Mrads. 0.8 Mrads seemed to be the minimum dosage required to obtain gelation without gravitational collapse of the polymer, while any dosage above 9 Mrads seemed to have little effect on the physical properties of the PEO.
A minimal dose of 2.5 Mrad was selected for the irradiation dosage, as it corresponds to the minimum dosage required for gamma ray sterilization. By using a higher dosage, it is possible to simultaneously crosslink and sterilize the PEO gel implant.
Referring again to FIG. 2, it can be seen that for a given crosslink density, the higher the PEO solute concentration, the lower the irradiation dose required. Initial testing performed with a PEO of approximately 200,000 daltons indicated that, below 0.5%, gelation is difficult to obtain, even at a high irradiation dosage. Thus, a solute concentration varying between 0.8% and 8.0% was selected.
With a 0.8% 200,000 dalton PEO solution irradiated at 5 Mrads, the crosslinked gel is transparent and can be used in ophthalmology for corneal tissue augmentation procedures such as Gel Injection Adjustable Keratoplasty (GIAK), which is described in U.S. Pat. No. 5,090,955, which is assigned to the same assignee of the present invention and is hereby incorporated by reference.
Visibility of the gel within the eye is a cosmetic and therapeutic concern related to the GIAK procedure. Gel visibility is related directly to both the reflectivity and absorbance properties of the gel used. Thus, at any visible wavelength, the percentage of transmission of light through the implant should be at least as great as that through the cornea. FIG. 3 shows a graph which illustrates light transmission through both a cornea and an implant prepared according to the present invention as a percentage of transmission of light through the cornea as a function of the wavelength of the light. The graph of light transmission through the gel is a dotted line designated as 2, while the graph of light transmission through the cornea is a solid line designated as 4. As can be seen in FIG. 3, for the visible light spectrum (from 400 nanometers to 800 nanometers) the percentage of light transmission through the gel approaches 100 percent. Therefore, the implant of the present invention is optically transparent to light passing through the implant. FIG. 3 also shows that the implant transmits more light in the near ultraviolet, visible and near infrared range than the normal cornea (wavelengths of 300 to 1350 nm).
As the eye can detect approximately 10% difference in reflection, it is important that the index of refraction of the gel differs no more than ±10% from the index of refraction of the cornea. FIG. 4A shows a beam of light passing through an implant which has been placed within the cornea of an eye. A beam 10 passes through the anterior section of cornea 12 and strikes the anterior surface 14a of implant 14, where it is partially reflected as shown at 16. As beam 10 continues through implant 14, it strikes the posterior surface 14b of implant 14, and is partially reflected as shown at 18.
Referring now to FIG. 4B, the reflection properties of the cornea are taken into consideration unless a beam passes through a cornea containing an implant. As beam 10' strikes the anterior surface 20a of the tear film 20 of cornea 12', it is partially reflected, as shown at 22. Beam 10' continues through tear film 20 and is partially reflected at anterior surface 12a' of cornea 12', as shown at 24. Beam 10' continues into cornea 12' where it is partially reflected at anterior surface 14a' of implant 14', as shown at 26. The posterior surface 14b' partially reflects beam 10' as it passes through posterior surface 14b', which is shown at 28. Finally, beam 10' is reflected as it strikes the posterior surface 12b' of cornea 12', as is shown at 32.
FIG. 5 illustrates the percentage of light reflected as a function of the refractive index of the implant produced using the method of the present invention. The curve designated at 36 shows the percentage of light reflected by the cornea and implant together as a function of the index of refraction of the implant. As can be seen from FIG. 5, if the index of refraction of the implant equals the index of refraction of the cornea (i.e., 1.376), the percentage of incident light that is reflected is at the minimum, which is approximately 4%. As it is desirable that the total reflection of the cornea and implant together will not differ from the total reflection of the cornea alone by more than approximately 10%, the total reflection of the implant plus cornea should be no greater than 4.4%. If we find the point on line 36 that gives a total reflection of 4.4% it can be seen that it corresponds to an index of refraction for the implant of approximately 1.52. Since a hydrogel is mostly water and the index of refraction of water is approximately 1.3, the index of refraction of the implant should be at least 1.3.
Therefore it is most desirable for the gel to be used in GIAK surgery to have an index of refraction greater than 1.3 and less than 1.52.
It is also essential that the absorbance of the injected gel closely match the absorbance of the cornea. This will be important if it becomes necessary to perform later procedures on the eye. If the gel has different absorbance characteristics, laser ocular surgery and photocoagulation may not be possible, as the light energy will not have a uniform effect on the gel and the cornea.
Another important characteristic of the injected gel that will affect its performance in the eye is its modulus of elasticity. This subject is discussed in an article entitled "Keratoprosthesis: Engineering and Safety Assessment", which was published in the May/June 1993 issue of Refractive and Corneal Surgery. If the injected implant is stiffer than the cornea, it will deform the cornea, while if the cornea is stiffer than the implant, it will deform the implant. For example, a keratoprosthesis which is composed of glass or polymethylmethacrylate (PMMA) is subject to extrusion from cornea, as these relatively hard materials have an elastic modulus much greater than that of the cornea. Therefore, to prevent extrusion of the gel from the cornea, its modulus of elasticity must be less than that of the cornea. FIG. 6 shows a representation of a cornea for the purpose of locating the site for selecting the proper modulus of elasticity in both the transverse and radial directions. Cornea 40 is composed of a plurality of layers or lamellae 42 which form the stroma 44. The corneal surface is indicated at 46, while the anterior chamber of the eye is indicated at 48. At the incision site in the cornea for this procedure (approximately 2.5 mm from the corneal center), the thickness of the cornea is between 550 and 650 microns. At the level at which the annular channel is formed which is indicated at 50 in FIG. 6, the cornea has both a radial elastic modulus and a transverse elastic modulus. The radial modulus is directed along a plane designated by 52 while the transverse modulus is directed along a plane designated by 54. The transverse modulus is between 2.19×10 4 and 4.12×10 4 newtons/m 2 , while the radial modulus is between 2×10 6 and 5×10 6 newtons/m 2 . In order to avoid any problems with extrusion, the gel should have an elastic modulus less than both the radial and the transverse moduli of the cornea.
Other necessary characteristics of an injectable gel for this procedure include: the prevention of cell migration into the implant which would impair its removal (if necessary to readjust corneal curvature); and the transmission of oxygen and other essential nutrients through the gel into all parts of the eye.
In an experiment using the procedure taught in the aforementioned patent the sterile crosslinked gel was injected into an annular intrastromal channel formed between the lameliar layers in the cornea of a rabbit at a distance spaced away from the central corneal region. After the channel was formed in the cornea, the gel was injected into the channel using a 19-25 gauge needle. The PEO gel was shown to be non-toxic to the rabbit cornea with an excellent corneal transparency, no surface opacification, no extrusion and no migration. Histologically, no giant cells, no necrosis, and a normal keratocyte population near the implant were found. In addition, the PEO gel was optically transparent in the visible spectrum and its index of refraction (1.334) was relatively close to the corneal refraction index (1.376). The modulus of elasticity of the gel was estimated with a penetrometer at 1.7×10 3 newtons/m 2 . It has been shown that gel produced by the method of the present invention remains stable over 22 months in the rabbit cornea. By using a solution during preparation of the PEO gel that approximates the electrolyte concentration or osmotic activity of the cornea, it would be possible to minimize any change in volume of the implant.
Other potential uses are for vitreous substitution and keratophakia lenticules. Increasing the PEO concentration increases the gel mechanical strength while decreasing transparency. For example, a 1% PEO solution irradiated at 5 Mrads will produce a tougher gel which can be used for subcutaneous tissue augmentation procedures performed in plastic and reconstruction surgery, oculoplasty, or other procedures where transparency is not necessary. Several experiments have been conducted in vivo to demonstrate the biocompatibility of this PEO gel when injected subcutaneously. Six rabbits received subcutaneous injection of a PEO gel prepared according to the present invention in the dorsal area and in the ears. The results showed a good tolerance of this material and no apparent degradation of the product after two months.
The gamma ray crosslinking process of PEO solutions produces an excess amount of free water (syneresis). The water may be unwanted in certain surgeries and has to be removed before transferring the gel from the canister to the syringe. To accomplish this task, the canister was equipped with a second chamber separated from the first by a fine mesh screen. After the irradiation procedure, the canister was inverted and the excess water drained into the lower container, while maintaining the crosslinked PEO in a sterile atmosphere.
In certain instances, it may be difficult to predict at the time of manufacture of the PEO what exact shape and size is necessary for a particular implant. In these situations, the PEO gel can be broken into smaller pieces (i.e. cracked) with an average particle size ranging from several microns (for use in filling a biological space with great precision) to over 1 cm for instances in which large volumes of gel are required. The cracking process may be done prior to the implantation or during the implantation process.
While the invention has been shown and described in terms of a preferred embodiment thereof, it will be understood that this invention is not limited to this particular embodiment and that many changes and modifications may be made without departing from the true spirit and scope of the invention as defined in the appended claims. | A biocompatible polyethylene oxide gel implant and method for production which can be injected into the human body for tissue replacement and augmentation. The implant is prepared by dissolving a sample of essentially pure polyethylene oxide in a saline solution in a sealed canister, removing all free oxygen from the container and replacing it with an inert gas, such as argon, and irradiating the canister with a gamma ray source to simultaneously crosslink the polyethylene oxide while sterilizing it. The gel can then be placed into a syringe and injected into the body. | 2 |
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention is broadly concerned with methods and compositions for protecting plants from bacterial diseases. More particularly, the inventive compositions comprise an aqueous solution of saponins. These compositions are directly applied to seeds, seedlings, shoots, foliage, etc. of the plant to be protected. In addition to bacterial diseases, the compositions are useful for protecting the plants against fungal and viral diseases.
2. Description of the Prior Art
There are numerous diseases which may harm or even kill plants. Fungal diseases are one such type of disease. For example, Rhizoctonia solani (Rhizoctonia Canker, Black Scurf, or Helminthosporium solani (Silver Scurf)) and Phytophthora infestans (Late Blight) are both fungal diseases which are extremely dangerous to potato crops. In rhizoctonia infections, sclerotia or mycelium invade emerging sprouts, potato stems, roots, and stolons after germination occurring in early spring. On mature tubers or potatoes, the disease appears as black hard bodies known as Black Scurf with the tuber skin underneath often remaining unharmed. The disease leads to a delay in the emergence of the sprouts and stems, and causes the sprouts and stems to have a reddish canker girdling them when they finally do emerge.
The symptoms of late blight first appear on older leaves soon after flowering of the plant. The leaves turn dark brown and brittle, while the tuber exhibits lesions which often appear around the eyes. Furthermore, the infected portions of the tuber are granular in nature and penetrate as much as 2 cm into the tuber. All of these symptoms cooperate to reduce tuber yields and quality.
Both rhizoctonia and late blight readily infect potato plants and require extreme measures to avoid or minimize transmission thereof. For example, crop rotation is commonly practiced in an attempt to avoid diseased crops. Additionally, growers often seek seeds that are certified as being disease-free. However, these and other currently available measures do not adequately protect against the diseases. There is a need for preventive treatments that will protect potatoes and other plants from these and other harmful diseases.
Bacterial diseases also pose significant problems to plants, especially, tomatoes. Such bacterial diseases include bacterial spot (caused by Xanthomonas campestris pv. vesicatoria ) and target spot (caused by Corynesporia cassiicola ). A number of bactericide compositions are presently available for combating these bacterial diseases. KOCIDE, available from Griffin, L. L. C., Valdosta, Ga., is a leading bactericide which utilizes copper as the primary antibacterial agent. However, due to the prolonged use of copper antibacterial agents, bacteria are showing signs of increased resistance to copper, thereby reducing the effectiveness of the bactericide in controlling disease. Furthermore, agricultural runoff from these agents is finding its way into coastal waters and potentially causing harm to various marine life, especially shrimp and other invertebrates.
Because of the problem of bacteria developing resistance to various antibacterial compositions, attempts have been made to develop compositions which stimulate the plant's own defense genes to cause the plant to produce proteins which inhibit disease. These products produce what is commonly known as a systemic activated resistance (SAR) response within the plant. ACTIGARD, available from Syngenta, Wilmington, Del., is one such product designed to stimulate a systemic response within the plant to combat the bacteria. ACTIGARD contains the active ingredient acibenzolar-s-methyl. While reasonably effective in controlling bacterial disease, it is a relatively expensive treatment option for farmers. Therefore, there is a need for an economical method for stimulating a plant's own immune system to combat bacterial diseases, preferably employing a naturally derived composition in order to lessen potential environmental concerns.
Quinoa is classified as a member of the Chenopodiaceae, a large and varied family which includes cultivated spinach and sugar beet. Quinoa is an extremely hardy and drought-resistant plant which can be grown under harsh ecological conditions—high altitudes, relatively poor soils, low rainfall, and cold temperatures—that other major cereal grains, such as corn and wheat, cannot tolerate.
Quinoa originated in the Andes region of South America where it was a staple grain in pre-Spanish Conquest times. Traditional uses of quinoa declined after the Spanish Conquest. Cultivation and use of the grain was not widespread until a recent revival due to Western interest in this crop as a high lysine, high protein grain for human consumption. The principal obstacle to even wider human consumption of quinoa has been, and continues to be, the bitter taste of the saponin present in the grain.
Saponins are a type of sterol glycoside widely distributed in quinoa as well as other plants. There are generally two types of saponin—triterpene saponins and steroidal saponins. Traditionally, saponin has been removed by washing the grain in running water, although new methods have been developed recently (see, e.g., WO 99/53933).
Attempts have been made to utilize saponin as a synergist for other compounds which are useful for controlling the growth of pathogens (e.g., fungi) on plants. For example, U.S. Pat. No. 5,639,794 to Emerson et al., is directed towards a method for treating agricultural crops comprising the step of applying a so-called “natural product” in combination with at least one saponin to kill, retard growth of, or displace pathogenic organisms. The natural products combined with the saponin are the various aldehydes, and particularly aromatic aldehydes, and the saponins are used to enhance the activity of the aldehyde (i.e., as a synergist). However, the use of aldehydes increases the cost of treating the plants and, in many instances, may be undesirable to the grower due to environmental concerns as well as the extra effort involved in handling these aldehydes.
There is a need for a cost-effective, environmentally friendly composition for effectively treating and/or preventing diseases in plants.
SUMMARY OF INVENTION
The instant invention overcomes the problems of the prior art by broadly providing effective compositions and methods for treating and/or protecting plants from diseases, especially bacterial disease.
In more detail, the Inventive compositions comprise (and preferably consist essentially of) saponins which act as a protectant for the plant independent of other compounds or agents (i.e., saponin is the principal and/or only active ingredient). As used herein, “plant” is intended to refer to any part of a plant (e.g., roots, foliage, shoot) as well as trees, shrubbery flowers, and grasses. “Seed” is intended to include seeds, tubers, tuber pieces, bulbs, etc., or parts thereof from which a plant is grown.
While any saponin is suitable for use in the compositions, the saponin should be derived from a plant different than the plant that the final saponin composition is intended to protect. Suitable sources of saponins include Quinoa, Quillaja, Primula (Primulae sp.), Senega ( Polyga senega ), Gypsophila, Horse chestnut (Aesculus sp.), Ginseng (Panax sp. and Eleutherocosus sp.), Licorice (Glycyrrhiza sp.). Ivy (Hedera sp.), Tea seed ( Camellia cinensis ), Alfalfa ( Medicago sativa ), Soya, Yucca (Yucca sp.), and Dioscorea. It is particularly preferred that the saponin be of the triterpene variety as found in quinoa and quillaja versus the steroidal types found in yucca.
A preferred method of extracting saponins from quinoa comprises placing a saponin-containing portion of a quinoa plant in an aqueous alcohol (e.g., methanol, ethanol) solution to form a saponin-containing solution and an extracted, solid residue. The alcohol is then removed from the solution followed by evaporation of the water to yield the saponin-containing product. Those skilled in the art will appreciate that the saponins can also be extracted from quinoa by other methods for use in the instant invention.
The saponin extract is preferably mixed with water to form the protective composition. If desired, the saponin extract can be mixed with water under mild heat (e.g., from about 10-35 E C) in order to effect mixing. Alternately, the saponin extract can be applied as a dry composition alone, or blended with a suitable carrier. Preferably, the composition comprises from about 25-300 g of saponin extract, and more preferably from about 50-200 g of saponin extract, per 100 liters of water, where the saponin extract has a triterpene saponin concentration of from about 10-70% by weight, and preferably at least about 50% by weight, based upon the total weight of the saponin extract taken as 100% by weight. Alternately, the saponins of the invention can be applied in a dry formulation using talc or some other particulate carrier. In such cases, the saponin component should be present at a level of from about 8-46% by weight, more preferably from about 16-36% by weight.
In use, plants or seeds are treated with the inventive compositions by simply contacting one or more portions of a diseased plant or seed, or a plant or seed susceptible to attack by disease, with a disease-inhibiting or protective amount of the composition so as to elicit a protective response in the plant or seed. This can be accomplished by spraying the plant or seed as well as by submerging it in the aqueous composition. Those skilled in the art will appreciate that portions of a plant can be selectively treated (e.g., infected leaves can be treated individually or the roots alone can be treated). Additionally, the seeds or tubers can be submerged in the aqueous composition and then planted and allowed to grow into a protected plant. Furthermore, the soil around the plant or seed can be treated as well. When the plant to be treated is a tree, the composition is preferably introduced into the vascular system of the tree by conventional methods. In a similar way, the dry saponin compositions can be applied by dusting or coating a plant part or seed.
It has also been found that the saponin products of the invention, and particularly the liquid versions thereof, are effective as foliar sprays. Such sprays would normally contain concentrations of saponin of from about 1 g/10 L to 150 g/10 L, and more preferably from about 10 g/10 L to 100 g/10 L.
Preferably, the plant or seed is not pre-treated with some other type of pathogen-controlling agent. Furthermore, it is preferred that the plant or seed is not treated with another pathogen-controlling agent simultaneous to treatment with the inventive composition. More specifically, it is preferred that the plants, seeds, or soils surrounding the plants have not been treated with some type of aldehyde composition. Thus, the plant and plant surfaces or the seed and seed surfaces should be essentially aldehyde-free (e.g., less than about 1 mg of aldehyde groups, per square centimeter of plant surface area to be treated) prior to treatment according to the invention.
Virtually any plant can be treated to prevent or lessen most plant diseases. For example, potato plants, tomato plants, sugar beets, canola, strawberries, chick peas, lentils, broccoli, cabbage, cauliflower, turf grass, tobacco, spinach, carrots, ginseng, radish, and field peas or seeds of any of the foregoing can all be protected with the inventive compositions. Furthermore, the compositions can be used to treat, control and/or prevent fungal diseases (e.g., rhizoctonia, late blight), Aphanomyces, Cercospora, Rhizopus, Sclerotium, ergot, Ascochyta, Fusarium, Anthracnose, Botrytis, and Ophiostoma (ceratocystis) ulmi (Dutch Elm disease). Plants or seeds treated according to the invention will remain essentially free of symptoms of the disease for at least about 20 days, preferably at least about 60 days, and more preferably at least about 100 days, after treatment. Thus, plants treated according to the invention, or plants grown from seeds treated according to the invention, will at least exhibit reduced levels of the disease compared to nontreated crops, and preferably will remain essentially free of symptoms of the disease throughout the natural growing season of the plant.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a graph illustrating average potato yield data for five test locations wherein potato seed was coated with the saponin products of the invention versus a non-treated control, as described in Example 2;
FIG. 2 is a graph illustrating Rhizoctonia level on tubers for two test locations, as described in Example 2;
FIG. 3 is a graph illustrating market yields obtained for various test compositions including the saponins of the invention in the late blight test described in Example 4;
FIG. 4 is a graph illustrating the percent of early blight plants recorded in Example 5;
FIG. 5 is a graph of late blight plants recorded in Example 5; and
FIG. 6 is a graph illustrating the percent late blight and number of stems per tuber recorded in Example 5.
DETAILED DESCRIPTION
The following examples set forth preferred methods in accordance with the invention. It is to be understood, however, that this example is provided by way of illustration and nothing therein should be taken as a limitation upon the overall scope of the invention.
Example 1 A quantity of the inventive composition was prepared by mixing 250 g of saponin extracted from quinoa with 200 liters of water. Fourth and fifth generation potato seeds were submerged in the solution after which the treated plants were planted along with untreated plants as the control. The quantity of treatment used was 125 g of saponin per acre of planted potatoes. The potato varieties tested were AC Ptarmigan, Norland, Nordonna, Yukon Gold, and Frontier Russet.
Portions of the potatoes were harvested 14 days, 28 days, and 49 days after top kill. The potatoes harvested 14 and 28 days after top kill exhibited no black scurf while 2% of the tubers harvested 49 days after top kill had black scurf. The treated tubers showed an increased yield of 42% above that of the control tubers. Furthermore, only 11% of the treated tubers weighed less than 4 ounces in size while 27% of the control tubers were less than 4 ounces in size. Finally, the control tubers exhibited visible signs of Rhizoctonia on one in three plants while the treated plants showed no signs of the disease until natural attrition or senescence of the pliants. The treated plants exhibited vigorous, healthy growth.
Example 2 In this example, Norland potato seed pieces were treated within the preferred saponin material in accordance with the invention at five Canadian sites (Yorkton, Sk., Oakburn, Mb., Abernathy, Sk., and Quill Lake, Sk., and Lethbridge, Ab.) in order to determine the efficacy of the treatment for control of diseases during the growing season, and on crop produced. Stand establishment, disease development during the growing season, final yield, marketable yield and disease levels on harvested crop were measured.
In particular, at each location a total of five treatments were carried out, namely a no-treatment control and four coating treatments using different levels of a saponin product. This product was alcohol-extracted saponins from quinoa dried to a solid residue as described above, and then mixed with water under mild heat to give treatment dispersions of various concentration. This product is referred to as “94815” and contains more than three saponin active components (sapogenins); the three major active ingredients are oleanolic acid, hederagenin and phytolaccinic acid, or analogs thereof.
In particular, the treatments were: 0.02 g/L (treatment #1); 0.1 g/L (treatment #2); 1 g/L (treatment #3); 10 g/L (treatment #4); and no-treatment control (treatment #5). Before coating, the trial seed pieces were suburized (the pieces were cut and allowed to heal) at Yorkton and Lethbridge, while at the remaining locations the treatment was carried out immediately after cutting (no suburization). Thereupon, the seed pieces were simply dip-coated in the respective test dispersions.
In each case, there were eight replications of the five treatments, using eight meter row lengths with common guard rows and two meter spacing between ends of blocks. The following randomized block design was used where “g” refers to guard rows, the numbers 1-4 refer to the above treatments and “C” refers to controls. The plot size in each case was 25 m×25 m (⅙ acre).
Block Design
Rep 1 Rep 2 Rep 3 Rep 4
g 1 4 C 2 3 g 4 1 2 3 C g 4 3 C 2 1 g 1 3 2 4 C g
8 meter rows
Rep 5 Rep 6 Rep 7 Rep 8
2 meter space
g 4 2 1 3 C g C 4 1 3 2 g 1 2 4 C 3 g 3 C 4 2 1 g
8 meter rows
The test seed pieces were planted 23 cm apart at a depth of 10 cm. At the time of planting, soil and air temperatures were recorded as well as soil type. During the growing season, dates of emergence, rainfall amounts, irrigation application's and the first visual symptoms of Rhizoctonia in each row were recorded. The test plots were maintained weed free and were beetle controlled. Also, other observable diseases affecting plant growth were monitored, as well as Rhizoctonia spores on stems (first appearance) in each row. Stem counts per row were made at 60 days after emergence. Plants on replications 1, 3, 5 and 7 were pulled at 60 days after emergence, and the following were recorded: Stem and cankor on plants, plant yield (tuber count, weight and range), and evidence of black scurf. At 70 days after emergence, a top kill was performed by shredding or spraying the plants with a commercial potato top dessicant, and harvesting took place at 90+ days after emergence. The following were recorded: total row yield (weight), total marketable yield (weight), number of tubers of uniform shape and those greater than 45 mm, tuber count per row and size distribution (4 categories, less than 45 mm, 45-55 mm, 55-75 mm and over 75 mm) and the number of tubers showing black scurf and the percentage of surface covered.
The following Table 1 sets forth the averaged 90 day yield data from all sites, and FIG. 1 graphically illustrates this data.
Table 2 sets forth the Rhizoctonia data for two locations, and FIG. 2 graphically illustrates the data.
TABLE 1
Yield Summary of Five Comparable Locations
Lethbridge must be reviewed on its own because the % count for
Rhizoctonia is grouped differently.
1: 1 gm/50 L
YIELDS: ALL SITES (kg)
TREAT
PLANTS
TUBERS
WEIGHT
Oakburn 90 day
125
447
61
Yorkton 90 day
119
789
111
Abernathy 90 day
94
293
61
Lethbridge 90 day
122
1340
165
Quill 90 day
94
791
108
Average 1 gm/50 L
110
732
101
2: 1 gm/10 L
YIELDS: ALL SITES
TREAT
PLANTS
TUBERS
WEIGHT
Oakburn 90 day
131
619
112
Yorkton 90 day
127
1063
138
Abernathy 90 day
95
311
65
Lethbridge 90 day
119
1346
169
Quill 90 day
114
876
120
Average 1 gm/10 L
117
843
121
2: 1 gm/10 L
YIELDS: ALL SITES
TREAT
PLANTS
TUBERS
WEIGHT
Oakburn 90 day
130
612
116
Yorkton 90 day
122
897
127
Abernathy 90 day
100
322
81
Lethbridge 90 day
120
1296
185
Quill 90 day
98
836
117
Average 1 gm/L
114
793
121
2: 1 gm/10 L
YIELDS: ALL SITES
TREAT
PLANTS
TUBERS
WEIGHT
Oakburn 90 day
132
607
122
Yorkton 90 day
132
932
122
Abernathy 90 day
99
362
77
Lethbridge 90 day
118
1204
144
Quill 90 day
101
863
110
Average 10 gm/L
116
794
115
Control
YIELDS: ALL SITES
TREAT
PLANTS
TUBERS
WEIGHT
Oakburn 90 day
126
384
54
Yorkton 90 day
117
986
134
Abernathy 90 day
92
196
31
Lethbridge 90 day
120
1276
170
Quill 90 day
111
804
99
Average Control
113
729
98
SUMMARY
YIELDS: ALL SITES
TREAT
PLANTS
TUBERS
WEIGHT
Average 1 gm/50 L
110
732
101
Average 1 gm/10 L
117
843
121
Average 1 gm/L
114
793
121
Average 10 gm/L
116
794
115
Average Control
113
729
98
Average all 94815
115
790
114
Yorkton tubers froze in the soil, hence rhizoctonia data not used.
Quill Lake: no rhizoctonia data supplied.
This example demonstrates the usefulness of the saponins of the invention in preventing and/or minimizing the effects of Rhizoctonia, and further shows that the saponin treatment increases potato yields. Other data confirms that better results are obtained when the saponin treatment is carried out on freshly cut (non-suburized) seed pieces, or on whole, uncut seed, versus suburized seed pieces.
Example 3 In this example, various potato seed piece treatments were compared for their effectiveness in the control of Rhizoctonia, Fusarium and Helminthosporium solani . The materials tested are set forth in Table 3, where “Trigger” is a saponin dispersion in accordance with the invention. All products save for the saponin dispersions are commercially available or experimental products designed for control of potato diseases.
METHODS: The test site was located in New Glasgow, Prince Edward Island. Soil type was a sandy loam with a pH of 6.0 and an organic matter content of 2.8%. The potato seed (Atlantic variety) used in the study had high levels of Rhizoctonia and was also infected with Fusarium by dipping the cutting knives in a slurry of diseased tissue before each cut. Seed was cut by hand on May 17, 2000 and seed treatments were applied on May 18, 2000 by shaking the seed pieces and the appropriate treatment in a plastic tote for two minutes. The saponin dispersion and in-furrow treatments were applied at planting on May 22, 2000. In-furrow treatments were dripped over uncovered seed pieces prior to row closure using a 1 row, hand-held, CO 2 sprayer equipped with a drop tube. The saponin dispersion was applied by placing cut seed in the saponin dispersion (10 g dry saponin dispersed in 10 L water) for 30 seconds. After 30 seconds seed was removed from solution and allowed to dry prior to planting. Control treatments received no treatment. Treatments and rates of all products are outlined in Table 3. Each treatment was replicated 4 times in a randomized complete block design. Seed was planted into rows spaced 0.9 m apart with a seed spacing of 35 cm and a depth of 15 cm. Plots were 6 m long and 4 rows wide. 15-15-15 fertilizer was banded during planting at a rate of 775 kg/ha. Insects were controlled with an in-furrow application of Admire (imidacloprid) at 850 ml product/ha at planting. Weeds were controlled with Sencor (metribuzin) at 2.0 kg product/ha on Jun. 4, 2000, and Fusilade II (fluazifop-p-butyl) at 2.0 L product/ha on Jul. 13, 2000. A regular preventative foliar, fungicide program was maintained throughout the growing season. In-season data collected included plant emergence, stem counts, vigor, final stand count, incidence of Fusarium in non-emerged seed pieces, and Rhizoctonia canker on stolons. Plant emergence, stem counts, vigor and final stand count was based on all plants in the two center rows of the plots. Incidence of Fusarium was completed by digging up non-emerged seed pieces in the two center rows. The non-emerged seed piece was identified as being infected by Fusarium, infected with some other pathogen or as a miss (blind seed piece). The percent Rhizoctonia canker rating was taken based on 5 plants per plot. Plots were top-killed on Sep. 10, 2000, using Reglone (diquat) at 2.0 L product/ha and harvested on Oct. 4, 2000. Total and marketable yield was determined at harvest. From the harvested tubers, 10 random tubers per plot were collected for determining the incidence of Silver Scurf (Helminthosporium) and Rhizoctonia after a period in storage. Each 10 tuber sample was placed in a plastic bag with holes punched in it and a wet paper towel was added to each bag to increase the humidity. All samples were stored in the dark until ratings were conducted. Rhizoctonia and Silver Scurf ratings were completed on Nov. 14, 2000. Silver Scurf tuber ratings involved looking at each tuber with a microscope and identifying the fungus as present or not present. Rhizoctonia tuber ratings involved washing the tubers and estimating the percent area covered by the fungus. Data was subjected to analysis of variance and mean separation was conducted where analysis indicated significant differences at the 0.95 level.
RESULTS: No significant differences were seen in emergence or final stand between any of the treatments. Two vigor assessments indicated all the treatments had higher vigor than Trt.#2 (infected check), however, not significantly different. A stem count indicated significant differences between some of the treatments. Trt.#7 (Maxim MZ) had the highest number of stems, while Trt.#9 and Trt.#10 produced the least number of stems. Assessment for incidence of Fusarium on non-emerged seed pieces indicated that no Fusarium was seen in any of the treatments. No significant differences were seen in Rhizoctonia stolon canker, however, Trt.#4 (TM-10%) produced slightly better control. Crop harvest revealed no differences in tuber yield or number of tubers in any size category between any of the treatments. Disease incidence at harvest yielded no significant amounts of late blight or Fusarium. Following approximately 6 weeks in storage Silver Scurf was easily visible on the tuber surface. Results indicated Maxim PSP provided 100% control of Silver Scurf infection, while Maxim MZ provided similar results. Both checks had nearly 50% infection, much higher than most treatments, indicating all treatments provided some control of the fungus. Maxim and Maxim MZ also provided the best control of Rhizoctonia on the tuber surface. All other treatments were not significantly different in their control of Rhizoctonia as compared to the checks. Treatments 3 and 10 did not provide any control of Rhizoctonia while all other treatments provided some control when compared to the checks, although not significantly different.
CONCLUSION: With the exception of slight differences in stem numbers, no differences between treatments were observed during the growing season or at harvest. Significant differences between the treatments became evident when storage ratings of Rhizoctonia and Helminthosporium were conducted. Maxim PSP and Maxim MZ gave much better control of Helminthosporium and Rhizoctonia on harvested tubers than any other treatment. All other treatments gave some control of Helminthosporium and all treatments except Nos. 9 and 10 provided some control of Rhizoctonia.
This example demonstrates that the saponin product of the invention is at least equivalent to commercially available products. However, the cost of the saponin dispersions is much less than the commercial products. Therefore, effective control can be obtained at less expense and using a preferable natural source product.
TABLE 3
Treatments Used in Study
Application
Treatment
Product
Rate
1
1 Healthy Check
—
2
2 Infected Check
—
3
3 PST - Mancozeb
10
g/kg seed
4
4 TM - 10%
5
g/kg seed
5
5 TM 2.5% and
10
g/kg seed
Mancozeb 6%
6
6 Maxim PSP
5
kg/kg seed
7
7 Maxim MZ
5
g/kg seed
8
8 Trigger liquid
dipped in 1
g saponin/L H 2 O
seed treatment
9
9 Treatment No. 9
50
ml/100 m2
10
10 Treatment No. 10
50
ml/100 m2
10
g/kg seed
Treatment Nos. 9 and 10 are experimental potato treatment agents.
Example 4 In this example, potato seed pieces were treated with various compositions to determine the effect thereof upon the control of late blight. The following Tables 4 and 5 set forth the treatment protocol and the coating compositions, respectively.
TABLE 4
Series 2000, Late Blight Seed Treatment
Prosper, ND Non-Irrigated Trials, 2000
Plot Design:
2 × 25 ft. rows; 4 replications/treatment, RCBD.
Planting Date:
May 23, 2000
Row Width:
38 inches.
Plant Spacing:
12 inches.
Cultivar:
Norvalley
Fertilizer:
250# 24-12-5 banded at planting.
Herbicide:
Treflan (previous fall)
Poast @ 1.5 pt/a on Jul. 10, 2000
Matrix @ 1.5 oz./a on Jul. 10, 2000
Insecticide:
Admire @ 18 oz./a banded at planting
Asana @ 6 oz./a broadcast on Jul. 10, 2000
Inoculation
Late Blight: For trials 2002-2008 inclusive, 200 fresh
Method:
cut seed pieces were tumbled with 7 infected seed pieces,
infected pieces were then removed and seed was
immediately planted; for trials 2001 and 2009-2011,
inclusive, induced airborne infection by
planting infected plants adjacent the trials.
Early Blight:
Natural infection
Fungicide
Application
July 9, July 13, July 20, July 27, August 3, August 10,
Dates:
August 18, August 24
Vine-kill:
Aug. 30, 2000, rotobeat.
Harvest:
Sep. 16, 2000.
Grade:
Sep. 18, 2000.
NOTE:
Due to heavy rain on Jun. 19, 2000 replications I
and II were destroyed.
TABLE 5
Late Blight Seed Treatment Prosper (2000 Series)
Acc. #
Treatment
Rate
NOTES
2001
Uninoculated,
—
UNTREATED
2002
Inoculated, UNTREATED
—
2003
Inoculated, Fungicide #1
12
oz/cwt
2004
Inoculated, Fungicide #1
8
oz/cwt
2005
Inoculated, Fungicide #2
8
oz/cwt
2006
Inoculated, Fungicide #3
8
oz/cwt
2007
Inoculated, Fungicide #4
8
oz/cwt
2008
Inoculated, Fungicide #5
16
oz/cwt
2009
Uninoculated, Trigger
1
g/L
no foliar fungicide
(60 sec dip)
2010
Uninoculated, Trigger
1
g/L
Bravo or MZ foliar,
(60 sec dip)
full season
2011
Uninoculated, Trigger
2
g/L
no foliar fungicide
(60 sec dip)
Variety: Norvalley
Planted: May 25, 2000
The “Trigger” products were saponin dispersions in accordance with the invention; all other products were experimental fungicides.
Test results demonstrated that use of the “Trigger” products gave a beneficial effect in controlling late blight, and it is believed that the product will have substantial utility in this context, particularly when used in conjunction with foliar applications through the growth period.
FIG. 3 is a graph depicting the marketable yields for the various treatments. It should be noted that the yield using Treatment #2009 was slightly greater than that using Treatment #2010. However, given the fact that Treatment #2009 involved no application of foliar fungicide, it will be seen that the Trigger product itself protected the plants. This is a substantial advantage inasmuch as the cost of repeated foliar fungicide applications was saved.
Example 5 In this example, the saponins of the invention were tested for potato late blight control at Outlook, Sk. The test was conducted exactly as set forth in Example 2. However, late blight infection set in during the growing season. Data was then recorded on the top growth, and mechanical top killing on Aug. 10, 2000 destroyed the top growth. The tubers were left in the ground and harvested on Sep. 1, 2000, and further data recorded. The following Table 6 sets forth the important data.
FIGS. 4-6 illustrate further the important data derived from this test.
TABLE 6
Data Averages: Average of Reps for Each Treatment - Outlook, Sk.
Treatment
Mainstem
Late blight
Early blight
Black leg
Canker
Leaf roll
Black scarf
#
(#/Pbl)
(%)
(%)
(# of Plants)
(# of Plants)
(# of Plants)
(%)
1: 1 gm/50 L
104
18.75
3.75
1
0
0
0.00
2: 1 gm/10 L
101
17.50
2.50
0
0
0
0.00
3: 1 gm/1 L
104
15.00
1.25
0
0
0
0.00
4: 10 gm/1 L
106
18.75
2.50
0
0
0
0.00
CONTROL
98
23.13
2.50
1
0
0
0.00
The data from this test also indicated that the treatment of the invention had an effect in controlling leaf roll virus.
Example 6 In this example, the saponin products of the invention were used to treat elm trees infected with Dutch Elm disease. Six elm trees in Winnipeg, Minn. were discovered showing signs of Dutch Elm disease, ranging from 20-45% infected. The diseased trees were injected with a saponin dispersion (1 g saponin/LH 2 O) prepared as described in Example 1. The application rate was 1 g of dry saponin/cm of trunk diameter at breast height. The dispersions were conventionally injected at the root flare, with the trees absorbing the dispersion within about 48 hours. The treated trees were monitored every day for approximately six weeks. The trees remained stable and exhibited no further wilt, flagging or leaf loss.
Example 7 In this example, the efficacy of several commercially available compositions was compared with that of the inventive composition (an aqueous solution consisting essentially of saponin extracted from quinoa) in controlling bacterial spot in tomatoes, more specifically transplanted greenhouse tomato plants (tomato cultivar BHN-555). The experiment was conducted at a farm located in Quincy, Fla. The tomato plants were transplanted from the greenhouse into plots of 20 plants arranged in a single row with 50×180 cm plant spacing in randomized complete block design.
Five-week-old seedlings were transplanted on to raised beds previously fumigated with methyl bromide (67%) and chloropcrin (33%) and covered with white polyethylene mulch. The plants were drip Irrigated, staked, and fertilized with 195-60-195 lb/acre N-P 2 O 5 -K 2 O. Foliar spray applications initially employed a spray volume of 26 gpa and were increased to a maximum of 65 gpa. Disease severity was assessed three times for bacterial spot (caused by Xanthomonas campestris pv. vesicatoria ) and target spot (caused by Corynesporia cassiicola ) over approximately a three month period. Fruit was subsequently harvested from 12 plants per plot.
The specific treatment methods are described in detail in Table 7. Each treatment method described below was replicated four times during the experiment.
TABLE 7
Treatment
Description
Control
Untreated control
KOCIDE DF +
KOCIDE at concentration of 4.8 g/L and MANZATE
MANZATE 1
also at 4.8 g/L were applied weekly at a foliar spray.
75DF
ACTIGARD
ACTIGARD at a concentration of 60 mg/L was applied
every 14 days as a foliar spray, for a total of six
applications.
Q.S. 1
Quinoa saponin at a concentration of 1 g/L applied one
time as a root dip immediately before to transplanting.
Q.S. 2
Quinoa saponin at a concentration of 1 g/L applied one
time as a foliar application 5 days before transplanting.
Q.S. 3
Quinoa saponin at a concentration of 1 g/L applied twice,
once as a foliar application 5 days before transplanting
and once as a root dip immediately before transplanting.
Q.S. 4
Quinoa saponin applied one time as a foliar spray three
days after transplanting.
1 A fungicide (manganese ethylene bisdithiocarbamate) available from Griffin, L.L.C.
The results of tomato plant trials are shown in Table 8 below. The effectiveness of the treatment method is indicated by the combined severity of bacterial and target spot diseases.
TABLE 8
% Disease Severity
7 weeks after
9 weeks after
11 weeks after
Treatment
transplant
transplant
transplant
Control
2.6
13.4
69.9
KOCIDE DF +
1.4
4.4
42.1
MANZATE 75DF
ACTIGARD
1.7
7.3
61.7
Q.S. 1
2.3
8.7
60.9
Q.S. 2
2.0
8.1
64.0
Q.S. 3
4.0
9.9
53.9
Q.S. 4
2.0
7.3
59.3
As expected, the untreated control plants exhibited the greatest disease severity, with almost 70% of the plants affected, and the KOCIDE and MANZATE treated plants exhibited the lowest disease severity. However, most notable is the comparison between the ACTIGARD and quinoa saponin treatments, both designed to elicit a protective response from the tomato plant's own immune system. In most cases, the quinoa saponin treatment method performed comparably with or even outperformed the ACTIGARD treatment method with the best results obtained by the Q.S. 3 method. The Q.S. 3 method also presents the advantage that all treatment was performed in the greenhouse thereby eliminating the need for application in the field.
Example 8 In this example, the efficacy of several commercially available biocontrol compounds (ELEXA, MYCONATE and MESSENGER) for controlling common scab (Streptomyces scabies) in potatoes was compared with a preferred inventive saponin solution extracted from quinoa (Q.S.). MYCONATE, available from VAMTech LLC, Lansing, Mich., is a water-soluble formulation of the potassium salt of 4′-methoxy, 7-hydroxy isoflavone, which is isolated from the roots of clover plants that were stressed by phosphorous deficiency. ELEXA, available from Glyco Genesysis, Boston, Mass., is a complex carbohydrate formulation containing no toxic active ingredients which inhibits fungal infections in a variety of plants. MESSENGER, available from Eden Bioscience Corp., Bothell, Wash., is a harpin protein containing composition.
The experiments were performed in Bath, Mich. Potatoes with minimal surface scab were selected for use in this example, and potato seeds were prepared by cutting two days prior to planting. The seeds were planted two-row by 20 ft. plots with approximately 10 in between plants so as to give a target population of 50 plants at 34 in row spacing. The planting pattern was replicated four times in a randomized block design The two-row beds were separated by a 5 ft. unplanted row.
In half of the trials, application of the biocontrol compound occurred in furrow over the seed at planting. In the In furrow trials, the compound was applied with a R&D spray boom delivering 5 gal/acre (80 psi) and one spray nozzle per row. In the remaining trials, the biocontrol compound was applied as a foliar spray. The first foliar application occurred approximately 5 weeks after planting with a second occurring a week later. Both applications were performed with an ATV rear-mounted R&D spray boom delivering 25 gal/acre (80 psi) with three nozzles per row.
Weeds were controlled by hilling and with the following herbicide applications: DUAL 8E at 2 pt/acre 10 days after planting (DAP), Basagran at 2 pt/acre 20 and 40 DAP, and POAST at 1.5 pt/acre 58 DAP. Insects were controlled by application of the following insecticides: Admire 2F at 1.25 pt/acre at planting, SEVIN 80S at 1.25 lb./acre 31 and 55 DAP, THIODAN 3 EC at 2.33 pt/acre 65 and 87 DAP, and POUNCE 3.2EC at 8 oz/acre 48 DAP.
Fertilizer was drilled into the plots before planting and formulated based on the results of soil testing. Additional nitrogen was applied to the growing crop with irrigation 45 DAP. Once the plant canopy was about 50% closed, Bravo WS 6SC fungicide was applied at a rate of 1.5 pt/acre on a seven-day interval for a total of 8 applications. A permanent irrigation system was established prior to the commencement of fungicide sprays and the fields were maintained at soil moisture capacity throughout the season by frequent (minimum 5 day) irrigations. The vines were killed with REGLONE 2EC at 1 pt/acre approximately 14 weeks after planting. The plots were harvested one week after the vines were killed.
Of the biocontrol materials tested, each was applied as an in furrow treatment and as a foliar treatment. In furrow applications were made over the seed at planting using a single nozzle R&D spray boom delivering 5 gal/acre (80 psi) and using one spray nozzle per row. Foliar applications were applied were performed approximately 5 and 6 weeks after planting using an ATV rear-mounted R&D spray boom delivering 25 gal/acre (80 psi) and using three spray nozzles per row. The application rates for each agent is given in Table 9.
TABLE 9
Application
Treatment
Method
Application rate
ELEXA
in furrow
Manufacturer's suggested application rate.
MESSENGER
in furrow
1.4 oz per 1000 ft. of row
Q.S.
in furrow
0.9 oz per 1000 ft. of row
MYCONATE
in furrow
Manufacturer's suggested application rate.
ELEXA
foliar
Manufacturer's suggested application rate.
MESSENGER
foliar
0.42 lbs. per acre per application
Q.S.
foliar
0.25 lbs. per acre per application
MYCONATE
foliar
Manufacturer's suggested application rate.
The results of the potato scab treatments are shown in Table 10. Effectiveness of the treatment was determined by measuring the percentage of the surface area of the tuber which the scab affected. Tubers exhibiting less than 5% affected surface area were considered to be marketable.
TABLE 10
Common Scab on Tubers (Percentage in surface area affected class)
Average surface
Treatment
0%
0-5%
5-10%
10-15%
15-20%
20-50%
>50%
area affected
ELEXA (IF)
22.5
38.8
18.8
5.0
2.5
7.5
5.0
10.8
MESSENGER (IF)
6.3
40.0
8.8
11.3
5.0
16.3
12.5
22.1
Q.S. (IF)
7.5
41.3
17.5
3.8
2.5
17.5
10.0
18.8
MYCONATE (IF)
11.3
41.3
20.0
7.5
7.5
11.3
1.3
11.3
ELEXA (FOL)
12.5
51.3
11.3
5.0
1.3
12.5
6.3
13.6
MESSENGER (FOL)
10.0
40.0
8.8
6.3
2.5
22.5
10.0
19.4
Q.S. (FOL)
21.3
51.3
12.5
3.8
3.8
3.8
3.8
8.8
MYCONATE (FOL)
11.3
41.3
11.3
5.0
1.3
20.0
10.0
20.7
Untreated
15.0
50.0
3.8
7.5
3.8
10.0
10.0
16.1
The results of this trial indicate that the quinoa saponin solution was extremely effective in controlling common scab when applied as a foliar spray. About 72.6% of all tubers treated in this manner showed 5% or less affected surface area. This method also showed the smallest average affected surface area of all methods tested. | Improved methods and compositions for protecting plants or seeds from plant diseases are provided. Broadly, the compositions comprise (and preferably consist essentially of) saponin, such as triterpene type saponins extracted from quinoa or quillaja. The methods comprise contacting the portion of the plant (e.g., foliage, shoot, etc.) to be treated with a disease-inhibiting or protective amount of the composition. The compositions can also be used to treat plant seeds or tubers prior to planting thereof, as well as soil adjacent a growing plant. The inventive compositions are particularly useful for the treatment, control and/or prevention of bacterial diseases. The saponins of the invention can be applied as liquids or dry particulates, and are especially suited for the treatment of tomato and potato plants and their respective seeds. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application 60/000,688, filed Jun. 21, 1995 and PCT International Application PCT/US96/10625, filed Jun. 19, 1996, wherein the United States was a designated country.
FIELD OF THE INVENTION
The invention generally relates to composite articles. In particular, the invention relates to inorganic fibers having a mullite-containing coating and to ceramic matrix composite articles reinforced with said fibers.
BACKGROUND OF THE INVENTION
Fiber-reinforced ceramic matrix composites comprising glass-ceramic matrices are known in the art. Fiber-reinforced ceramic matrix composites are useful as structural elements in high temperature environments such as heat engines. For these and other applications, the materials to be employed must exhibit good strength and toughness at ambient as well as elevated temperatures.
An important problem which has been identified in silicon carbide fiber reinforced ceramic matrix composites, particularly after exposure to temperatures above about 800° C. in an oxidizing environment, is that microcracks can form causing embrittlement. Instead of exhibiting increased toughness and strength after exposure to high temperatures, the materials become brittle and are subject to catastrophic breakage, rather than more gradual failure as is typical of the original material. These physical problems can be attributed, in-part, to the effect of the interface between the silicon carbide fibers and the ceramic matrix composite.
Physical testing of ceramic matrix composites, embrittled during or subsequent to high temperature exposure, shows decreases in fracture toughness through changes in the fracture properties of the material, leading to a degradation of the material. Thus, the predominant fracture mode changes from one characterized by fiber pullout from the matrix to one wherein woody fracture, or ultimately, brittle fracture occurs. Woody fracture surfaces display some crack propagation parallel to the stress axis, indicating localized shear failure without fibrous pullout, while brittle fracture surfaces display merely planar fracture surfaces as the composite exhibits no plastic deformation.
The onset of brittle fracture behavior in these composites typically occurs in conjunction with significant reductions in fracture toughness. One indicator of this reduced toughness is a drop in the extent of strain of sample elongation observed above the so-called microcrack stress point of the material. Among the factors believed to influence fracture toughness are fiber debonding and fiber pullout behavior, including the degree of frictional resistance to fiber pullout from the matrix, as well as crack deflection occurring in the matrix and at the fiber-matrix interface. Modifications to the matrix or fiber reinforcement can significantly aid in the development of composites exhibiting good high temperature fracture toughness and strength.
It is known to provide coatings on reinforcement fibers to be incorporated in composite materials to modify the behavior of the materials therein. For example, boron nitride coatings have been applied to silicon carbide fibers or other fibers that are subsequently incorporated in ceramic matrix materials such as SiO 2 , ZrO 2 , mullite and cordierite (see e.g., U.S. Pat. No. 4,642,271 (Rice)).
It is established that the interface between fibers and the matrix is critical to the mechanical properties of brittle-matrix composites. In particular, the debonding and frictional characteristics of the interface control the mode of fracture (multiple cracking vs. single crack), and mechanical properties such as fracture toughness. Desired interfacial properties are usually achieved by the incorporation of a coating between the fiber and matrix.
For example, Beall et al., European Patent Application Publication Number 366234 A1, disclose ceramic matrix composite articles comprising a ceramic, glass-ceramic or glass matrix and a fiber reinforcement phase disposed within the matrix. The fiber reinforcement phase consists of amorphous or crystalline inorganic fibers, wherein there is provided, on or in close proximity to the surfaces of the inorganic fibers, a layer of sheet silicate crystals. The layer of sheet silicate crystals are used to improve fiber pullout behavior and to improve toughness retention at elevated temperatures.
At present, however, there are only a few other successful coating materials, most notably, carbon, although some success has been reported with metallic and porous coatings. In most of the composite systems that have been studied to date, exposure of the coating to high temperatures in air seriously degrades its properties. For example, in the case of lithium aluminum silicate matrix reinforced with carbon-coated silicon carbide fibers, heat treatment in air leads to a strong SiO 2 interface, and the material loses its quasi-brittle mechanical properties. There is therefore great interest in developing alternative coatings for fibers in brittle-matrix composites.
Oxides are a class of materials which have intrinsic high temperature stability in air. A particular interest has been to look at using oxidation resistant materials as potential fiber coatings in ceramic matrix composites for high temperature/high stress applications. An important consideration in choosing an interfacial material is its ability to form uniform coatings on the fibers in question.
Clearly, coating materials having excellent film-forming capability, and which can be coated successfully onto fibers such as SiC and borosilicate glass fibers, are needed. Such materials need to provide debonding coatings on the surfaces of fibers used in ceramic matrix composites, wherein such coatings remain stable at elevated temperatures. Moreover, such ceramic matrix composites need to have high strength and fracture toughness, even at elevated temperatures. As a result, it is an object of the present invention to provide coatings for fibers and ceramic matrix composites that overcome the problems and deficiencies of the prior art. Other objects and advantages of the present invention will become apparent to those skilled in the art upon reference to the attached drawings and to the detailed description of the invention which hereinafter follows.
SUMMARY OF THE INVENTION
The invention provides for an improved ceramic matrix composite article comprising:
(a) a matrix phase comprised of a ceramic material selected from the group consisting of crystalline ceramics, glass ceramics, glasses, and combinations thereof; and
(b) a fiber reinforcement phase comprised of a plurality of amorphous or crystalline inorganic fibers disposed within the matrix phase,
wherein the improvement comprises the inorganic fibers having a mullite-containing coating on the surface of said inorganic fibers and wherein the inorganic fibers are not comprised of a mullite-precursor.
The invention also provides for a method of coating an inorganic fiber with a mullite-containing coating, comprising the steps of:
(a) modifying a smectite clay by ion-exchange in solution to provide sufficient amounts of aluminum ions in the clay;
(b) adding a pillared smectite clay to the solution to form a suspension;
(c) drawing an inorganic fiber through the suspension of step (b) and drying the fiber thereafter;
(d) repeating step (c) a plurality of times until the desired amount of coating is deposited on the surface of the fiber; and
(f) heating the coated fiber to a temperature sufficient to convert the clay coating to a coating containing mullite. Optionally, excess salts may be removed after step (b) and before step (c).
The above procedure can be modified slightly to provide for making a ceramic matrix composite article. In this modified process, prior to step (f), the following step can be incorporated:
(e) combining a plurality of coated fibers with a matrix phase comprised of a ceramic material selected from the group consisting of crystalline ceramics, glass-ceramics, glasses and combinations thereof, to form a ceramic matrix composite such that the plurality of coated fibers are disposed within the matrix phase.
The invention also provides an amorphous or crystalline inorganic fiber having a mullite-containing coating wherein the inorganic fiber is not a mullite precursor.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1(a) shows room temperature x-ray diffraction data for bentonite and FIG. 1(b) shows comparative room temperature x-ray diffraction data for Al-bentonite clays, both as a function of thermal treatment: (a) and (f) are at room temperature; (b) and (g) are after heating to 500° C.; (c) and (h) are after heating to 800° C.; (d) and (i) are after heating to 1000° C.; and (e) and (j) are after heating to 1200° C.
FIG. 2(a) is a SEM micrograph of a SiC fiber with a bentonite clay coating.
FIG. 2(b) is an optical micrograph of a cross-section of the glass/SiC composite.
FIG. 2(c) is a SEM micrograph of the interfacial coating between the glass and SiC fiber (single dip).
FIGS. 3(a) and 3(b) are SEM micrographs of the residual displacement of a fiber in a ceramic matrix composite after indentation of the fiber in the matrix (FIG. 3(a) uncoated and FIG. 3(b) coated).
FIG. 4 shows typical results of four-point bend tests on four types of specimens: (1) glass matrix material; (2) glass matrix with uncoated fibers; (3) Al-bentonite (i.e., mullite) coated fibers in glass matrix tested in air; and (4) Al-bentonite coated fibers in glass matrix tested in water.
FIG. 5 is an SEM showing multiple matrix cracks in an Al-bentonite coated sample after testing in water.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides for novel ceramic matrix composites, comprising a matrix phase and a fiber reinforcement phase wherein the fibers have a mullite-containing coating on their surfaces. Novel inorganic fibers having a mullite-containing coating are also provided.
The invention further provides for a novel process for the low-temperature formation of mullite-containing coatings, from pillared smectite clay precursors, on fibers, for use in ceramic matrix composites (CMC's). Smectite clay precursors display excellent film-forming capability and can be uniformly coated onto inorganic fibers. Mechanical tests on composites of such coated fibers in a glass matrix demonstrate the fibers are successful as debondable coatings. In particular, alumina-pillared bentonite can be converted substantially to mullite at the unusually low temperature of about 800° C.
One embodiment of the invention involves a ceramic matrix composite article. As is known in the art, composites typically comprise a matrix phase and a fiber reinforcement phase. The fiber reinforcement phase is typically combined with, and hence disposed within, the matrix phase, the two phases then being heated to form a composite article.
The improvement lies in the fact that the inorganic fibers in the fiber reinforcement phase have a mullite-containing coating on their surface, thus forming an interfacial layer between the fibers and the matrix. In composites, these coated fibers show debonding characteristics, as well as evidence of being tough materials, i.e., multiple matrix cracking and non-linear stress-strain response prior to peak stress. Additionally, since mullite is an oxide, stability at elevated temperatures is achieved.
As used herein, "mullite-containing coating" means a coating that comprises between about 1-100 wt. % mullite (i.e., an orthorhombic silicate of aluminum, Al 6 Si 2 O 13 or 3Al 2 O 3 .2SiO 2 ), although other phases may be present. Preferably, the coating is at least about 40 wt. % mullite.
The matrix phase can comprise a ceramic material selected from crystalline ceramics, glass-ceramics, glasses and combinations thereof. This can include borosilicate glasses, aluminosilicate glasses, lithium aluminosilicate glasses, and alkaline earth aluminosilicate glasses, silicon carbide, boron nitride, silicon oxynitride and silicon nitride.
The fiber reinforcement phase comprises amorphous or crystalline inorganic fibers having a mullite-containing coating on their surfaces. Useful inorganic fibers include fibers having one of the following compositions: silicon carbide, boron nitride, silicon oxycarbide, carbon, alumina, boron carbide, zircon, spinel, silicon nitride, silicon oxynitride, titanium carbide, and titanium diboride.
A proportion of at least about 1% fiber reinforcement by volume is preferred to be included in the ceramic matrix composite of the invention herein. Most preferably, the percentage of fibers by volume should be in the range of about 30 to 80%. The fibers may vary in size and shape, since this aspect is not considered critical to the invention.
Layered aluminosilicate oxides have been found to be good film-formers which can be subsequently thermally, and in some cases, chemically altered to give new coatings with interesting properties, such as a mullite-containing coating. Pillared smectite clays are used as precursor materials, which can be coated onto inorganic fibers. Being inexpensive and excellent film-formers, these clays show promise as fiber coatings for brittle-matrix composites. Being oxides, they provide enhanced stability at elevated temperatures.
An important feature of these clay-based materials is the ease with which thin films can be formed. FIG. 2(a) shows a SiC fiber which has been coated with a bentonite clay. The coating is seen to be uniform after three dips and calcination at 500° C. The clay suspension in water has good film-forming properties as compared to analogous sol-gel derived suspensions where excessive cracking occurs upon drying. Drawing SiC fibers through an ion exchanged-bentonite suspension readily coats the fiber to uniform thicknesses of 50-250 nm, and the process can be repeated to build-up coatings of different thicknesses.
FIG. 2(b) shows a transverse section of a composite specimen, hot-pressed at 900° C. FIG. 2(c) shows the thin interfacial coating (approximately 30 nm). The presence of the coating was confirmed by energy dispersive x-ray analysis (EDX), which showed aluminum at the edge of the fiber.
Montmorillonite (ideally, [Na 0 .33.xH 2 O] 1/3+ [(Al 1 .67 Mg 0 .33)Si 4 O 10 (OH) 2 ] 1/3- ) is a preferred smectite clay which consists of hydrated ions charge compensating for and sandwiched between partially substituted 1:2::Al:Si aluminosilicate layers. Bentonite is a naturally occurring montmorillonite-related mineral. FIGS. 1(a) and 1(b) compare the structural evolution of bentonite and [Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ -exchanged bentonite as a function of thermal treatment, see Example 1.
As provided for in the process embodiment of the invention, clay-based precursors are used to form oxide coatings on inorganic fibers. The alumina-pillared bentonite clay which is coated on the inorganic fiber can be transformed to mullite at temperatures as low as about 800° C. Thus, as noted before, the invention also provides for inorganic fibers having a mullite-containing coating on their surfaces.
Composites can be formed by combining the mullite-containing coated fibers with a matrix phase. Composites of fibers coated with a mullite-containing coating in a borosilicate glass show considerable debonding in indentation tests, and all the signatures of a tough material: multiple matrix cracking and a nonlinear stress-strain response prior to peak stress. Since the coefficient of thermal expansion of mullite is well-matched to that of SiC, a preferred matrix and inorganic fiber phase material is silicon carbide.
Hot-pressed composites of clay-coated SiC fibers with borosilicate glass have been fabricated and mechanical tests using single-fiber indentation and four-point bending of composite beams have been used to study the potential of such coatings as debonding interfaces. Indentation experiments conducted on composites with coated and uncoated fibers under loads in the range of 5-30 N showed residual displacement after indentation of an order of magnitude greater for the coated fibers compared to uncoated fibers (see Example 2). FIGS. 3(a) and 3(b) show SEMI micrographs of coated (3(b)) and uncoated (3(a)) fibers after indentation.
Another embodiment of this invention involves a method for making a ceramic matrix composite article. The first step of the method comprises modifying a smectite clay by ion-exchange to provide sufficient amounts of aluminum ions in the clay. This can be accomplished by forming a solution containing a soluble aluminum ion, preferably a polyoxo-aluminum Keggin ion, ([Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ ). Other cations or cationic clusters are contemplated, e.g., Al 3+ , Ga based or Ga/Al based clusters. Thereafter, a pillared smectite clay, e.g., montmorillonite/bentonite, is added to the solution to form a suspension. The resulting ([Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ )-exchanged bentonite will be referred to as Al-bentonite, for purposes of this invention.
The next step in the method involves drawing an inorganic fiber through the suspension. By doing so, a coating of the suspension is deposited on the surface of the inorganic fiber. After coating, the fiber should be dried to solidify the coating. This is generally accomplished by heating the fiber, typically to a temperature ranging from about 150° C. to about 250° C. After drying, the inorganic fiber can be drawn through the suspension a number of additional times until the desired thickness of coating is achieved, making sure to dry the fiber as described above after each successive coating. The concentration of the smectite clay in the suspension may vary depending on the desired coating thickness on the fiber. Typical coating thickness will range from about 50 nm to about 250 nm.
The next step in the method involves combining a plurality of coated inorganic fibers with a matrix phase comprised of a ceramic material described hereinbefore. Combining the coated inorganic fibers with a matrix phase causes the coated fibers to be disposed within and throughout the matrix phase. Finally, the ceramic matrix composite is then heated to a temperature sufficient to convert the clay coating on the fibers to a coating containing mullite. The temperature is preferably at least about 800° C., and usually no higher than about 1700° C. The result is a ceramic matrix composite article wherein the inorganic fibers have a mullite-containing coating which acts as an interfacial layer between the fibers and the matrix, and thus serves as a debonding interface.
Prior to coating, the suspension can be optionally treated to remove excess salts. This is preferably done by dialyzing the suspension. The step of dialyzing typically comprises placing the suspension in a dialysis membrane (which can be purchased commercially from e.g., Spectrum Medical Industries, Inc. of Los Angeles, Calif.), and placing the membrane containing the suspension in excess dionized water, e.g., 2000 mL of deionized water for 100 mL of the suspension. The membrane should remain in the deionized water for a sufficient time to allow removal of the excess salts. The water is preferably stirred periodically and replaced after 24 hours.
Additionally, the optional step of removing excess salts can also be accomplished by filtering the suspension and then washing the collected filtrate with water.
Another embodiment of this invention involves a method for coating fibers with a mullite-containing coating. The method is similar to the method of forming a ceramic matrix composite article discussed above, but does not include the step of combining the coated fibers with a matrix phase. Instead, the coated fibers can be made and transported for later use in a ceramic matrix composite. After coating and drying the fibers, the fibers are heated to a temperature sufficient to convert the clay coating to a coating containing mullite, preferably at least about 800° C.
Fibers having a mullite-containing coating have not been found to fail catastrophically in a ceramic matrix, and the stress does not fall to zero in four-point bend tests. The failure occurs in steps, gradually, and the ceramic remains in tact. This is a significant improvement over non-coated fibers which fail catastrophically and the stress goes to zero in the same tests.
EXAMPLES
The following non-limiting inventive examples and comparative examples are presented to further illustrate the invention.
Comparative Example A
Fibers Coated With Bentonite Clay
Silicon carbide fibers, nominally 100 microns in diameter with a tungsten core (SCS fiber, Textron Specialty Materials, Lowell, Mass.), were coated with a naturally occurring bentonite clay (Volclay MBS-1, American Colloid Company) by drawing the fibers through an aqueous suspension of the clay. The fibers, as received, have a polyvinyl alcohol coating which was removed by feeding the fiber continuously through a furnace in air at 500° C. The fibers were then coated with the bentonite by feeding them directly from the furnace through a 1.5% (by weight) suspension of the clay. The fibers were dried at 200° C. and re-coated three times. Each dip gave a coating of about 0.03 microns, resulting in a final coating thickness of about 0.1 microns. FIG. 2(a) shows a micrograph from an Scanning Electron Microscope (SEM) of the SiC fiber with a bentonite clay coating showing the uniformity of the coating. The fibers were then subjected to temperatures up to 1200° C.
Samples of the bentonite clay were taken for x-ray diffraction after heating to temperatures of 500° C. (FIG. 1(a)-(b)), 800° C. (FIG. 1(a)-(c)), 1000° C. (FIG. 1(a)-(d)), and 1200° C. (FIG. 1(a)-(e)).
Example 1
Fibers Coated With Alumina Pillared Bentonite
Mullite-containing debondable coatings were prepared as follows: To a stirred aluminum trichloride (2.4 g of AlCl 3 .6H 2 O in 50 mL of water) solution, sodium hydroxide (40 mL of a 0.5 M NaOH solution) was added over about 1 hour to provide a final ratio of OH/Al of 2.0. The solution was stirred and heated to 60° C. for two hours. To this solution, 50 mL of a 2% by weight suspension of naturally occurring bentonite clay (Volclay MPS-1, American Colloid Company of Belle Fourche, S. Dak.) was added and the mixture was stirred for 24 hours. The resulting suspension was then dialyzed (Spectra/Por 3, Spectrum Medical Industries, Inc.) for 24 hours with de-ionized water to remove the excess salt formed. This suspension of a polyoxo-aluminum Keggin ion [Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ -exchanged bentonite (referred to as Al-bentonite) was used to coat fibers directly. For mechanical testing, silicon carbide fibers, nominally 100 microns in diameter with a tungsten core (SCS fiber, Textron Specialty Materials of Lowell, Mass.), were coated directly with the clay suspension. The fibers, as received, have a polyvinyl alcohol coating which was removed by feeding the fiber continuously through a furnace in air at 500° C. The fibers were then coated with the Al-bentonite by feeding them directly from the furnace through the suspension of the clay. The fiber was dried at 200° C. and re-coated three times. Each dip gave a coating of about 0.03 microns, resulting in a uniform coating (see FIG. 2(c)) having a final coating thickness of about 0.1 microns. The fibers were then subjected to temperatures up to 1200° C.
Samples of the alumina pillared bentonite were taken for x-ray diffraction after heating to temperatures of 500° C. (FIG. 1(b)-(g)), 800° C. (FIG. 1(b)-(h)), 1000° C. (FIG. 1(b)-(i)), and 1200° C. (FIG. 1(b)-(j)).
X-ray Diffraction Results
The distinction to be made between coating made of bentonite clay (COMPARATIVE EXAMPLE A) and those made of alumina-pillared bentonite clay (EXAMPLE 1) is revealed by powder x-ray diffraction as shown in FIGS. 1(a) and 1(b). The room-temperature x-ray diffraction pattern of bentonite clay (FIG. 1(a)-(a)) reveals a characteristic layer spacing of 1.27 nm. The presence of quartz and cristobalite impurities is also noted and acts conveniently as an internal standard. Upon heating the bentonite clay to 800° C. (FIGS. 1(a)-(b) and 1(a)-(c)), the basic structure of the aluminosilicate layers is maintained while the layer spacing decreases with loss of interlayer water to 0.96 nm. At 1000° C. (FIG. 1(a)-(d)) the layer structure collapses as evidenced by loss of the (100) peak and cristobalite forms (note the intensity change of the cristobalite peak relative to quartz). Presumably, the aluminum oxide-containing component of the clay is amorphous. Upon further heating to 1200° C. (FIG. 1(a)-(e)), mullite Al 6 Si 2 O 13 is formed and the excess silica which would be expected for a 1:2::Al:Si bentonite clay is converted completely to cristobalite.
In FIG. 1(a)-(f) the pattern of bentonite clay exchanged with [Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ ions is shown. The increase in the layer spacing to 1.74 nm indicates that the Keggin ions are intercalated between the clay layers. The rest of the spectrum is similar to that of bentonite (FIG. 1(a)-(a)) with the invariant peaks presumably indexing as (hk0). Upon heating Al-bentonite to 500° C. (FIG. 1(b)-(g)), the layer peak disappears indicating a disorder in the stacking upon formation of alumina pillars between the sheets. However, the crystallinity within the Si-Al-Si oxide sheet is maintained, as evidenced by the continued presence of the (100) reflection. At 800° C., Al-bentonite forms mullite as shown in FIG. 1(b)-(h). As noted above, upon similar heat treatment of the unexchanged bentonite no evidence of mullite formation was observed (FIG. 1(a)-(c)). While this invention is not bound by any particular theory or observation, it is speculated that this observation is attributable to the intimate mixing at the atomic scale of the [Al 13 O 4 (OH) 24 (H 2 O) 12 ] 7+ Keggin ions with the Si-rich aluminosilicate clay layers. At higher temperatures (1000° and 1200° C.; FIGS. 1(b)-(i) and 1(b)-(j), respectively) the mullite pattern sharpens indicative of increasing crystallinity and, as in the pure bentonite case, excess silica converts to cristobalite. The increase in the amount of mullite formed compared to that in the case of pure bentonite (FIGS. 1(a)-(e) and 1(b)-(j)) is consistent with the increased aluminum content of the Al-bentonite sample.
Example 2
Composite Frabrication Using Coated Fibers
Composites of the coated fibers and a borosilicate glass (Corning Glass 7740 of Corning, N.Y.) were fabricated. Several samples with widely dispersed fibers were fabricated to be sectioned and prepared for indentation experiments. Other samples contained approximately 30% fibers (by volume); these were used for four-point bend tests. The composites were laid-up by hand in a 5 cm diameter graphite die (typically 14.0 g of glass to 3.0 g of SiC fiber). These were vacuum hot-pressed in 10 torr pressure at 900° C. for 15 minutes, cooled at 10° C./minute to 570° C., held at 570° C. for 30 minutes, and furnace-cooled to room temperature. A pressure of 13 Mpa was applied during hot-pressing at 900° C., and released during cooling. The hot-pressed samples were ejected from the graphite die at room temperature. Sections normal to the orientation of the fibers were cut and polished to a grit size of 1 micron for the indentation experiments. Samples for bend tests were cut, typically with dimensions of 45 mm×4 mm×1.5 mm.
Comparative Example 3
Composite Fabrication Using Uncoated Fibers
Composites of uncoated fibers and a borosilicate glass (Corning Glass 7740) were fabricated. Several samples with widely dispersed fibers were fabricated to be sectioned and prepared for indentation experiments. Other samples contained approximately 30% fibers (by volume); these were used for four-point bend tests. The composites were laid-up by hand in a 5 cm diameter graphite die (typically 14.0 g of glass to 3.0 g of SiC fiber). These were vacuum hot-pressed in 10 torr pressure at 900° C. for 15 minutes, cooled at 10° C./minute to 570° C., held at 570° C. for 30 minutes, and furnace-cooled to room temperature. A pressure of 13 MPa was applied during hot-pressing at 900° C., and released during cooling. The hot-pressed samples were ejected from the graphite die at room temperature. Sections normal to the orientation of the fibers were cut and polished to a grit size of 1 micron for indentation experiments. Samples for bend tests were cut, typically with dimensions of 45 mm×4 mm×1.5 mm.
For both coated and uncoated fibers, individual fibers were indented with a Vicker's diamond tip (Zwick 3212) with loads in the range of 5-30 N. The indentation caused the fibers to debond. The residual displacement after indentation was seen to be an order of magnitude greater for the coated fibers compared to the uncoated fibers. FIGS. 3(a) and 3(b) show SEM micrographs of coated and uncoated fibers after indentation. In all cases, the indentation spawned radial cracks. These, however, do not seriously affect the primary measurement from this experiment: the residual out-of-plane displacement of the fiber. Upon unloading, the residual displacement of the fiber with respect to the matrix, u r , was used to estimate the frictional resistance of the interface. Its average value was 0.1±0.02 microns for the uncoated fibers and 1.0±0.3 microns for both the bentonite and Al-bentonite coated fibers. Using equation (1) (below), the sliding resistance t was estimated to be about 1.0 GPa for the uncoated fibers and 100 MPa for the coated fibers. The sliding resistance for the coated fibers is large compared to commonly measured values for carbon interfaces, but sufficiently low compared to the uncoated fibers to promote debonding at the interface in the bend tests described below.
The samples had a relatively small volume fraction of fibers (about 30%), and a glassy matrix was chosen for ease of processing, rather than as a candidate for ultimate use. It is contemplated that performance could be improved by increasing the volume fraction of the fibers, and/or by using different matrix materials.
The residual displacement was measured directly from scanning electron micrographs taken at known tilts, and by surface profile measurements. It is used to estimate the (assumed) constant shear t which resists sliding of the fiber-matrix interface. This allows a comparison of different coatings using a single parameter and a simple indentation test. Then, t can be estimated as:
t=F.sup.2 /(8 π.sup.2 R.sup.3 u.sup.r E.sup.f) (1)
where F is the indentation load, R is the fiber radius, and E f is the Young's modulus of the fiber (=400 GPa). Four-point bend tests were conducted in air or in water using inner/outer spans of 10/40 or 20/40 mm, at a ram displacement rate of 25 mm/s.
FIG. 4 shows typical results from four-point bend tests for four types of specimens: (1) glass matrix material; (2) glass matrix with uncoated fibers; (3) Al-bentonite coated, which is substantially mullite coated, fibers in glass matrix tested in air; and (4) Al-bentonite coated fibers in glass matrix tested in water. The measured force-displacement data were converted into stress and strain, based on a nominally undamaged material. The three composite specimens have a greater initial stiffness than the glass specimen due to the greater stiffness of the fibers. The glass and the composite without a coating both show brittle behavior. Failure for these specimens was from a single crack with little pull-out of fibers in the composite. The stress-strain behavior of the bentonite-coated composites (data not shown here) is similar to the uncoated composite samples.
In contrast, the composite with the Al-bentonite coating, tested in air, shows distinct non-linearity prior to the peak stress. The test was interrupted for a few specimens after the onset of non-linearity but prior to the peak stress. These specimens showed multiple-matrix cracking on the tensile side of the specimen with typical crack spacing of 0.75-1.00 mm. Most of the Al-bentonite coated samples showed a single large decrease in the stress, corresponding to fiber-failure in one of the matrix cracks. However, the specimens continued to exhibit stable deformation by steady-state propagation of a delamination crack along the beam. When tested in water, the specimens with the Al-bentonite coating displayed much greater matrix cracking, and stable deformation without fiber failure up to much larger strains. The glass, uncoated, and bentonite-coated specimens continued to fail in a manner similar to failure in air. FIG. 5 shows the tensile surface of a sample with an Al-bentonite coating after bending in water with multiple matrix cracks.
FIG. 2(b) shows an SEM micrograph of a cross section of a composite of the SiC fibers (with tungsten cores) in a glass matrix. FIG. 2(c) shows an SEM micrograph of a SiC fiber with an interfacial mullite-containing coating in a glass matrix. FIG. 2(c) clearly shows the uniformity of the coating.
Although particular embodiments of the present invention have been described in the foregoing description, it will be understood by those skilled in the art that the invention is capable of numerous modifications, substitutions and rearrangements without departing from the spirit or essential attributes of the invention. Reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention. | A ceramic matrix composite article comprised of inorganic fibers having a mullite-containing coating disposed within a matrix phase. The invention also provides a method for mating such an article, as well as for preparing a fiber having a mullite-containing coating. The mullite-containing coating on inorganic fibers within a matrix acts as a debonding coating, and the ceramic matrix composite article exhibits high strength and fracture toughness, even at elevated temperatures. | 2 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) from U.S. Provisional Patent Application No. 60/879,710, filed on Jan. 10, 2007, which is incorporated herein by reference.
STATEMENT REGARDING SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
REFERENCE TO SEQUENCE LISTING
[0003] Not Applicable.
BACKGROUND OF THE INVENTION
[0004] 1. Field of the Invention
[0005] This invention relates generally to devices and methods for in vitro analysis of fluid flow (e.g., hemodynamics) on cells (e.g., endothelial cells). More specifically, this invention relates to a method of using a device that permits more than one different cell types to be physically separated within the culture dish environment, while the inner cellular surface is exposed to the simulated hemodynamic flow patterns.
[0006] 2. Description of Related Art
[0007] Atherosclerosis is a vascular inflammatory disease characterized by lesion formation and luminal narrowing of the arteries. Endothelial cell (EC) and smooth muscle cell (SMC) regional phenotypes have significant implications in the progression of vascular disease. During early atherogenesis, the endothelium becomes activated, leading to increased adhesion molecule expression, permeability to lipoproteins and cytokine generation. Such environmental changes can influence SMCs to undergo “phenotypic switching” characterized by morphological changes, increased proliferation and migration, and decreased expression of defining quiescent SMC markers.
[0008] Atherosclerosis is further characterized by its focal development in large arteries at hemodynamically defined regions, such as at bifurcations that produce complex flow patterns. Atheroprone regions, susceptible to plaque formation, are subjected to low time-averaged shear stress and “disturbed” oscillatory flow patterns. In contrast, atheroprotective regions, which are less susceptible to plaque formation, are exposed to relatively higher time averaged shear stress and pulsatile laminar flow (13, 39). In regions of chronic disturbed flow, changes in EC phenotype, such as increased adhesion molecule expression, (i.e., vascular cell adhesion molecule 1 (VCAM-1), intercellular adhersion moldule 1 (ICAM-1), e-Selectin), and transendothelial permeability to low density lipoproteins (LDL), will effect the local signaling environment and can alter SMC phenotype, leading to proliferation, migration and the pathogenesis of atherosclerosis.
[0009] The factors controlling changes in SMC phenotype involving EC's and hemodynamic flow patterns are not fully understood. However, a hallmark of SMC phenotype switching in atherosclerosis is the suppression of contractile proteins that define the differentiated SMC, including SMMHC, SMαA, and myocardin.
[0010] To understand the role of shear stress on the endothelium in atherogenesis, in vitro models that expose ECs to a variety of shear stress conditions have been extensively studied. Since ECs can discriminate variations in flow patterns and are sensitive to both shear stress magnitude and time-varying features of hemodynamics, emulating in vivo flow environments appears to have a greater impression on recapitulating the in vivo phenotype of the endothelium. Additionally, few studies have shown the intricate interactions and cross-communications of ECs and SMCs in the presence of any type of flow, and no known studies to date have examined how in vivo-derived human hemodynamic forces on the endothelium regulate SMC phenotypic switching, as it is classically defined by the literature.
SUMMARY OF THE INVENTION
[0011] An aspect of the invention is, but not limited thereto, an in vitro biomechanical model used to apply hemodynamic (i.e., blood flow) patterns modeled after the human circulation to human/animal cells in culture. This model replicates hemodynamic flow patterns that are measured directly from the human circulation using non-invasive magnetic resonance imaging and translated to the motor that controls the rotation of the cone. The cone is submerged in fluid (i.e., cell culture media) and brought into close proximity to the surface of the cells that are grown on the plate surface. The rotation of the cone transduces momentum on the fluid and creates time-varying shear stresses on the plate or cellular surface. This model most closely mimics the physiological hemodynamic forces imparted on endothelial cells (cell lining blood vessels) in vivo and overcomes previous flow devices limited in applying more simplified nonphysiological flow patterns.
[0012] Another aspect of this invention is directed to incorporate a commercially available transwell co-cultured dish, for example a 75 mm-diameter transwell. This permits two, three, or more different cell types to be physically separated within the culture dish environment, while the inner cellular surface is exposed to the simulated hemodynamic flow patterns. Other significant modifications include in-flow and out-flow tubing to supply media, drugs, etc. separately and independently to both the inner and outer chambers of the coculture model. External components are used to control for physiological temperature and gas concentration. The physical separation of adherent cells by the artificial transwell membrane and the bottom of the Petri dish permits each cell layer, or surface, to be separately isolated for an array of biological analyses (i.e., protein, gene, etc.).
[0013] The directed use of this invention includes 1) to study the cross-talk between human/animal endothelial and smooth muscle cells—two critical cell types that comprise the blood vessel wall and involved in the pathological development of atherosclerosis (heart disease, stroke, peripheral vascular disease) and other vascular diseases. 2) This model may also be used as a diagnostic model in testing novel drug-based therapies for toxicity, inflammation (e.g. monocyte adhesion, inflammatory cytokine release, inflammatory gene induction) and permeability.
[0014] Some exemplary novel aspects of various embodiments related to this invention include, but not limited thereto, the following, in no specific order:
[0015] The device can replicate with the highest level of fidelity the hemodynamic shear stress profiles in the arterial circulation susceptible to and protective of atherosclerosis and from patients susceptible to other physiological (e.g., exercise) or pathological conditions (e.g., hypertension, diabetes, dyslipidemia).
[0016] The device can replicate with the highest level of fidelity any type of measurable or idealistic shear stress profiles from the arterial, venous, or any organ circulation.
[0017] Exposure of the hemodynamic flow patterns on the inner surface of a transwell membrane, with or without another cell type cultured on the opposing side of the membrane.
[0018] Exposure of the hemodynamic flow patterns on the inner surface of a transwell membrane, with or without another cell type cultured on the bottom surface of the transwell dish.
[0019] Exposure of the hemodynamic flow patterns on the inner surface of a transwell membrane, with or without another cell type cultured on the opposing side of the membrane and with or without a third cell type cultured on the bottom surface of the transwell dish. The third cell may include monocytes or macrophages for inflammatory cell adhesion assays.
[0020] Exposure of the hemodynamic flow patterns on the inner surface of a transwell membrane, with or without another cell type cultured on the opposing side of the membrane and with or without a third cell type in suspension in the media of the inner surface of the transwell membrane.
[0021] Clamps mount on the sides of the transwell used to hold in place the inflow and out-flow tubing for both the inner (upper) chamber and outer (lower) chamber. This is used to perfuse in and out media, biochemical compounds agonist, antagonists, etc of the upper and/or lower chamber of the transwell separately without disturbing the flow environment. Media extracted from the experiment can be used to further test cytokine or humoral factor secretion from either layer.
[0022] The ability to isolate each cell type independently (one, two, or three different cell types used) from a single experiment for post-processing biological (proteomic/genomic) analyses, including gene arrays, proteomics.
[0023] The device can accept and test any cell type from any species that is adherent or nonadherent.
[0024] The device can be used as a vascular biomimetic cell culture model for investigating all phases from embryonic vascular development to the severe cases of atherosclerosis in adults. For example, endothelial cells may be plated in the inner surface and/or smooth muscle cells plated on the opposing side of the transwell membrane and/or macrophages (or leukocytes) in the upper or lower chamber.
[0025] The device can be used to test the compatibility, cellular adhesion, and phenotypic modulation of cells from vascular stent material under hemodynamic conditions. For example, endothelial and/or smooth muscle cells may be seeded next to, on top of, or underneath the material, mounted on the stationary surface of the device. Materials include but are not limited to metallic nanoporous metals, polymers, biodegradable polymers, carbon surfaces, scratched or etched surfaces.
[0026] The device can be used to test drug (i.e., compound) elution from vascular stent material under hemodynamic conditions in the presence or absence of cells.
[0027] The device can be used to test the compatibility, cellular adhesion, and phenotypic modulation of cells seeded on or adjacent to surfaces coated with polymeric material under hemodynamic conditions.
[0028] The device can be used as a vascular biomimetic cell culture model for the investigation of the blood-brain barrier. For example, endothelial cells may be plated in the inner surface and/or glial cells and/or astrocytes and/or neurons plated on the opposing side of the transwell membrane and/or the bottom Petri dish surface.
[0029] The device can be used as an airway biomimetic cell culture model for the investigation of the development and progression of asthma. For example, epithelial cells may be plated in the inner surface and/or smooth muscle cells plated on the opposing side of the transwell membrane and/or macrophages (or leukocytes) in the lower chamber. Rhythmic breathing patterns are emulated by the movements of the cone in close approximation to secrete and/or artificial mucosal layer between the cone and epithelial surface.
[0030] The device can be used as renal biomimetic model for the investigation endothelial cell and epithelial podocyte interaction.
[0031] The device can be used to create a specific humoral environment that mimics patient drug therapy and then determine compatibility of a known or unknown drug compound in conjunction with the patient drug therapy. For example, the device can be run for a specific time with the drug Lipitor in the media and then an unknown drug can be added to determine changes in toxicity, inflammation (e.g. monocyte adhesion, inflammatory cytokine release, inflammatory gene induction) and permeability.
[0032] The device can be used to determine functional changes in vascular cells or other organ cells types taken from patients with an identified genotype linked to drug toxicity or some pathophysiological endpoint. For example, endothelial cells from a patient with a single nucleotide polymorphism (SNP) identified to be associated with drug toxicity can be used to test novel or known compounds for changes in toxicity, inflammation (e.g. monocyte adhesion, inflammatory cytokine release, inflammatory gene induction) and permeability. This is commonly referred to as pharmacogenomics.
[0033] An embodiment of this invention is a method of applying hemodynamic patterns to cells in culture, said method comprising the steps of plating a first set of cells on a transwell, plating a second set of cells on said transwell, wherein said first set of cells are separated from said second set of cells, adding a fluid to said transwell; and causing rotation of said fluid for a period of time, wherein said medium thus exerts a shear force upon said second set of cells.
[0034] Another embodiment of this invention is a method of applying hemodynamic patterns to cells in culture, said method comprising the steps of monitoring the hemodynamic pattern of a subject; modeling said hemodynamic pattern into a set of electronic instructions; and using a device to cause a shear stress on a plurality of sets of cells on a transwell based upon said electronic instructions.
[0035] Another embodiment of this invention is a hemodynamic flow device, comprising an electronic controller; a motor, wherein said motor is operated via said electronic controller; a cone connected to said motor, whereby said cone is rotated by said motor; a transwell with a membrane, wherein said cone is at least partially submerged in a medium in said transwell and wherein said cone exerts a rotational force upon said medium; an inlet flow tube to add media to said transwell; and an outlet flow tube to withdraw media from said transwell.
BRIEF DESCRIPTION OF FIGURES
[0036] FIG. 1 provides an exemplary view of EC/SMC plating on a transwell;
[0037] FIG. 2 provides a view of the cone and plate flow device, modified to accommodate a Transwell culture dish;
[0038] FIG. 3 provides a graph displaying an exemplary hemodynamic flow pattern derived from an MRI of a the human common carotid artery (CCA) and internal carotid sinus (ICS). Also shown is such an exemplary MRI;
[0039] FIG. 4 shows exemplary confluent layers of ECs and SMCs twenty-four hours following EC seeding;
[0040] FIG. 5 shows exemplary transverse sections stained for F-actin and FM 4-64 or visualized by differential interference contrast showing cellular processes within membrane pores;
[0041] FIG. 6 shows exemplary immunofluorescence images of EC/SMC morphology and orientation;
[0042] FIG. 7 shows exemplary normalized histogram plots of shape factors (SF) for ECs and SMCs;
[0043] FIG. 8 shows average angles of direction for SMCs and ECs relative to the direction of atheroprotective flow (0°);
[0044] FIG. 9 shows orientation histograms of SMC direction (or angle) relative to the direction of flow;
[0045] FIG. 10 shows an exemplary graph demonstrating normalized gene expression;
[0046] FIG. 11 shows an exemplary graph of normalized mRNA expression;
[0047] FIG. 12 shows the results of an exemplary protein analysis;
[0048] FIG. 13 shows an exemplary graph of normalized mRNA expression;
[0049] FIG. 14 shows an exemplary graph of normalized mRNA expression;
[0050] FIG. 15 shows the results of an exemplary blot analysis;
[0051] FIG. 16 shows the results of an exemplary ELISA analysis for IL-8 performed on atheroprone and atheroprotective flow-conditioned media;
[0052] FIG. 17 shows an exemplary graph of normalized mRNA expression;
[0053] FIG. 18 shows an exemplary scanning electron micrograph of the surfaces of the membrane; and
[0054] FIG. 19 shows a graph of exemplary fold enrichment.
DETAILED DESCRIPTION OF THE INVENTION
[0055] Atherosclerosis.
[0056] Atherosclerosis preferentially develops at arterial regions, such as bifurcations and regions of high curvature, characterized by disturbed, low time averaged and oscillatory wall shear stress. Atheroprone regions in vivo and atheroprone shear stress on the endothelium in vitro can induce proinflammatory priming indicated by the activation and regulation of downstream inflammatory targets. Although ECs and SMCs are two major cell types known to undergo phenotypic modulation, or “switching,” during initiating atherosclerotic events, until this invention it was unknown whether hemodynamic forces on ECs regulated or contributed to this process in SMCs. Human-derived atheroprone shear stresses applied to ECs modulate a proinflammatory phenotype in ECs and SMCs and proatherogenic phenotypic switching in SMCs via epigenetic modifications at the chromatin level. This is a process referred to as mechanotranscriptional coupling.
[0057] Results from the present coculture process support the hypothesis that hemodynamics induce vascular EC and SMC priming toward a proatherogenic response, thus validating the use of the coculture system as a new physiologically relevant biomimetic vascular model for the study of early atherosclerotic events. These results are consistent with previously published atherosclerosis-related in vivo and in vitro flow studies (see FIG. 10 ). Moreover, previous Transwell cocultured models of ECs and SMCs have been restricted to statictype experiments, with the exception of a few flow studies, and no known studies have employed physiologically relevant, human-derived hemodynamic flow patterns. The present process overcomes these limitations by directly comparing two hemodynamic flow patterns, yielding a more physiologically relevant model for accurately comparing in vivo regions in the vasculature, and focused on classic SMC differentiation markers.
[0058] A hallmark of SMC phenotypic modulation in vascular disease is altered expression of genes that define the contractile phenotype. SMC differentiation markers and transcription factors that are delineators of a differentiated SMC are affected by atheroprone flow. The loss of expression of differentiation markers (SMαA and myocardin) and induction of the inflammatory marker VCAM-1 at both mRNA and protein levels confirmed that ECs exposed to atheroprone flow differentially regulate the SMC phenotype compared with atheroprotective flow. ChIP analysis revealed that the mechanism initiating atheroprone-induced loss of CArG-dependent SMC gene expression involved reduction of SRF binding to CArG box regions of SMαA and SMMHC and deacetylation of histone H4 compared with atheroprotective flow. This was not the case for the early growth response gene c-fos. These results are consistent with a monoculture SMC study in response to PDGF-BB treatment and, most importantly, the epigenetic fingerprint for SMαA, SMMHC, and c-fos in intact blood vessels in response to acute vascular injury. Thus, the general paradigm that histone H4 acetylation is critical for maintaining CArG chromatin promoter regions in a SRF-accessible state is differentially regulated by two distinct hemodynamic flow patterns exposed to ECs. The SRF coactivator myocardin plays a critical role in forming a higher-order complex with SRF for the positive regulation SMC selective CArG-dependent genes. In contrast, KLF4 can abrogate myocardin-dependent regulation of CArG-dependent SMC differentiation genes. Myocardin expression was significantly reduced in response to atheroprone flow, whereas KLF4 tended to have increased expression. Since KLF4 gene expression can be rapidly and transiently induced in response to PDGF-BB in cultured SMCs and transiently induced in intact vessels following acute vascular injury up to six hours and returning to baseline by twenty-four hours, it is possible that the maximal and most significant changes in KLF4 expression were not captured at this time point. Nevertheless, gene profiles generated in this study correlate with existing data from the literature, and, taken together, the results suggest that phenotypic modulation of SMCs exposed to atheroprone flow occurs at the transcriptional level and involves the well-characterized SRF/myocardin and KLF4 signaling axis.
[0059] Of interest, ECs exhibited reduced KLF4 expression in atheroprone flow. KLF4 has been shown to be regulated by flow in ECs in monoculture; however, it was previously not known that KLF4 is differentially expressed by atheroprone flow compared with atheroprotective flow. The functional significance of KLF4 in ECs has recently been shown to be similar to that of KLF2 (i.e., anti-inflammatory, atheroprotective, and hemostasis control). Moreover, KLF4 has been implicated in cell cycle regulation, and greater cell cycle activity has been reported for atheroprone relevant flow in vitro and regions in vivo. Thus, the regulation of KLF4 transcription may serve an equally vital role in regulating vascular EC and SMC proliferation. Furthermore, while myocardin has been shown to decrease with acute, mechanical vascular injury and KLF4 increases, this process provides evidence that these transcription factors are differentially regulated in a model that mimics early atherogenic events. Regulation in vivo in atherosclerosis is currently unknown.
[0060] Surprisingly, SMMHC was the only SMC marker that did not follow the expected modulation trends. This may be due to RT-PCR primer recognition of both SMMHC isoforms (SM-1 and SM-2). Analysis of each isoform separately may elucidate a response consistent with the other SMC markers. Analysis at later time points (i.e., forty-eight hours) may resolve this. The combined phenotypic responses of both ECs and SMCs in the presence of atheroprone flow are strikingly similar to historical EC and SMC phenotype profiles defined in human and experimental models of atherosclerosis ( FIG. 10 ).
[0061] Evaluation of EC gene expression in response to atheroprone relative to atheroprotective flow is consistent with the only EC monoculture study using similar flow profiles as well as studies using similar magnitudes of steady shear stress and in vivo models of atherosclerosis, emphasizing that hemodynamics more robustly regulate the EC phenotype than the presence of SMCs. ECs exposed to twenty-four hours of atheroprone flow induced higher levels of proatherogenic and proliferative genes and proteins for IL-8, VCAM-1, and PCNA commensurate with reductions in eNOS, Tie2, and KLF2. The expression loss of eNOS and Tie2 suggests higher rates of remodeling and increased permeability, characteristic features of atherosusceptible regions in vivo. Evidence has established the role of KLF2, and possibly KLF4, as an upstream transcriptional regulator of atheroprotection. Atheroprotective hemodynamics in vitro and regions in vivo appear to be a key modulator of KLF2 expression and transcriptional control. SMCs also exhibited an early inflammatory response to atheroprone flow, as indicated by increased VCAM-1 mRNA levels. VCAM-1 modulation has been observed in SMCs of human atherosclerotic plaques and has been linked to proliferation during early atherogenesis in vitro and in vivo. However, since the proliferative marker PCNA showed no change in SMCs for atheroprone flow, it is possible that a more migratory SMC phenotype is present in this system.
[0062] The EC-secreted cytokine(s)/mitogen(s) that regulates SMC phenotypic modulation during early atherogenesis has yet to be elucidated and includes candidates such as PDGF-BB, IL-1, and IL-8. Here, we show ECs increase IL-8 mRNA production and IL-8 secretion following atheroprone flow. Indeed, IL-8 can stimulate the induction of a migratory phenotype in SMCs. Therefore, IL-8 secretion by ECs may be one mechanism by which SMCs regulate a more synthetic phenotype. Of interest, a recent study in apolipoprotein E −/− mice showed that experimentally induced low shear stress resulted in an increase in growth-related protein (Gro)-α mRNA. However, given the in vivo nature of this study, it was not determined whether changes in Gro-α mRNA were in ECs, SMCs, or both. Although Gro-α binds the same receptors as IL-8, no murine homolog of IL-8 exists. The human coculture model is therefore ideal for examining the role of EC-derived IL-8 on SMCs, and future studies are ongoing to establish the relative contributions of such cross-communication mechanisms.
[0063] Cell morphology changes observed in atheroprone versus atheroprotective flow were also signs of early remodeling that could lead to localized downstream atherogenic responses. ECs are known to reorient in the direction of flow under pulsatile physiologic conditions and maintain a more polygonal shape after exposure to disturbed flow, as observed in our system. However, our understanding of SMC reorientation due to shear stress sensed by the endothelium is in its earliest stages. SMCs orient more perpendicular to hemodynamic flow under the atheroprotective waveform, whereas SMCs exposed to atheroprone flow resulted in more random alignment. Importantly, this SMC orientation is nearly identical to the spatial patterning of SMCs in an intact blood vessel at bifurcating regions, regions highly susceptible to atherosclerosis. Together, this suggests that hemodynamic flow can regulate both EC and SMC orientation by unique control mechanisms inherent to distinct atheroprone or atheroprotective flow patterns.
[0064] This inventions presents a novel in vitro coculture model using human ECs and SMCs that shows that human hemodynamic forces, atheroprotective or atheroprone, applied directly to the endothelium can modulate the SMC phenotype and influence SMC remodeling, a process we defined as mechanotranscriptional coupling. Moreover, the snapshot of phenotypic and morphologic alterations in ECs and SMCs indicates that hemodynamic forces on the endothelium are an important modulator of atherogenesis.
[0065] As shown in FIG. 1 , a transwell 100 is used in the hemodynamic flow process. The transwell allows multiple cells 110 , 120 to be tested in parallel and also provides a porous interface. An exemplary process for plating to coculture is also shown; however, this process may be altered by processes available to one skilled in the art. In this embodiment, SMCs 110 are plated at an initial time, after which the transwell is inverted. The SMCs 110 are incubated for twenty-four to forty-eight hours, after which ECs 120 are plated on the transwell and incubated. The bottom of the Petri dish for which the transwell is inserted may also serve as a third surface to plate an additional cell type or the same cell type as ones plated directly in the transwell membrane 170 .
[0066] As shown in FIG. 2 , a motor and cone device 200 is used to apply the shear forces upon the cells. A motor 230 causes the cone 240 to rotate at a precise rotational velocity, and can effect the rotation in either direction (i.e. clockwise or counterclockwise). This rotational force is applied to a liquid medium by the cone. In turn, this medium applies shear forces directly to the cells 260 on the transwell membrane 270 . Software is programmed to control the continuous motion of the cone. This software file is uploaded to a motor controller unit, and the information is then sent directly to the motor to perform the programmed task.
[0067] In a preferred embodiment, the medium is a cell culture broth that is formulated to sustain the integrity and health of the cells during the experiment. The formulation is not limited and may vary depending on the cell types being use and experimental study. Additionally, drug compounds may be a part of this formulation either initially, or perfused into the cell culture environment during the course of a flow experiment. This may include, but is not limited to compound that can inhibit, activate or alter the function of proteins/genes in the cells.
[0068] In one embodiment, the device can be used to test the compatibility, cellular adhesion, and phenotypic modulation of cells from vascular stent material under hemodynamic conditions. For example endothelial and/or smooth muscle cells seeded next to, on top of, or underneath the material, mounted on the stationary surface of the device. Materials include but are not limited to metallic nanoporous metals, polymers, biodegradable polymers, carbon surfaces, scratched or etched surfaces. These materials further include, non-degradable polymer or co-polymer, such as polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate, and can be coated onto the transwell surface. These materials further include biodegradable polymer or co-polymer, such as polylactic acid glycolic acid (PLGA) or phosphorylcholine, and can be coated onto the transwell surface. These materials further include nanoporous surface modification, such as a ceramic, metal or other material and can be added to the transwell surface as a nanoporus surface modification. These materials further include microporous surface modification, such as a ceramic, metal, physical etching (such as sand blasting) or other material added to the transwell surface to form a microporous surface modification.
[0069] In another embodiment of this invention, the device can operate with cells plated on either one or both sides of the transwell membrane. The membrane portion of the transwell membrane can comprise any biological or synthetic material, with a range of porosities and thicknesses. Similarly, the structure that holds and supports the transwell membrane can be made of any synthetic material.
EXAMPLE
[0070] The following is an example of a method of using the present invention, and is not intended to limit the scope of the invention to the exact method described in this example.
[0071] Human Cell Isolation and Culture.
[0072] Primary human ECs and SMCs were isolated from umbilical cords, expanded, and used as cell sources. Human ECs were isolated from the umbilical vein (human umbilical vein ECs) as previously described, followed by isolation of SMCs from the vein using a similar method as previously described.
[0073] ECs were used for experimentation at passage 2 and SMCs were for experimentation used up to passage 10 , both of which have been established to retain the basal EC/SMC phenotype based on the retention of specific EC and SMC markers. Cell types were separately cultured and passaged using medium 199 (M199; BioWhitaker) supplemented with 10% FBS (GIBCO), 2 mM L-glutamine (BioWhitaker), growth factors [10 μg/ml heparin, (Sigma), 5 μg/ml endothelial cell growth supplement (Sigma), and 100 U/ml penicillin-streptomycin (GIBCO)].
[0074] Transwell Coculture Plating Conditions.
[0075] As shown in FIG. 1 , porous Transwell membranes (polycarbonate, 10 μm thickness and 0.4 μm pore diameter, no. 3419, Corning) were initially coated with 0.1% gelatin on the top and bottom surfaces. The Transwell was inverted, and SMCs were plated at a density of 10,000 cells/cm 2 on the bottom surface for 2 h. The Transwell was then turned back over into the holding well for forth-eight hours in reduced serum growth medium (M199 supplemented with 2% FBS, 2 mM L-glutamine, and 100 U/ml penicillin-streptomycin). ECs were then plated on the top surface of the membrane at a density of 80,000 cells/cm 2 under the same media conditions for an additional twenty-four hours. For hemodynamic flow experiments, two dishes were prepared in parallel.
[0076] Coculture Hemodynamicflow Device and Flow Patterns.
[0077] As shown in FIG. 2 , the novel coculture in vitro model of this process uses arterial flow patterns modeled from the human circulation were applied to human ECs. A version of the cone and plate device is a direct drive, whereby the cone is directly driven by the motor (rather than off to one side through a timing belt connection). This model was modified to incorporate a 75-mm-diameter Transwell coculture dish (polycarbonate, 10 μm thickness and 0.4 μm pore diameter, Coming). Additional modifications included a base to securely hold the Transwell dish, a smaller cone (71.4 mm diameter and 1° cone angle) to fit inside the Transwell compartment, and special mounting brackets for in-flow and out-flow tubing for both the inner and outer chambers of the Transwell, which provides direct access to the culture fluid environment to continuously exchange media to both EC and SMC layers. Through the rotation of the cone, the system imposes hemodynamic shear stress on the EC layer of the EC/SMC coculture.
[0078] Hemodynamic flow patterns used in this process were derived from MRI of the human common carotid artery (CCA) and internal carotid sinus (ICS) to best simulate atheroprotective (CCA) and atheroprone (ICS) shear stress patterns in vitro, respectively. The two hemodynamic flow conditions were run in parallel for each EC/SMC subpopulation. FIG. 3 shows human hemodynamic flow profiles (left) from the common carotid (CCA; atheroprotective, right, 310 ) and internal carotid sinus (ICS; atheroprone, 320 ) were imposed on the EC surface of the Transwell.
[0079] Real-time RT-PCR.
[0080] After the application of hemodynamic flow patterns for twenty-four hours, SMCs and ECs were rinsed two times in PBS with Ca 2+ /Mg 2+ . The membrane was removed from the holding dish and inverted. SMCs were gently scraped toward the center of the dish with small flexible cell scrapers. Cells were then rinsed onto a sterile surface using 1 ml PBS, which was then transferred to a microcentrifuge tube on ice. The membrane was turned over and placed flat on a sterile surface, and ECs were scraped in 1 ml PBS and then transferred to a separate microcentrifuge tube on ice. Tubes were centrifuged, and PBS was removed. Total RNA was extracted using TRIzol reagent (Invitrogen) and reverse transcribed using the iScript cDNA Synthesis Kit (Bio-Rad). Primers were designed using Beacon Designer 2.0 for smooth muscle α-actin (SMαA), myocardin, smooth muscle myosin heavy chain (SMMHC), VCAM-1, monocyte chemoattractant protein-1 (MCP-1), endothelial nitric oxide synthase (eNOS), angiopoiten receptor Tie2, IL-8, and Kruppel-like transcription factors (KLF2 and KLF4). Table 1 shows sense and antisense primers used for each human gene. The expression of mRNA was analyzed via real-time RT-PCR using AmpliTaq Gold (Applied Biosystems), SYBR green (Invitrogen), and an iCycler (Bio-Rad).
[0000]
TABLE 1
RT-PCR primers designed for gene and ChIP analyses
Sense Primer
Antisense Primer
Real-time RT-PCR primers
β 2 -Microglobulin
5′-AGCATTCGGGCCGAGATGTCT-3′
5′-CTGCTGGATGACGTGAGTAAACCT-3′
eNOS
5′-CTCCATTAAGAGGAGCGGCTC-3′
5′-CTAAGCTGGTAGGTGCCTGTG-3′
IL-8
5′-CATGACTTCCAAGCTGGCCG-3′
5′-TTTATGAATTCTCAGCCCTC-3′
KLF2
5′-GCACCGCCACTCACACCTG-3′
5′-CCGCAGCCGTCCCAGTTG-3′
KLF4
5′-GGCCAGAATTGGACCCGGTGTAC-3′
5′-GCTGCCTTTGCTGACGCTGATGA-3′
MCP-1
5′-CCAGCAGCAAGTGTCCCAAAG-3′
5′-TGCTTGTCCAGGTGGTCCATG-3′
Myocardin
5′-TGCAGCTCCAAATCCTCAGC-3′
5′-TCAGTGGCGTTGAAGAAGAGTT-3′
SMαA
5′-CACTGTCAGGAATCCTGTGA-3′
5′-CAAAGCCGGCCTTACAGA-3′
SMMHC
5′-AGATGGTTCTGAGGAGGAAACG-3′
5′-AAAACTGTAGAAAGTTGCTTATTCACT-3′
Tle2
5′-CCGTTAATCACTATGAGGCTTGGC-3′
5′-GTGAAGCGTCTCACAGGTCCA-3′
VCAM-1
5′-GTTTGTCAGGCTAAGTTACATATTGATGA-3′
5′-GGGCAACATTGACATAAAGTGTTT-3′
ChIP analysis primers
SMαA, 5′-CArG
5′-AGCAGAACAGAGGAATGCAGTGGAAGAGAC-3′
5′-CCTCCCACTCGCCTCCCAAACAAGGAGC-3′
SMMHC. 5′-CArG
5′-CTGCGCGGGACCATATTTAGTCAGGGGGAG-3′
5′-CTGGGCGGGAGACAACCCAAAAAGGCCAGG-3′
c-fos
5′-CCCGCACTGCACCCTCGGTG-3′
5′-TACAGGGAAAGGCCGTGGAAACCTG-3′
ChIP. chromatin immunoprecipitation; eNOS, endothelial nitric oxide synthase; KLF, Kruppel-like factor. MCP, monocyte chemoattractant protein: SMαA, smooth muscle α-actin: SMMHC, smooth muscle myosin heavy chain; CArG, CC(A/T) 6 GG.
[0081] Western Blot Analysis.
[0082] Vascular SMCs and ECs were collected as described in Real-time PCR and lysed in RIPA buffer (1% Nonidet P-40, Na-deoxycholate, 1 mM EDTA, 1 mM PMSF, 1 mM Na3VO4, 1 mM NaF, 1 μg/ml aprotinin, 1 μg/ml leupeptin, and 1 μg/ml pepstatin). Total protein lysates were resolved on a 7.5% SDS-PAGE gel and blotted on a polyvinyl derivative membrane. Primary antibodies [SMαA (Sigma, 1:1,000), eNOS (BD Transduction Laboratories, 0.1 μg/ml), VCAM-1 (R&D Systems, 1:500), and PCNA (Cell Signaling, 1:1,000)] were incubated with the blot for one hour at room temperature or overnight at 4° C. Horseradish peroxidase-conjugated secondary antibodies [goat anti-rabbit, goat anti-mouse (Santa Cruz Biotechnology, 1:5,000), and donkey anti-goat (1:5,000)] were incubated with the blot for one hour at room temperature. An Alphalmager 8900 and AlphaEaseFC software were used for acquisition of blot image and densitometry analysis, respectively.
[0083] ELISA.
[0084] Cocultured Transwells were prepared and exposed to differential hemodynamic environments. Media perfused throughout the flow experiment were collected on ice after 4, 8, 12, and 24 h for each chamber of the membrane (i.e., EC- and SMC-conditioned media from atheroprone and atheroprotective flows). Samples were then stored at −80° C. until they were assayed for IL-8 secreted protein via ELISA (GE Healthcare). The concentration of protein was determined using a spectrophometer at 450 nm and normalized to the volume of media collected per hour.
[0085] Chromatin Immunoprecipitation Assay.
[0086] After the application of flow patterns, chromatin immunoprecipitation (ChIP) was performed as previously described with modifications allowing for a quantitative analysis of protein:DNA interactions (30). Outflow media from each experiment were supplemented with 1% formaldehyde and then incubated with cells for 10 min immediately following 24 h of flow. Antibodies included rabbit polyclonal anti-serum response factor (SRF; Santa Cruz Biotechnology, 5 μg/ml) and anti-histone H4 acetylation (Upstate Biotechnologies, 5 μg/ml). Recovered DNA was quantified by fluorescence with picogreen reagent (Molecular Probes) according to the manufacturer's recommendations. Real-time PCR was performed on 1 ng genomic DNA from ChIP experiments with minor modifications as previously described. Real-time PCR primers were designed to flank the 5′-CC(a/T) 6 GG (CArG) elements of SMaA, SMMHC, c-fos CArG. Table 1 shows the primers used for ChIP analysis. Quantification of protein:DNA interaction/enrichment was determined by the following equation: 2 (C t Ref -C t IP )−2 (C t Ref -C t No antibody control ), where C t Ref is the reference threshold cycle (C t ) and C t Ip is the C t of the immunoprecipitate. ChIP data are representative of five to six independent experiments pooled together and analyzed in duplicate.
[0087] Immunofluorescence.
[0088] For immunofluorescence (IF), Transwell membranes were fixed in 4% paraformaldehyde for both en face preparations and transverse sections. En face preparations were permeabilized in 0.2% Triton X-100. Primary antibody for SMCs was pipetted onto a piece of parafilm [Cy3-SMαA (Sigma, 4 μg/ml) and SMMHC (Biomedical Technologies, 1:100)], and the sample well was placed on top. Primary antibody for ECs [vascular endothelial cadherin (VE-cad; Santa Cruz Biotechnology, 2 μg/ml)] was then added directly to the inside of the well, and both antibodies were simultaneously incubated for one hour. Similarly, secondary antibodies [Cy2 donkey anti-goat (Jackson ImmunoResearch, 4 μg/ml) and Alexa fluor546 goat anti-rabbit (Molecular Probes, 6 μg/ml)] were added to samples as required and incubated for 1 h. Samples were mounted by adding Prolong Gold Antifade Reagent with 4′,6-diamidino-2-phenylindole (DAPI; Molecular Probes) to a large coverslip and dropping the well on top. Another drop of DAPI was added to the inside of the well, and a 22-mm-diameter coverslip was placed on top and allowed to solidify. The holding well was removed from the mounted samples using a scalpel to allow for imaging. Confocal microscopy was used to image en face samples through the z-axis from the EC to SMC layer (Nikon Eclipse Microscope TE2000-E2 and Melles Griot Argon Ion Laser System no. 35-IMA-840).
[0089] To prepare the transverse sections, EC/SMC cultures were stained with phalloidin-488 (Molecular Probes) or FM 4-64FX (Molecular Probes) using the methodology described above, immersed in 30% sucrose overnight, frozen in OCT compound, sliced into 5-μm-thick sections with a cryostat, and then mounted for assessment by confocal microscopy. IF stained samples were analyzed using a confocal microscope and differential interference contrast for cell-to-cell interactions within the pores of the Transwell membrane under static conditions, as previously described.
[0090] EC/SMC Orientation and Morphometric Measurements.
[0091] The orientation of ECs and SMCs relative to the direction of flow was quantified using confocal microscopy of IF stained samples. Following hemodynamic flow, the coculture was fixed as described above, and isosceles triangular samples from the 75-mm-diameter dishes were cut with the apex of the triangle pointing toward the center of the dish. This method established the correct orientation relative to the direction of flow. Samples were then stained as described above and mounted between two coverslips. For imaging, samples were oriented on the confocal stage with the triangle apex facing to the right, so that the direction of flow was consistent across all samples. Images were taken of ECs and SMCs in the same location, separated only by the membrane distance.
[0092] At least three microscopy fields were acquired over three independent experiments. MetaMorph software was used to determine the angle of orientation and shape factor (SF) for each cell analyzed relative to the direction of flow. To determine the elongation of cell types, borders stained for VE-cad ( FIG. 2A ) and β-catenin (not shown) of ECs (CCA: n=111 and ICS: n=53) and SMαA ( FIG. 2A ), SMMHC, and β-catenin (not shown) of SMCs (CCA: n=64 and ICS: n=25) were outlined, and measurements of the area and perimeter were outputted. SF was calculated using the following equation: SF=(4πA)/P 2 , where A is the cell area and P is the perimeter. For each SF bin in the histogram range, the number of cells per bin was normalized to the total number of cells analyzed over the whole range to yield a normalized frequency. Histograms were plotted to show the distribution of SFs for each condition (see FIG. 4B ). For the angle of orientation, lines were drawn in both the direction of flow and along the long axis of the SMCs from both flow patterns (CCA: n=119 and ICS: n=104) and ECs for atheroprotective flow only (CCA: n=124). The angle between the two lines was measured as the orientation angle relative to the flow direction, and histograms were plotted so that the frequency of cells having the same orientation was represented as the bar length.
[0093] Data Analysis and Statistics.
[0094] Real-time RT-PCR results are reported as the fold induction of cycle amplification times for atheroprone flow samples compared with atheroprotective flow and normalized to endogenously expressed gene β 2 -microglobulin. Student's t-test was conducted for mRNA, orientation, and elongation data to determine the significance in expression level or morphological changes as a function of hemodynamic flow pattern and time. Data from at least three independent experiments per condition were used for analysis and evaluated at P<0.05.
EXEMPLARY RESULTS
[0095] Optimization of EC/SMC Coculture Plating and Growth Conditions.
[0096] Coculture conditions for human EC and SMC plating were optimized so that each cell type reached confluence prior to the application of hemodynamic flow. FIG. 4 shows confluent layers of ECs and SMCs twenty-four hours following EC seeding More specifically, FIG. 4 shows ECs (left) and SMCs (right) cocultured for twenty-four hours showing confluency status (Top, en face images; bottom, transverse section). ECs retained their classic polygonal morphology, forming adheren junctions, as demonstrated by the continuous peripheral staining of VE-cad, whereas SMCs were elongated and randomly oriented in the typical “hill and valley” formation. In SMCs plated alone, reduced serum media (2% FBS compared with 10% FBS) increased the mRNA expression of SMC markers SMαA and myocardin, indicating a more differentiated SMC phenotype (normalized gene expression with 2% FBS: SMA, 2.51±0.36 and myocardin, 2.07±0.05; with 10% FBS: SMA, 0.69±0.23 and myocardin, 0.54±0.14; see FIG. 9 ).
[0097] A murine coculture model has recently demonstrated that ECs and SMCs physically interact and communicate via gap junctions through linear pores of the Transwell membrane. This model emulates myoendothelial junctions present within the vascular wall in vivo, creating a means for ionic communication via gap junctions and physical heterocellular adhesion. To determine whether EC/SMC physical interactions are formed in our human coculture model, transverse sections of the Transwell membrane were IF labeled for F-actin or FM 4-64FX and analyzed using confocal and phase contrast microscopy. The results shown in FIG. 5 demonstrate that cellular processes are present in the pores, establishing heterocellular interactions. Transverse sections are stained for F-actin (top) and FM 4-64 (middle) or visualized by differential interference contrast (bottom) and showed cellular processes within membrane pores 510 , 520 , 530 . Shown are representative images from three independent experiments. Bars on en face images equal 50 μm; bars on transverse sections equal 10 μm.
[0098] EC/SMC Morphological Remodeling is Altered in Atheroprone Flow.
[0099] The morphology of ECs and SMCs in vivo is highly ordered, with ECs being elongated and aligned with the direction of hemodynamic flow and SMCs oriented perpendicular to the long axis of the artery and direction of blood flow. However, the endothelium in regions of complex flow, such as in arterial bifurcations, is more polygonal and less aligned, and SMCs do not consistently align perpendicular to flow. To determine whether hemodynamic flow on the endothelium induces morphological changes to ECs and SMCs, the following SF measurements for both cell types were determined: 1) alterations in elongation and 2) orientation angle measurements relative to the direction of flow. Significant differences in both cell shape (SF) and cell orientation were observed after the application of atheroprone flow compared with atheroprotective flow as shown in FIGS. 6-8 . SF indicates the extent of cellular elongation, where a value of 1 specifies a circle (i.e., no elongation) and a value closer to 0 specifies an elongated cell. Representative IF images are shown in FIG. 6 . As previously established, ECs exposed to atheroprone flow maintained a more polygonal shape (SF=0.75±0.002), whereas ECs under atheroprotective conditions were more elongated (SF=0.64±0.015). EC/SMC morphology and orientation were determined by immunofluorescence following flow. ECs were stained for vascular endothelial cadherin (VE-cadherin) and SMCs were stained for smooth muscle α-actin (SMαA). The arrow in FIG. 6 indicates the direction of net flow and the bars equal 50 μm.
[0100] FIG. 7 shows the distribution of EC SF normalized to the number of cells analyzed. The alignment of ECs coincided with the direction of flow when exposed to atheroprotective flow (angle relative to flow=8.6±4.01°; FIG. 8 ), whereas no preferential polarity of ECs under atheroprone flow could be measured due to the rounded morphology.
[0101] SMCs on the Transwell exposed to atheroprone flow showed a significant but small increase in elongation (SF=0.26±0.009) than those exposed to atheroprotective flow (SF=0.31±0.018; FIGS. 6 and 7 ). Interestingly, SMCs in atheroprotective flow consistently aligned more toward a perpendicular orientation relative to the direction of flow ( FIGS. 8 and 9 ), whereas, in contrast, SMCs under atheroprone conditions exhibited a more random, less coordinated orientation (−47.9±1.3° vs. −13.1±5.0°, respectively, P<0.0001). FIG. 6 shows representative images of SMC orientation relative to flow, and FIG. 9 shows the histogram distribution of SMC orientation.
[0102] Purity of RNA and Protein Isolation from ECs/SMCs Following Hemodynamic Flow.
[0103] The purity of collected RNA and protein from each cell layer following the flow experiment was assessed by real-time RT-PCR and Western blot analysis for the presence of EC-and SMC-specific proteins (eNOS and SMaA, respectively; FIG. 11 and FIG. 12 ). No cross-contamination at the mRNA or protein level was detectable.
[0104] FIG. 11 shows real-time RT-PCR on EC and SMC populations following twenty-four hours of atheroprotective flow. Both cell types expressed respective SMC and EC markers [SMαA and endothelial nitric oxide synthse (eNOS), respectively] after the isolation of each cell type. SMCs expressed significantly larger quantities of SMαA than ECs, and the EC expression of eNOS was significantly greater than that of SMCs after CCA flow, showing that the populations of cells analyzed for differential gene regulation were pure. Values are mean±SE; n=3;*P>0.05.
[0105] FIG. 12 shows protein analysis confirming that only SMCs express SMαA and only ECs express eNOS. IB, immunoblot analysis.
[0106] Atheroprone Flow Differentially Regulates EC and SMC Phenotypes and Promotes Pro Inflammatory Priming.
[0107] The major goal was to determine whether differential humanderived hemodynamic flow patterns applied to ECs influence SMC phenotypic modulation. Given this objective, changes in established markers indicating EC and SMC phenotypic modulation were examined twenty-four hours after the application of atheroprone or atheroprotective flow. Genes of interest were classified as EC- or SMC-specific cell markers (EC: eNOS, Tie2, and KLF2/KLF4; SMC: SMαA, SMMHC, and myocardin) or inflammatory markers (VCAM-1, IL-8, and MCP-1). Additionally, protein analysis was performed on a subset of markers (eNOS, SMαA, VCAM-1, and PCNA). Modulation of genes and proteins was determined by the relative change in atheroprone compared with atheroprotective flow.
[0108] Consistently, significant reductions in mRNA levels of EC quiescent markers eNOS, Tie2, KLF2, and KLF4 were observed in response to atheroprone flow ( FIG. 13 ), which was also confirmed by changes in protein levels of eNOS ( FIG. 15 ). Modulation of these EC markers has previously been demonstrated via shear stress stimuli relating to atherosclerosis; however, such a comprehensive examination of EC phenotype has never occurred in the presence of SMCs for hemodyanamic flow patterns.
[0109] Classic SMC differentiation markers have never before been analyzed for gene modulation in a coculture model exposed to any shear stress stimulus. Hallmarks of SMC phenotypic modulation associated with atherosclerosis included a decrease in genes defining the quiescent contractile phenotype (e.g., SMαA, SMMHC, and myocardin), an increase in genes associated with the synthetic phenotype (e.g., KLF4 and VCAM-1), and the initiation of proliferative and migratory events. In the presence of atheroprone flow, SMCs showed a significant reduction in SMC differentiation markers SMαA and myocardin ( FIG. 13 ). Protein analysis further confirmed this observation for SMαA ( FIG. 15 ). Although the transcription factor KLF4, which was recently discovered to be important in suppressing myocardin-dependent transcription, was not significantly induced (P=0.10) for atheroprone relative to atheroprotective flow, this trend may still point toward a mechanism of regulating SMC phenotypic switching. Since vascular injury maximally induced KLF4 after just 4 h, it is possible that at twenty-four hours of flow, the maximal response of KLF4 was missed. Notably, SMMHC was not significantly modulated (P=0.62).
[0110] Most interesting was that the reduction in EC quiescent markers and SMC contractile markers corresponded with the upregulation of several proinflammatory genes. VCAM-1 was significantly upregulated in both ECs and SMCs at both the mRNA and protein level ( FIGS. 14 and 15 ). A significant increase in IL-8, a proinflammatory gene downstream of NF-κB activation, was also observed in ECs at the mRNA level. Secretion of IL-8 from EC and SMC layers was further measured as a function of time during the application of both flow patterns and was only significantly augmented in ECs during later time points of atheroprone flow ( FIG. 16 ). In contrast, decreases in IL-8 and MCP-1 were concurrently observed in SMCs ( FIG. 14 ). Finally, analysis of the proliferative marker PCNA showed increased protein levels in ECs exposed to atheroprone flow but no change for SMCs ( FIG. 15 ).
[0111] To control for a flow-induced EC influence on the SMC response, SMCs were plated under two conditions in monoculture: 1) on the bottom of the Transwell holding dish in the presence of a Transwell membrane (SMC D) or 2) on the bottom of the Transwell membrane (SMC T), as shown in FIG. 17 . For each condition, flow was applied to the top of the Transwell membrane without ECs. Real-time RT-PCR analysis of samples showed that significant differences existed between each condition for SMαA and VCAM-1 but not for myocardin ( FIG. 17 ). VCAM-1 was the only gene appreciably inducted by atheroprone flow for both conditions. Potential confounding factors introduced for the SMC T condition were smooth muscle cellular processes that extruded through the porous membrane to the top of the Transwell where flow was being applied ( FIG. 18 ), which was not observed in the experiments with ECs present. The significant changes between each condition (SMC D vs. SMC T) indicate the sensitivity of SMCs to their local environment. Thus, for this study, comparison between the two distinct flow patterns applied in the presence of both cell types was the most robust method to control for all features (e.g., media exchange, experimental setup, time in culture, and heterocellular presence) of the hemodynamic coculture environment.
[0112] Arterial Hemodynamics Control Epigentic Regulation of SMC Gene Expression.
[0113] Many of the promoter regions of genes that encode SMC-selective contractile proteins contain CArG cis-regulatory elements that bind SRF, including SMαA and SMMHC. ChIP experiments were conducted to determine whether SRF binding and histone H4 acetylation in 5′-CArG promoter regions of the SMαA, SMMHC, and c-fos promoters were regulated at the epigentic level by hemodynamic flow. The results indicated a reduction of histone H4 acetylation and SRF binding in response to atheroprone flow relative to atheroprotective flow for SMαA and SMMHC ( FIG. 19 ). Conversely, histone H4 acetylation and SRF binding to the c-fos CArG region was not statistically different among flow conditions ( FIG. 19 ). This epigenetic fingerprint was identical to in vitro experiments in SMCs in response to PDGF-BB and in vivo in response to acute vascular injury.
[0114] Drugs
[0115] The drug may be selected from a group comprising actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine, and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, an anti-restenosis agent, an anti-thrombogenic agent, an antibiotic, an anti-platelet agent, an anti-clotting agent, an anti-inflammatory agent, an anti-neoplastic agent, an anti-hypertensive agent, a chelating agent, penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, a cholesterol lowering agent, a statin, an agent that raises HDL, a cyclyoxygenase inhibitor, Celebrex, Vioxx, a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments, antibodies, live cells, therapeutic drug delivery microspheres or microbeads, and any combinations thereof.
[0116] Additional advantages and modifications will readily occur to those skilled in the art. Therefore, the invention in its broader aspects is not limited to the specific details and representative embodiments shown and described herein. Accordingly, various modifications may be made without departing from the spirit or scope of the general invention concept as defined by the appended claims and their equivalents. | An in vitro biomechanical model used to applied hemodynamic (i.e., blood flow) patterns modeled after the human circulation to human/animal cells in culture. This model replicates hemodynamic flow patterns that are measured directly from the human circulation using non-invasive magnetic resonance imaging and translated to the motor that controls the rotation of the cone. The cone is submerged in fluid (i.e., cell culture media) and brought into close proximity to the surface of the cells that are grown on the plate surface. The rotation of the cone transduces momentum on the fluid and creates time-varying shear stresses on the plate or cellular surface. This model most closely mimics the physiological hemodynamic forces imparted on endothelial cells (cell lining blood vessels) in vivo and overcomes previous flow devices limited in applying more simplified nonphysiological flow patterns. Another aspect of this invention is directed to incorporate a transwell co-cultured dish. This permits two to three or more different cell types to be physically separated within the culture dish environment, while the inner cellular surface is exposed to the simulated hemodynamic flow patterns. Other significant modifications include custom in-flow and out-flow tubing to supply media, drugs, etc. separately and independently to both the inner and outer chambers of the coculture model. External components are used to control for physiological temperature and gas concentration. The physical separation of adherent cells by the artificial transwell membrane and the bottom of the Petri dish permits each cell layer, or surface to be separately isolated for an array of biological analyses (i.e., protein, gene, etc.). | 2 |
TECHNICAL FIELD
[0001] The present invention relates to the detection of unwanted defects in the geometry or surface finish of cylindrical cans or canisters. In particular, the present invention is concerned with the detection of unwanted indentations (dents) or protuberances on the surface of canisters used in medical devices such as metered dose inhalers (MDI).
BACKGROUND
[0002] Canisters used in MDI applications are manufactured to very high standards in terms of geometrical tolerances and surface finish. In an MDI application the quality of the canister must be close to perfect due to regulatory and customer requirements. Any minor defect leads to the canister with the defect being rejected or an entire batch being manually inspected.
[0003] MDI canisters are typically manufactured from aluminium or other light-weight materials. This makes MDI canisters prone to damage during conveying, filling and labelling.
[0004] A further complication is the speed with which canisters need to be processed and filled to meet customer demands whilst minimising manufacturing costs. Achieving the tolerances required by the medical industry at high manufacturing speeds presents significant technical barriers. For example, MDI canisters have extremely tight tolerances since any protuberance or dent of a significant size on the surface of the canister is regarded as an unacceptable cosmetic defect and may prevent the canister from being used in an inhalation device.
[0005] Whilst the manufacture of canisters is relatively common, preventing defects such as dents from occurring during handling is very difficult, particularly at high manufacturing speeds. Thus it is important that an accurate, fast and robust quality control system is used.
[0006] Conventional systems involve visual inspection of the canister. This may for example be an individual testing samples of canisters or by some form of automated visual assessment, such as video or still camera.
[0007] However conventional testing techniques are not highly accurate and either fail to detect damaged canisters or dramatically slow down the production lines as canisters are assessed.
[0008] The inventors have devised an alternative way to meet the strict requirements of the medical industry whilst allowing manufacturing speeds to be maintained. They have further devised a highly reliable apparatus which can be conveniently retrofitted to existing manufacturing lines.
SUMMARY
[0009] Particular aspects and embodiments are set out in accompanying claims.
[0010] According to a first aspect a dent detection apparatus for a canister is provided. In particular, a dent detection apparatus for an MDI canister is provided. The apparatus includes a conduit, wherein the width of the conduit is equal to the maximum allowable diameter of the canister; a transportation portion arranged to transport a canister through the conduit; and a rotation arrangement arranged to cause rotation of the canister as it is transported through the conduit.
[0011] Advantageously the width of the conduit is selected so as to correspond to the acceptable geometry of the canister. The rotation arrangement ensures that the canister is rotated within the conduit as it passes along the conduit. This allows defects in canisters to be detected as will be further described below.
[0012] It has been identified that an indentation in the side wall of a canister, such as an MDI canister, will cause some form of protuberance or projection extending from the outer wall of the canister. If the dent is very small, then the corresponding projection is also likely to be small. Small projections can be tolerated but at a certain defect tolerance the canister's cosmetic finish specification limit has been exceeded and the canister can no longer be safely used in an inhalation device.
[0013] A defect tolerance can thereby be determined below which the defect will not interfere with the functionality and use of the canister, or the aesthetic appearance of the canister before sale. The defect tolerance corresponds to the radial distance a defect extends beyond the outer radius of an undamaged canister. Put another way: the maximum allowable diameter of the canister at any point around the circumference is the nominal diameter plus the defect tolerance. If the diameter measurement at a particular location exceeds the maximum allowable diameter then the canister should be rejected.
[0014] According to the invention the geometry of the defect in combination with rotation of the canister can itself be used to identify defective canisters.
[0015] By defining the width of the conduit with respect to the desired defect tolerance the conduit (also herein termed channel) can be spaced such that a canister with a defect greater than the defect tolerance will engage in the channel and will not continue to rotate.
[0016] For example, if a canister has a diameter within the defect tolerance then it will continue to rotate within the channel. If the canister has a defect causing a projection which is dimensionally beyond the defect tolerance then as the canister rotates the projection will engage with one wall of the channel and the opposing side of the canister with the opposing side of the channel. Further rotation of the canister is thereby prevented.
[0017] The width of the conduit may be between 15 mm and 100 mm. One example width of the conduit is 21.5 mm. These widths correspond to the diameter of canisters used in metered dose inhalers such as asthma inhalers. The conduit may however be arranged so that the width can be adjusted to allow the apparatus to handle different diameter canisters and different tolerances.
[0018] The transportation portion may be a first conveyor belt. Using a conveyor belt is a quick and efficient way of transporting products and thus allows for high volumes of canisters to be moved through the apparatus and assessed for dents.
[0019] The rotation arrangement may include a first portion provided on an interior side surface of the conduit. The rotation arrangement may further include a second portion provided on an opposing interior side surface of the conduit to the first portion. At least one of the first and second portions of the rotation arrangement may be a second conveyor belt.
[0020] Conveyor belts advantageously provide a smooth and uninterrupted moving surface against which the canister may engage. This minimises the risk of damage occurring to the canisters as they pass through the conveyor. For example the conveyor belts themselves may be a rubber or other semi-flexible material.
[0021] Alternatively at least one of the first and second portions of the rotation arrangement may be a plurality of rollers.
[0022] In a further alternative at least one of the first and second portions of the rotation arrangement is a belt and pulley system. The pulleys may be in the form of two rollers one arranged at either end of the conduits with a flexible member looping around both rollers. The flexible member could be a single rubber band for example arranged such that it contacts the canisters on an inner wall of the conduit to effect the desired rotation. The band (or in another arrangement plurality of bands) may be recessed into grooves or channels formed in the inner wall of the conduit.
[0023] Thus a variety of different devices for rotating canisters may be used.
[0024] The apparatus may include a tapered portion provided at the entrance to the conduit. This can act as a funnel to help guide canisters into the conduit and ensure the canisters are aligned in single file.
[0025] The rotation arrangement may extend along an interior side surface of the tapered portion. This allows canisters to begin rotation before entry to the conduit which ensures canisters are already rotating on entering the channel which can increase efficiency and reduce the length of channel required.
[0026] Advantageously the rotation arrangement may be arranged to cause the canister to complete at least a 360 degree revolution within the conduit. The rotation arrangement may be arranged to cause the canister to complete at least a 420 degree revolution within the conduit. By providing that each canister is rotated through at least a complete revolution, the entire outer surface of the canister is checked for dents.
[0027] An indication that a defective canister is passing through the apparatus may be brought to the attention of the operator in a number of ways.
[0028] In one arrangement the width of the conduit is adapted such that a canister having a defect beyond an acceptable limit will be caused to engage with the conduit inner walls as it rotates and lock in position (jam) preventing any further movement along the conduits. In effect the defective canister is ‘captured’ in the conduit owing to its dimensions being greater than the dimensions of the conduit.
[0029] Alternatively the apparatus may further include a sensor configured to detect if a canister stops rotating within the conduit. This might be by means of a video camera with suitable image processing apparatus or by means of a physical sensor arranged to detect a lack of rotation of individual canisters.
[0030] Thus a defective canister may be efficiently detected.
[0031] The apparatus may further include a notification system configured to provide a notification when the sensor detects that a canister has stopped rotating within the conduit. By providing a notification, an operator is alerted to the fact that a dented canister has been identified. The canister can then be manually removed from the production line and thus only undented cans are permitted to pass.
[0032] The notification portion may include a visual device such as a display screen on which an alert is displayed or a light. The notification portion may include an audio device. Thus an operator can be immediately informed when a dented can is identified.
[0033] The notification portion may additionally or alternatively be adapted to operate a part of the conveyor which automatically removes the defective canister from the production line. For example a side wall of a production line conveyor may be provided with an opening into which a defective canister could be pushed by an actuator in response to a control signal from the notification portion. Thus, a canister could be automatically removed without interrupting the production line and/or requiring the intervention of an operator.
[0034] According to a further aspect, there is provided a method of detecting dents in a canister, in particular an MDI canister. The method includes the steps of moving a canister through a channel, wherein the width of the channel is dimensioned to be the maximum allowable diameter of the canister; rotating the canister whilst it is moved through the channel; detecting when a canister stops rotating within the channel; and providing a notification when a canister stops rotating within the channel. By dimensioning the width of the channel to be the maximum allowable diameter of the canister, any dented canisters will necessarily stop rotating within the channel and are thus detected by the detector. A notification is then provided thus allowing all dented canisters to be identified and removed.
[0035] Viewed from another aspect, there is provided an apparatus for detecting defects in canisters, in particular metered dose inhaler canisters, comprising: a channel, a rotator arranged to rotate a can located within the channel, a detector arranged to detect when a can ceases to rotate within the channel, and a communication portion arranged to communicate when a can ceases to rotate within the channel.
[0036] In such an arrangement the rotator is adapted such that a canister with a defect on its surface cannot be rotated by the rotator i.e. forced to rotate. This may for example be achieved by limiting the torque that the rotator can apply to the canister so as to allow a defective canister to be detected.
[0037] Thus an alternative arrangement of a dent detection apparatus is provided.
[0038] Viewed from a further aspect, there is provided a canister, in particular an MDI canister, dent detection apparatus comprising a pair of opposing surfaces defining a channel therebetween and being spaced apart by a predetermined distance; wherein the predetermined distance is equal to the outer diameter of a canister plus a defect tolerance.
[0039] In such an arrangement the channel itself is configured with respect to a defect being greater than an acceptable threshold (a defect tolerance). It will be recognised that a canister with a defect greater than the tolerance is likely to engage with a wall of the channel as it travels along the channel unless the defect is facing in a forwards or backwards direction with respect to the direction of the channel. In such a situation the defect may not engage with the channel wall.
[0040] Thus, advantageously one or both of the opposing surfaces may be adapted to cause a canister to rotate as the canister passes through the channel. One or both surfaces may include a movable portion adapted to cause rotation of a canister. The movable portion may be in the form of a belt, roller, band or conveyor integrated into a side surface and against which a canister may engage. A variety of different devices that cause rotation of the canister can therefore be utilised.
[0041] The opposing surfaces may have differing coefficients of friction so as to cause a canister to rotate. For example one of the opposing surfaces may have a higher coefficient of friction than the other. Thus rotation is achieved by the canister slipping against the surface with a lower coefficient of friction and being gripped by the surface with a higher coefficient of friction.
[0042] The predetermined distance between opposing surfaces may be selected such that a canister with a defect greater than a predetermined limit engages with one guide surface and an opposing side of the canister engages with the opposing guide surface thereby preventing the canister travelling along the channel.
[0043] A canister may be caused to rotate by at least one complete revolution as it passes along the channel. Thus the entire surface of the canister can be assessed to ensure compliance with the desired dimensional tolerance.
[0044] One or both surfaces may include a movable portion adapted to cause rotation of a canister. Thus a means for rotating the canister is provided.
[0045] Viewed from a further aspect, the present invention provides a method of manufacturing a plurality of metered dose inhalers comprising the steps of: providing a plurality of metered dose inhaler canisters; detecting canisters with dents within said plurality of metered dose inhaler canisters using a device, method, or the apparatus according to the previously disclosed aspects of the invention; discarding canisters with dents so detected; and assembling a plurality of metered dose inhalers using the remaining canisters. Assembling the plurality of metered dose inhalers will typically comprise inserting each canister into a metered dose inhaler actuator body.
[0046] Further feature combinations provided by the present teachings will be understood from the following detailed description and the accompanying figures.
DESCRIPTION OF DRAWINGS
[0047] The present teachings will now be described by way of example only with reference to the following figures in which like parts are depicted by like reference numerals:
[0048] FIG. 1 illustrates a dented canister;
[0049] FIG. 2 is an enlarged view of region A in FIG. 1 ;
[0050] FIG. 3 is a top view of a dent detection apparatus;
[0051] FIG. 4 is a schematic view of the dent detection apparatus of FIG. 3 ;
[0052] FIG. 5 is a flow diagram illustrating steps in an example process;
[0053] While the invention is susceptible to various modifications and alternative forms, specific embodiments are shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the drawings and detailed description of the specific embodiments are not intended to limit the invention to the particular forms disclosed. On the contrary, the invention is covering all modifications, equivalents and alternatives falling within the spirit and the scope of the present invention as defined by the appended claims.
DETAILED DESCRIPTION
[0054] FIG. 1 shows a metered dose inhaler canister. The inhaler canister comprises a cylindrical outer body with a generally smooth outer surface and a metering valve. The canister is formed of aluminium or another other suitable material.
[0055] In FIG. 1 the canister has been damaged and comprises an indentation A on a side wall of the canister. This may for example be caused in transportation or through the filling or labelling process. As discussed above the presence of indentations is undesirable in canisters in particular canisters which are inserted into inhaler devices.
[0056] FIG. 2 is an enlarged view of the indentation ( 2 a ) in the surface of a canister in cross-section.
[0057] A consistent feature of an unwanted indentation in a canister is a corresponding protrusion to the side wall of the can. This might for example be caused by the can striking a conveyor wall at an angle causing material to be deformed and an indentation and protrusion being formed. As shown in FIG. 2 the dent ( 2 a ) in a surface ( 1 a ) results in a corresponding protrusion ( 2 b ) adjacent to the indentation ( 2 a ). It is this property of an indentation that is exploited in the present disclosure in order to accurately detect dents in the circumferential surface of a canister.
[0058] FIG. 3 is a top view of a dent detection apparatus ( 100 ) according to the present disclosure. The apparatus is suitable for placing into production and conveyor lines at various stages of a metered dose inhaler process including conveying, filling and labelling. However, it is most suited for analysis of canisters before filling so as to prevent unnecessary filling of damaged canisters with medicament.
[0059] The dent detection apparatus ( 100 ) has a channel or conduit ( 12 ) through which canisters ( 1 ) are conveyed.
[0060] The channel ( 12 ) is formed of two parallel opposing surfaces separated by a distance w. Distance w is dimensioned to be the maximum acceptable diameter of the canisters ( 1 ).
[0061] In an example where the canisters ( 1 ) are for use in asthma inhalers distance w is 21.5 mm but may be between 15 mm and 100 mm.
[0062] However the skilled person will appreciate that the apparatus can be used for any sized canister by altering the width of the conduit according to the desired diameter of the canister. A particular sized canister can be used to set the width of the conduit and can be used to retest the apparatus at regular intervals to ensure the apparatus is still operating effectively.
[0063] Canisters may travel along conveyors in a production facility as wide flows of canisters more than 1 canister wide. Thus, the apparatus has a tapered portion ( 14 ) leading into the entrance to the conduit ( 12 ) in order to focus canisters towards the entrance of the conduit ( 12 ) and to bring the canisters into single file for assessment.
[0064] Alternatively or additionally canisters may travel along the conveyors in a production facility as a continuous line of touching cans. A mechanism may therefore be provided to separate the canisters prior to entry to the conduit such that each individual canister may be freely rotated.
[0065] In order to transport canisters ( 1 ) through the apparatus ( 100 ) a first conveyor belt is provided on the base of the conduit ( 12 ). This may be a conventional conveyor belt used in canister processing. Canisters ( 1 ) are placed on the conveyor belt and conveyed through the conduit ( 12 ).
[0066] The apparatus is configured such that as a canister ( 1 ) is carried through the conduit ( 12 ) it is rotated by at least 360 degrees. In one example each canister ( 1 ) completes 1.2 revolutions whilst passing through the conduit ( 12 ). In this manner every possible diameter of a canister ( 1 ) is compared to the width of the conduit ( 12 ) (which is the maximum acceptable diameter of a canister).
[0067] In order to rotate a canister ( 1 ) as it passes through the conduit ( 12 ), a second conveyor belt is provided on an interior side surface of the conduit. When a canister ( 1 ) enters the conduit it touches the second conveyor belt and is thereby rotated as it passes through the conduit ( 12 ). The second conveyor belt may be arranged to start at a position along the length of the interior side surface of the tapered portion ( 14 ). In effect the tapered channel may itself have a side wall that is moving relative to the base (the first) conveyor on which the canister is being conveyed. In such an arrangement as the canister moves along the tapered portion towards the conduit or channel it eventually makes contact with the second conveyor and is caused to rotate. Thus, a canister ( 1 ) can begin to be rotated before it enters the conduit ( 12 ). This allows the channel to be as short as possible in length.
[0068] The relative speeds of the base (first) and side (second) conveyors are selected to ensure the canisters each make a full revolution before they exit the channel. This ensures that any protrusion on an outer surface of a canister comes into contact with a side wall (to effect blockage of the channel) or sensor (to indicate a defective canister).
[0069] The conveyors may alternatively or additionally move in different directions.
[0070] In one example a third conveyor belt is provided on the opposing interior side surface of the conduit ( 12 ) to the second conveyor belt. The combination of the second and third conveyor belts is used to rotate a canister ( 1 ) as it passes through the conduit ( 12 ).
[0071] Due to the width of the conduit ( 12 ) being dimensioned to be the maximum allowable diameter of a canister ( 1 ), when a dented canister is rotated within the conduit ( 12 ) it will jam or become stuck in the conduit ( 12 ) since the protrusion adjacent to the dent results in the diameter of the canister at the protrusion being greater than the width of the conduit ( 12 ).
[0072] In order to prevent the dented canister ( 1 ) from permanently blocking the apparatus, a detector is provided along the length of the conduit ( 12 ) in order to detect any canister that has stopped rotating and is therefore jammed in the conduit ( 12 ). The jammed canister is a faulty canister since it has a diameter greater than maximum allowed diameter and therefore needs to be permanently removed from production.
[0073] FIG. 4 illustrates a schematic drawing of an in-vehicle apparatus according to the present example. The system of the present example includes a sensor ( 20 ) operable to detect when a canister has stopped rotating within the conduit.
[0074] In one example the sensor is a sensor arrangement formed from a plurality of retro reflective LED sensors placed along the length of the conduit. In operation when a canister passes the first sensor the system expects to see the canister pass the next sensor within a certain period of time. If the sensor does not detect the passage of the canister within the relevant time period then a notification is provided to the operator.
[0075] In an alternative example only a single sensor is used at the exit of the conduit. In this example the sensor detects canisters exiting the conduit. When no canister has been detected exiting the conduit for a certain period of time, a notification is provided to the operator informing them that a defective canister has been identified.
[0076] The sensor ( 20 ) is connected to an electronic control unit (ECU) which processes the detection results generated by the detector ( 20 ) and sends signals to a notification device in accordance with the results of the detector ( 20 ). The notification device may be a visual device such as a screen ( 21 ) or light located adjacent to the apparatus, or any other visual device capable of providing a visual notification to the user. The notification device may be an audio device operable to play a sound in order to provide a notification to the user. In one example both a visual and an audio device may be used in order to provide both visual and audio alerts to the user. In one example the notification device is a Man Machine Interface Display. The user on receiving the alert knows that a faulty canister has been detected and can remove the canister from production.
[0077] Although in the example illustrated a single conveyor belt is used to rotate canisters within the apparatus, other alternative arrangements can also be used. For example in one alternative a plurality of narrower conveyor belts may be provided on the interior of the conduit. In an alternative embodiment a series of rollers can be used to rotate the canisters.
[0078] In one particular embodiment rotation of canisters is achieved due to differing frictional properties of the two interior side surfaces of the channel. For example one interior side surface may have a high coefficient of friction whereas the other interior side surface may have a low coefficient of friction. This may for example be realised by applying a rubber strip or bead (or other suitable material) along the inner surface of one side of the channel. As the canisters travel along the channel one side engages with the bead and the canister is caused to roll and rotate by means of contact with the bead. This allows for a very simple construction and removes the need for a side conveyor arrangement. It has been identified that this embodiment may be useful for canister detection in technical fields outside the pharmaceutical environment.
[0079] Although the apparatus has been described as having a single sensor, in an alternative example a plurality of sensors arranged along the length of the conduit may be used.
[0080] Although the apparatus has been described as having a first conveyor belt, in an alternative embodiment the apparatus may be retrofitted to an existing conveyor belt on a production line and thus the apparatus itself does not include a first conveyor belt.
[0081] FIG. 5 illustrates a flow chart of steps carried out in this example. S 1 is a detection step during which it is detected whether a can has stopped rotating in the conduit. If it is detected that a can has stopped rotating in the conduit the method continues to step S 2 . If it is detected that the canister keeps moving through the conduit then the method returns to the start.
[0082] S 2 is a notification step during which notification is provided that a canister has stopped rotating within the conduit. The notification may be a visual and/or audio notification and may be provided using the visual and/or audio devices of the apparatus. Once the notification has been provided the method ends.
[0083] Thus there has now been described an example of an apparatus and method whereby a detection of a dented canister can be made and a notification provided to the user of the apparatus so that the dented can may be removed from production. | The present disclosure is in the technical field of dent detection in canisters. Accurate and consistent detection of dents in canisters has been a problem in the industry for some time. The present disclosure describes an apparatus and method that addresses this technical problem in a repeatable and easily implemented manner. There is provided a dent detection apparatus including a conduit dimensioned to be the maximum allowable diameter of a canister, a transportation portion for transporting a canister through the conduit and a rotation portion for rotating the canister as it passes through the conduit. A sensor detects when a canister stops rotating and gets stuck in the conduit and alerts the user. Thus faulty canisters can be detected and removed from production. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the invention
The invention relates to electrostatic painting apparatus comprising: a support which is movable at high speed through the intermediary of a least one drive member and which carries a pneumatic sprayer with a nozzle supplied with paint and pressurized gas through pneumatic valve means and means for electrostatically charging the sprayed jet, raised to a high voltage; a paint feed assembly controlled by air pressure and comprising a paint pressure regulator and a discharge valve; gas pressure regulating means for the sprayer and the pressure regulator, electrically controlled; electrically controlled pneumatic valves for controlling the discharge valve of the feed assembly and the valve means of the regulator; and programmed logic means adapted to define operating sequences.
2. Description of the prior art
Pneumatic sprayers are usually of two types designated round jet and flat jet. Round jet sprayers, utilized primarily for painting objects featuring openings, generally comprise a paint nozzle on the axis of a sprayer chamber into which open two pressurized gas distributors, the first of which is axial and causes the actual spraying and the second of which is tangential to generate a vortex.
Flat jet sprayers are designed primarily for painting large surfaces, such as automobile bodies, and also comprise a paint nozzle and an axial first pressurized gas distributor which surrounds the nozzle and a second pressurized gas distributor with oblique passages converging towards the axis of the sprayed jet, from either side thereof, so as to flatten the jet.
Note that for both types of sprayer the axial first pressurized gas distributor primarily conditions the fineness of the spray whereas the second, which is oblique relative to the axis of the nozzle, primarily conditions the shape of the sprayed jet (vortex aperture or flattening of the jet).
Nevertheless, there are interractions between the pressure at which the paint is delivered to the nozzle, the pressure of the gas supplied to the first distributor and that to the second distributor, to determine the discharge rate of paint from the sprayer and the shape of the jet, for adequate spraying quality. It will be understood that since the quality of spraying is a condition with which compliance is mandatory, there correspond to a pair of output parameters (paint discharge rate and jet shape) which relate to with the part which is to be painted, three input parameters: the pressure at which paint is admitted to the nozzle, the pressure of the gas supplied to the first distributor and the pressure of the gas supplied to the second distributor. Where relatively small quantities of parts are to be painted, these parameters are adjusted by an operator. For larger quantities correspondences are defined between the output and input parameters and recorded in the form of algorithms by means of which the input parameters may be obtained by entering the required output parameters.
French Pat. No. 1,537,997 describes a sprayer in which the three input parameters are modified by manipulating a single member which adjusts conjointly the fluid passage cross-sections.
As has already been implied, electrostatic painting aparatus for mass production lines must be able to work at the same rate as the line and be adaptable to the specific conditions for painting parts. In particular, it must be possible to adjust the sprayer in mid-cycle to modify the shape of the jet, the paint discharge rate and possibly the high voltage (in the case of hollow parts, for example). Also, it must be possible to shut off and restart the sprayer during each cycle, implying on/off valve means controlling the admission of fluids to the nozzle. All these operations may be controled according to predefined operating sequences by a microprocessor-based process control computer.
Incidentally, these operations form part of more extensive operating sequences, including for example adjustments concerning the travel of the support over a guide, displacement speed and change of direction point, in particular. In certain cases, displacements of the guide must be added to that of the support, in order to accompany a moving part or to dip into a cavity, for example. If the support is mounted on a multiple axis robot, an arrangement which is currently in widespread use, the operating sequence encompasses control of the robot relative to these various axes. Note that movements of the sprayer, in correspondence with the operating conditions, govern the adjustments specific to the sprayer: paint discharge rate, jet shape, high voltage.
Painting apparatus for mass production lines also incorporates color change sub-sequences which are commanded between the cycles for painting two consecutive parts. The color change processes, known per se, involve rinsing with a solvent to avoid one color being polluted by the preceding color.
The various aspects of automation of electrostatic painting apparatus for mass production lines have often been considered separately, the interface units between the painting apparatus and the controlling computer being progressively added or substituted for less effective units on older apparatus. It has been realized that the general organization of painting apparatus should take into account the response times of these interface units, these times including transmission times over the connecting lines.
These times are determined by the speed of movement of the support which carries the sprayer. On a reciprocating carriage the displacement speed is usually around one meter per second. In reciprocating movement, direction changes involving accelerations of 10 ms -2 last 0.2 seconds. The sprayer adjustments must also be carried out in less than 0.2 seconds, representing a travel of 0.2 m. The time to output a digital control signal is expressed in microseconds; there is no problem from this point of view. Slaving the position of a fluid pressure adjusting member to an electrical control signal involves time constants on the order of one hundredth of a second, which is entirely acceptable. However, the transmission of a fluid pressure along a pipe is significantly slower, depending on the length and cross-section of the fluid passage.
With multiple axis robots, the tolerable adjustment times are at least as short as in the case of a reciprocating carriage.
In a similar manner, adjusting the high voltage applied to the members for electrostatically charging the jet involves a time constant which, broadly speaking, is defined by the impedance of the supply as seen by the charging members and the capacitance as seen by the supply. To give an idea of the orders of magnitude involved, to obtain in 0.1 seconds a voltage of 60 kilovolts with a supply producing 60 microamperes, the maximum capacitance is 100 picofarads. The self-capacitance of a shielded connecting cable rated at 60 kilovolts is routinely between 30 and 40 picofarads per meter.
If the support were made to carry all the electrically controlled adjuster devices and the pneumatically controlled actuator devices, in order to reduce the distance of these devices from the sprayer and the control time constants, the weight carried by the support would be incompatible with the accelerations which must be applied to it, unless the support, its guides and the drive means which actuate it were reinforced. Such reinforcing arrangements are inevitably costly and bulky, and are often of an illusory nature; when the weight of the active members becomes negligible in comparison with that of the accessory and supporting members, the gain resulting from such reinforcement is virtually all absorbed by the resulting increase in weight due to the reinforcement.
An object of the invention is a sprayer apparatus in which the weight carried by the mobile support is reduced to a minimum although the time to execute adjustments is compatible with carrying out the same while in operation.
SUMMARY OF THE INVENTION
In one aspect, the invention consists in an electrostatic painting apparatus comprising a drive member; a support which is adapted to be moved at high speed by the drive member; a sprayer which is carried by the support and which comprises a paint sprayer nozzle and two distributors adapted to be supplied with pressurized gas, a first of which is substantially coaxial with the apparatus and the second of which is oblique relative to the axis of the apparatus, and which are adapted to cooperate with one another to form a shaped paint jet, pneumatic valve means for the fluids supplied to the nozzle and means for electrostatically charging the sprayed jet; a paint feed assembly which is juxtaposed to the sprayer and which comprises a pneumatically controlled paint pressure regulator and a valve for discharging the pneumatically controlled regulator; an electrical supply for the charging means which comprises a controlled low-voltage supply and a high-voltage generator connected to the low-voltage supply and adapted to generate a high DC voltage; three electrically controlled gas pressure regulators, one for each of the distributors and one for the paint pressure regulator; two electrically controlled pneumatic on/off valves respectively connected to the pneumatic valve means and the discharge valve; programmable logic means adapted to distribute electrical control signals to the aforementioned electrically controlled means in sequences which correspond to predetermined operating sequences; a chassis which is disposed on the drive member at a position immediately adjacent a center position of the support and which carries the high-voltage generator, the gas pressure regulating means and the two electrically controlled pneumatic valves; and a harness adapted to connect the means disposed on the chassis to the means disposed on the support, the length of the harness being substantially equal to the minimum length necessary for movement of the support relative to the chassis.
The juxtaposing of the paint feed assembly on the sprayer on the mobile support authorizes automatic color changes in the time interval separating the passage of two consecutive parts through the painting station, especially when the dead volumes between the feed assembly and the sprayer are reduced to the minimum, which reduces the quantity of ringing solvent to be fed into the nozzle. This arrangement is routine for sprayers which are not moved at high speed. The arrangement of the feed assembly has been designed, however, so that the weight carried by the support (sprayer and feed assembly) does not exceed two kilograms, which is compatible with the displacement control systems previously used.
The grouping together of the units to be mounted on the chassis is a concrete solution to the problem previously outlined, with regard to the time to transmit pressure changes along pipes and the necessity for a compromise with regard to the reduction of the weight carried by the support. The number of control devices grouped together on the chassis has been limited to that strictly necessary so that the assembly is compact and does not entail any lengthening of the pipes between any of the aforementioned units and the connecting harness. This is particularly remarkable in the case of the high-voltage supply. This has been divided into two subassemblies, one containing all the control and safety circuits and having a relatively low AC output voltage at a low impedance and the other subassembly comprising only those units needed to generate the high DC voltage which is produced at a high impedance, this latter subsystem, which is adapted for compact implementation, being disposed on its own on the chassis. The various connecting lines all terminate at substantially the same locations and are thus of the same length so that they can be grouped together to form a harness. This enables the support to be moved over the full extent of its possible travel, while keeping the length of the connecting lines to the minimum.
The apparatus preferably further comprises a pneumatic actuator and the sprayer preferably comprises, in an assembly aligned with the pneumatic actuator, a first valve connected to the actuator and disposed on the inlet side of the second pressurized gas distributor, a second valve coupled to the actuator with a first clearance and disposed on the inlet side of the first distributor, and a needle valve coupled to the actuator with a second clearance and disposed on the inlet side of the sprayer, the first and second valves and the needle valve each comprising elastic means whereby the obturator is normally urged against the seat so as to close the valve and the first and second clearances being such that operation of the actuator lifts successively or simultaneously from their seats the obturators of the first and second valves and the needle valve. Thus the valves and the needle valve bear independently on their respective seats, and wear affecting any one of them does not compromise the seal at the others.
The gas pressure regulators associated with the pressurized gas distributors each preferably comprise an electrically controlled pressure modulator and a flowrate amplifier which is pneumatically controlled by the pressure modulator. The flowrate amplifier, which is known per se, comprises, on respective sides of a diaphragm, a first chamber exposed to the control pressure and a second chamber with a large needle valve and connected, on the inlet side of the needle valve, to a supply of pressurized gas. Displacement of the needle valve due to pressure differentials between these chambers ensures that the outlet pressure from the second chamber is substantially the same as that applied to the first chamber, even when the discharge rate into the second chamber is high.
A correlator device preferably controls the three gas pressure regulators and is adapted to output three control signals to the regulators in response to two input parameters processed by a predetermined algorithm.
In a preferred arrangement the feed assembly, juxaposed to the sprayer, comprises, machined into a common block of material, a regulator which has two chambers and a diaphragm separating the chambers, a control air line connected to a first of the chambers, a paint outlet passage leading from the second of the chambers to the sprayer, a discharge passage, a paint inlet passage and a needle valve in the paint inlet passage coupled to the diaphragm, whereby the needle valve obturator is raised from its seat when the pressure in the first chamber exceeds that in the second chamber, and the discharge valve comprises a chamber, a diaphragm closing the chamber, a control air inlet to the chamber, a needle valve adapted to shut off the discharge passage of the regulator and a spring adapted to urge the needle valve towards the closed position, in opposition to the pressure of the air acting on the diaphragm.
Other subjects and advantages will appear from the following description of an example of the invention, when considered in connection with the accompanying drawings, and the novel features will be particularly pointed out in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic representation of apparatus in accordance with the invention.
FIG. 2 shows in axial cross-section a sprayer adapted to be fitted to apparatus in accordance with the invention.
FIG. 3 shows in cross-section part of the feed assembly to be juxtaposed to the sprayer of FIG. 2.
FIG. 4 is a cross-section through a gas flow-rate amplifier.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, the apparatus comprises a pneumatic sprayer 1 resting on a feed assembly 2 and mounted on a support or carriage 3 which can move to and fro on a vertical slide 4 forming a guide when acted on by a drive assembly (not shown). The feed assembly 2 is connected to a chassis 5 by a flexible connecting harness 6. The chassis 5 is mounted at the level of a central part of the slide 4 in the immediate vicinity of the latter, and the length of the harness 6 is determined so that the support 3 can move over all of the slide 4 but so that at the two end positions of the support the harness 6 is almost stretched; in other words, the length of the harness 6 is the minimum length compatible with the maximal travel of the support 3.
As will emerge in more detail hereinafter, supplying the sprayer 1 involves a paint feed line, two compressed air lines adjusted for spraying and shaping the sprayed paint jet, a compressed air line for controlling the fluid valves of the sprayer and a high-voltage line for electrostatically charging the jet. As will be explained hereinafter, all these lines pass through the feed assembly 2 which itself comprises a paint pressure regulator which is pneumatically controlled and a regulator discharge valve, also pneumatically controlled. The paint feed line passes through the regulator. For operating the feed assembly there are a paint discharge line, a compressed air line adjusted to control the regulator and a compressed air line for controlling the discharge valve. Thus the harness 6 comprises a high-voltage feed cable, three compressed air lines, two for the sprayer jet and one for controlling the paint pressure regulator, two compressed air lines for controlling the sprayer valves and the discharge valve, and two paint lines, a feed line and return line.
Disposed on the chassis 5 are connection devices for the lines of the harness 6, except for the paint feed line 76 and paint return line 77 which are directly connected to a color changing system of known type.
Thus there is disposed on the chassis a high-voltage generator 50 consisting of only those items necessary to generate a high DC voltage from a low voltage supplied over a line 50a. The generator is typically a voltage multiplier comprising rectifier diodes and capacitors supplied with a voltage of not more than a few thousand volts at a frequency of a few hundred Hertz from an oscillator supplied at a few tens of volts. Mounted on a compressed air distribution manifold 51 are three electrically controlled gas pressure regulators 52, 53 and 54. These pressure regulators (or modulators), which are known devices, incorporate a control system using an analog electrical signal as the set point signal and, as an actuator member, a needle valve admitting air into a measuring chamber from the compressed air manifold 51, such that the pressure in this measuring chamber is proportional to the set point signal. The regulators 53 and 54 drive respective flowrate amplifiers 55 and 56 also mounted on the distribution manifold 51. These flowrate amplifiers, the construction of which will be described hereinafter, are known devices which deliver gas at a pressure substantially equal to a control pressure, over an extended range of flowrates.
The pressure regulators 52, 53 and 54 are controlled from a correlator device 72 which receives the input parameters over lines 72a. This correlator device, of which further mention will be made hereinafter, is a logic device which converts two input parameters into signals fed to the three pressure regulators so that spraying occurs as required, with a jet shape and paint discharge rate as required.
Two solenoid valves 58 and 59 are mounted on the manifold 51, for controlling the valve means of the sprayer and the discharge valve of the regulator, respectively.
The sprayer, shown in FIG. 2, is in this instance a flat jet sprayer. It comprises a conductive paint nozzle 10 which is fed with paint by a paint line 16 shut off by an axial needle 13. The nozzle is also connected to a high-voltage terminal 10b through resistors 10a intended to prevent the formation of sparks. Note that the terminal 10b is surrounded by two concentric skirts 10c so as to break the surface leakage lines.
The nozzle 10 is centered in an annular chamber 11 supplied parallel to the axis from a first compressed air line 11b and an annular distributor 11a. The end of the nozzle 10 forms a point to favor ionization. The line 11b is fed by the line 17 through a valve 14.
On opposite sides of the axis of the jet produced by the nozzle 10 are disposed two ejectors 12a and 12b directed obliquely towards the axis of the nozzle 10, forward of the latter, and forming outlet orifices 11c and 11d from a distributor 12 fed by a line 12c connected to an input line 18 via a valve 15.
Behind the sprayer 1 is a pneumatic actuator 19 which comprises a diaphragm 19b delimiting a chamber supplied with compressed air via the line 19a. The valve 15 is attached to the center of the diaphragm 19b and is held against its seat 15b by a spring 15a.
The valve 14 is mounted slidably in the valve 15 and has at its rear end a shoulder 14c. A cup spring 14a bearing on the bottom of a cavity formed in the valve 15 to permit displacement of the shoulder 14c urges the valve 14 against its seat 14b. The needle 13 passes axially through the valve 14 and is anchored in a shouldered plunger 13c; a spring 13a is inserted between the back of the actuator 19 and the plunger 13c, so as to urge the needle 13 against its seat 13b. It will be understood that admitting compressed air through the line 19a pushes the diaphragm 19b towards the rear of the sprayer 1 and entrains the valve 15 which is lifted from its seat 15b, establishing communication between the line 18 and the distributor 12 with oblique ejectors 12a, 12b. In moving back, the valve 15 entrains the valve 14 by its shoulder 14c, which establishes communication between the line 17 and the distributor 11a which feeds the chamber 11 axially. As it continues to move back the valve 15 comes into contact with the plunger 13c which causes the needle 13 to lift off its seat 13b. The paint under pressure in the line 16 reaches the nozzle 10. Note that the clearance between the valve 15 and the shoulder 14c of the valve 14 is small and is primarily intended to permit the valve 14 to bear on its seat 14b when acted on by the cut spring 14a independently of the bearing of the valve 15 on its seat 15b. On the other hand, the clearance between the valve 15 and the plunger 13c is significantly greater so that not only is the bearing of the needle 13 on its seat 13b independent of the bearing engagements of the valves, but also the needle 13 does not lift off its seat 13b until after the flow from the distributors 11a and 12 is established. As a subsidiary feature, these clearances represent the differential wear tolerances within which operation of the valves remains correct.
The feed assembly 2 shown in FIG. 3 is juxtaposed to the sprayer 1 in such a way that the high-voltage contact 10b plugs into a complementary socket electrically connected to a high-tension cable input 29. The fluid inlets to the sprayer 16, 17, 18, 19a communicate, with appropriate seals, with the corresponding channels in the feed assembly 2. In the case of the lines 17, 18, 19a the passages in the assembly 2 make direct connection to the connectors for the flexible lines of the harness 6.
The assembly 2, which is constructed from an insulative material, is hollow out to accommodate a paint pressure regulator. This regulator comprises a flexible diaphragm 20 disposed between two chambers 20a and 20b. The chamber 20a communicates with a control air line 21 through passages 21a. The chamber 20b in which the paint circulates is provided with an outlet passage 22 to the sprayer line 16, a discharge passage 23 and a valve 24 urged against its seat 24a by a spring 24b and bearing on the diaphragm 20. At the rear of the valve 24 is a line 25 which receives the pressurized paint.
The discharge passage 23 is shut off by the obturator 27 of a discharge valve, this obturator 27 being urged onto a seat 27a, in the direction from the passage 23 towards the obturator 27, by a spring 28. The discharge valve comprises a diaphragm 26 between a control chamber 26a with which a control air line 26c opens and a discharge chamber 26b into which the obturator 27 communicates and from which the return line 23a extends. The diaphragm 26, lifted by the air pressure in the chamber 26a, pushes the obturator 27 off its seat 27a and establishes communication between the passage 23 and the return line 23a.
Although the feed assembly is sell known in its broader aspects, since electrostatic painting apparatus featuring quick color change utilizes functionally identical devices, it should be remembered that the pressure of the paint in the chamber 20b is substantially equal to the pressure of the air in the control chamber 20a, entry via the valve 24 being regulated by the pressure differential across the diaphragm 20, so as to balance the flowrate through the line 22 at the regulated pressure.
To effect a change of color the paint of the first color is passed through with a cleaning solvent, with intervening air blasts, with the sprayer actuator in the closed position and the discharge valve 26, 27 open so that excess paint and the rinsing solvent escape through the line 23a. The discharge valve is then briefly closed with the sprayer open so that a small quantity of solvent is ejected, removing any paint remaining in the sprayer and rinsing the latter. It goes without saying that this color change operation must be carried out in the time interval between two consecutive parts. The user may be recommended to locate the sprayer in an extreme end of travel position, facing a receptacle, to prevent traces of paint being projected into the spraying booth.
After rinsing the sprayer, the new paint is admitted and the operating cycle resumes.
The air pressure regulators shown in FIG. 4 comprise a pressure modulator 53 with a slaved proportional valve coil 53a fed from the manifold 51 through the line 51c and applying to the line 55a a pressure proportional to an electrical voltage applied to the proportional valve 53a. The pressure modulator 53 controls the flowrate amplifier 55 which comprises a diaphragm 55b between a control chamber 55c into which the line 55a opens and a slave chamber 55d. This is connected to an inlet passage connected to an outlet 51b of the manifold 51 through a valve 55e the obturator of which is urged against its seat and against the diaphragm 55b by a spring 55f. The slave chamber has an outlet passage 55g for connection to the device output.
Note that the flowrate amplifier is analogous to the paint pressure regulator. However, note also that the needle 55e is of significantly greater diameter than the needle of the regulator, so as to limit head losses at high flowrates.
After describing in detail the individual functioning of the component parts of the apparatus, reference will again be made to FIG. 1 to describe their conjoint operation. The computer-generated control sequences are addressed to units situated on the chassis 5 over the conductors 75 which comprise a high-voltage control conductor 71, a sprayer fluid adjustment conductor 72a and a solenoid valve control conductor 73. The conductor 71 carries digital signals indicative of the high voltage. The supply 70 comprises a digital-to-analogue converter and a generator producing a DC voltage of a few tens of volts. The output voltage of this generator is slaved to the analogue signal from the converter. The voltage applied over the line 50a to the generator 50 generates a high DC voltage for elecrostatically charging the jet, through the intermediary of an oscillator running at several hundred Hertz and a rectifier/voltage multiplier.
The signals addressed to the correlator 72 over the line 72a are digital and represent a paint discharge rate, a spray particle size and a jet flattening factor. The correlator converts these signals into paint pressure set points for the regulator 52 and air pressure set points for the axial distributor and the oblique distributor for, respectively the regulators 53 and 54. The pressure set points are converted to actual pressure, from the regulator 52 by the feed assembly regulator (FIG. 3) and from the regulator 53 and 54 by the flowrate amplifiers. The sprayer is ready to be operated. Conjointly with this, signals addressed to the drive equipment for the support 3 has indicated the displacement speed and the change of direction points. When a part reaches the coverage area of the sprayer the solenoid valve 58 is opened so as to operate the actuator 19 of the sprayer 1. The painting cycle begins, and during it the various adjustments in respect of the fluid pressures, the high voltage and the support displacement speed may be varied. The painting cycle is terminated by de-energizing the solenoid valve 58. The sequence corresponding to a color change has already been discussed. During this the solenoid valve 59 commands the discharge valve of the feed assembly 2 to open so as to discharge excess paint and rinsing solvents.
MODIFICATIONS
It will have been understood that the chassis 5 is attached to the slide 4 so that the harness 6 authorizes movement of the support 3 over this slide. However, the combination of the chassis 5 and the slide 4 may be rendered movable at moderate speed if the operating sequence requires this, in order to accompany the part to be painted as it moves or to reach certain portions of the parts, for example. Note that the reduction in the weight of the units carried by the support 3 is at least as necessary when the slide 4 is mobile as when it is fixed since, as follows from what has been explained hereinabove, increasing the load on the support 3 results in an increase in the weight of the slide 4 and the driving means which displace the support on the slide; the devices which displace the frame which carries the slide, complementing the displacements of the support on the slide, must be adapted to the load to be displaced.
There has been described apparatus equipped with a flat jet sprayer. It goes without saying that the apparatus could be equipped with a vortex type round jet sprayer, in particular by merely replacing the nozzle. In any event, a round jet sprayer comprises the same feed arrangements as a flat jet sprayer, namely a paint feed assembly, respective pressurized gas supplies for an axial distributor and an oblique distributor, a high-voltage supply and an actuator control system for the valves for the fluids supplied to the nozzle. By virtue of the flexibility of the various adjustments, changing the sprayer type does not entail any modification of the layout of the various units constituting the apparatus in accordance with the invention.
It will be clear that the apparatus as described could be applied to a multiple axis robot having a multiple pivot arm and capable of offering up the sprayer in a continuous sequence of positions relative to the surfaces to be painted. The chassis would then be attached to one of the last segments of the arm, in the immediate vicinity of the end to which the sprayer support is attached.
It is emphasized that the units which are mounted on the chassis are all known per se so that their replacement with functionally equivalent members would in no way depart from the scope of the invention.
Finally, it goes without saying that if the sprayer mounted on the support did not involve electrostatically charging the sprayed jet of paint, the chassis would not carry any high DC voltage generator, without the functional arrangements specific to the invention being consequently modified. Further, apparatus incorporating a pneumatic sprayer with no charging of the jet would remain within the scope of the invention.
More generally, it will be understood that various changes in the details, materials and arrangements of parts which have been herein described and illustrated in order to explain the nature of the invention may be made by those skilled in the art with the principle and scope of the invention as expressed in the appended claims. | Electrostatic painting apparatus comprises a support moveable at high speed along a slide. On this support is a pneumatically controlled paint sprayer producing an electrostatically charged jet of paint. A paint feed assembly comprising a pressure regulator and a discharge valve is juxatposed with the sprayer. Sprayer control devices are disposed on a chassis connected to the feed assembly by a harness. These control means comprise three gas pressure regulators supplying the sprayer and controlling the paint pressure regulator and a high DC voltage generator. The position of the chassis relative to the slide is determined such that the harness is as short as possible, so as to reduce to a minimum the command transmission time. This arrangement makes it possible to reduce the weight carried by the support. The units carried by the chassis are remotely controlled by a microprocessor-based unit over a remote control line. | 1 |
This is a divisional patent application based on U.S. Continuation patent application Ser. No. 10/154,356 filed on May 23, 2002, now a U.S. Pat. No. 6,634,665 B2 issued Oct. 21, 2003.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of wheelchairs and, more specifically, to an electrical braking system and quick release, detachable wheels for manual wheelchairs.
2. Description of the Related Prior Arts
Numerous types of braking mechanisms for manual wheelchairs are known in the art. The most typical manual wheelchair brake is a manual “over center” locking device which is activated by a lever arm and, when forced into its locking position, presses a braking member against the surface of the wheelchair tire creating a frictional braking action. Several factors mitigate against the usefulness and reliability of these types of brakes. Loss of tire pressure reduces the frictional force exerted by the crossbar on the tire and hence reduces the braking effect. A significant air pressure loss leaves these brakes useless. During transfer in and out of the chair, this type of brake allows the tire to slide underneath the crossbar and the wheelchair to move. Similarly, the brakes are ineffective and will not adequately hold the wheelchair on an incline. Other types of manual brakes include caliper type brakes manually activated with a lever arm mounted to a cable and brake assembly causing brake pads to press against the rim of the wheelchair wheel.
In these types of brakes, the frictional braking force exerted is directly related to the manual force which must be exerted on the lever arm by the brake operator to activate the brake. Wheelchair users who have arm or hand limitations may not be physically able to operate these brakes. These braking mechanisms only apply a braking force to one wheel. If an equal braking force is desired on both wheels, the user is required to use both arms and attempt to apply an equal force to both lever arms at the same time. This is difficult, if not impossible. Wheelchair frame and wheel design most often require the placement of the lever arms on the frame of the wheelchair near the user's knees. The placement of these lever arms interferes with the user's transfer in and out of the wheelchair. These lever arms require lifting the user's body in order to clear the lever during transfer.
A patent to Ross and Gunther, U.S. Pat. No. 5,358,266 describes a plate attached to a braking member, which applies a braking frictional force to the wheelchair tire when electronically activated by a solenoid rod. The solenoid rod is activated by means of a switch attached to the seat of the wheelchair. When the wheelchair user is raised out of the seat, the switch is activated and operates the braking mechanism. Also disclosed in this patent is a manually activated lever arm to operate the same braking member when the wheelchair user is seated. The same deficiencies discussed above apply to this wheelchair while the wheelchair user is seated. A wheelchair user with arm or hand limitations may not be able to operate the hand lever and the lever arm braking mechanism to apply a braking force to one wheel. In addition, the position of the lever arm may interfere with transfer in and out of the wheelchair.
Electric wheelchairs with various forms of braking means are common in the prior art. These braking means include gear reduction mechanisms, electromagnetic braking by means of a resistance applied to the electric motors, electronically activated frictional braking mechanisms where a solenoid is electrically energized to move brake shoes into frictional contact with a brake drum, and conventional manual brakes operated by a lever mechanism. These electric wheelchairs are heavy, cumbersome, difficult to transport, and do not promote physical activity by the user.
Wheelchair users have reason to frequently remove the wheels from their wheelchairs. It is often done for storage purposes, for brake adjustment, for wheel repair, and for wheel exchange. For example, in order to store a wheelchair in a vehicle, it is often desirable to remove the wheels.
Heretofore, the wheels on manual wheelchairs and other types of wheelchairs have been attached to the wheelchair frame by some type of hub with the wheels secured to the hub with nuts and bolts. In order to remove the wheels from the wheelchair, it has been necessary to unscrew and remove each of the nuts and bolts securing the wheel to the hub. This is a time consuming and cumbersome process. Once again, wheelchair users who have arm or hand limitations may not be physically able to remove the nuts and bolts.
More recently, it has become common in the art to attach wheels to manual wheelchairs using quick release locking pins which hold the wheel to the axle. In this type of design, it is difficult to also have a braking means on the wheelchair wheel other than the manual “over center” locking device which presses a braking member against the surface of the tire as described herein. Heretofore, other brakes have been ineffective on wheelchairs with quick release locking pins because the braking means had to be released and moved or disassembled in order to remove the wheel and thereby defeating the purpose of the quick release locking pin.
It is desirable to have a lightweight, manual wheelchair with an effective easily operatable electronic braking mechanism and, at the same time, quick release detachable wheels.
SUMMARY OF THE INVENTION
It is an object of this invention to provide an electronically activated braking system for a lightweight, manual wheelchair, which allows the wheelchair to maintain its lightweight and maneuverability characteristics.
It is a further object of this invention to have an electronically activated braking system for manual wheelchairs which eliminates the need for users of the wheelchair to manually operate brakes by means of a lever mechanism.
It is a further object of this invention to provide a braking system for manual wheelchairs, which provides equal braking force to both wheels of a wheelchair simultaneously.
It is a further object of this invention to provide a braking means for a manual wheelchair, which can be activated without the use of a manually operated lever that interferes with transfer in and out of the wheelchair by the user.
It is a further object of this invention to provide a braking means for manual wheelchairs, which eliminates movement of the wheelchairs on inclines and during transfer in and out of the wheelchair by the user.
It is a further object of this invention to provide a braking means for manual wheelchairs, which allows for detaching the wheelchair wheels without disturbing the braking means.
It is a further object of this invention to provide for quick release, easily detachable wheels.
It is a further object of this invention to provide for detachable wheels, which eliminates the need for users of the wheelchair to unscrew numerous nut and bolt combinations in order to remove the wheel.
It is a further object of this invention to provide for quick release, easily detachable wheels which allow the wheels to be removed without removing the disk and brake assembly.
In order to achieve these objectives, this invention provides for an electronic braking system, which is comprised of a braking means, a cable pulley system for activating the braking means, a DC liner actuator with actuator rod connected to the cable pulley system, a motion limit switch, a rechargeable twelve-volt battery electronically connected to the DC actuator, and a double throw control switch electronically connected to the battery for activating the battery power.
It is anticipated that the preferred braking means is a caliper-type brake positioned to clamp onto a metal disk mounted axially to a hub which rotates on the axle of each wheelchair wheel. The hub on which the disk is mounted interlocks with the hub on which the wheelchair wheel is mounted. The interlocking hubs are locked together with a locking pin, which extends axially through the center of the mated hubs such that the hubs are locked and rotate together when the wheelchair wheel is turned.
The locking pin is equipped with retractable nipples which, when extended, hold the locking pin securely in place. The retractable nipples are spring biased in the extended position and are activated by a push button at one end of the locking pin which releases the spring and allows the nipples to retract. When the nipples are in the retracted position, the locking pin can be removed simply by sliding it out of the axle. This allows the wheelchair wheel to be removed since there is no longer anything holding the mated hubs together.
The braking means for each wheel are connected to opposite ends of a cable wire. The cable wire passes around a pulley such that displacement of the pulley provides equal force and displacement to said opposite ends of the cable wire. The ends of the cable wire are directed through small openings in a mounting bracket. The openings are spaced a distance equal to the diameter of the pulley so the cable wire remains parallel as it extends from the pulley through said openings. A circular pulley cap is placed concentrically over the pulley. The vertical side of the pulley cap has two openings to allow for the passage of the wire cable into the pulley cap through the first opening, around the pulley and out the second opening. The pulley cap, pulley, and cable wire assembly is then connected to the outer end of the actuator rod by a coupling bracket.
The DC linear actuator is mounted on the wheelchair in a manner to allow the actuator rod to extend and displace the pulley and cable wire in line with the actuator rod's axis. The DC linear actuator is electronically powered by a twelve-volt rechargeable battery mounted to the wheelchair. The battery power is activated by a double throw control switch mounted to the wheelchair in a position where it is easily accessed by both the wheelchair user and a person assisting the wheelchair user.
The double throw toggle switch can be thrown in two different directions. When the double throw toggle switch is thrown in the first direction, it will cause the actuator rod to retract, pulling the pulley and cable wires and activating the braking force. When the toggle switch is thrown in the second direction, it will cause the actuator rod to extend, pushing the pulley and cable wire and deactivating the braking force.
In order to limit the tension in the cable wire, a motion limit switch can be added to the electrical brake system. The motion limit switch is wired into the circuit between the double throw toggle switch and said DC linear actuator. The motion limit switch is activated by displacement of the actuator rod in the direction which pulls the cable wire and activates the braking means. Once a selected braking force is attained, the motion limit switch opens the circuit and stops the displacement of the actuator rod.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a elevational side view of a manual wheelchair depicting a caliper braking mechanism mounted to the wheelchair frame and positioned to clamp onto a metal disk mounted axially to the hub of the wheelchair wheel.
FIG. 2A is an enlarged exploded perspective view depicting the locking pin, wheelchair wheel, hub, disk, and axle assembly which has a spring biased push button type locking pin and first interlocking hub design.
FIG. 2B is an enlarged exploded perspective view depicting the locking pin, wheelchair wheel, hub, disk, and axle assembly wherein the locking pin is equipped with a lever which activates an expandable tip.
FIG. 2C is an enlarged exploded perspective view depicting FIG. 2A from the opposite angle.
FIG. 2D is an enlarged exploded perspective view depicting the locking pin, wheelchair wheel, hub, disk, and axle assembly. This figure depicts a second interlocking hub design.
FIG. 2E is an enlarged exploded perspective view depicting FIG. 2D from the opposite angle.
FIG. 3 is a bottom view of the wheelchair seat depicting the toggle switch, the battery recharging outlet, the electrical wiring, the twelve-volt rechargeable battery, the DC linear actuator, the cable wire and pulley assembly, and the motion limit switch.
FIG. 4 is an enlarged perspective view depicting the caliper braking mechanism.
FIG. 5 is an exploded perspective view depicting the cable wire and pulley assembly and actuator rod mount.
FIG. 6 is a bottom view of the cable wire, pulley, and actuator rod assembly brackets and the motion limit switch.
FIG. 7 is a elevational side view of the coupling bracket.
FIG. 8 is an electrical circuit diagram illustrating the electrical control circuit of this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1 , a lightweight manual wheelchair 10 is equipped with a solid seat base 11 , seat cushion 12 , and seat back 13 mounted between first and second wheelchair wheels 24 generally to a frame 14 . The frame 14 has a vertical component 15 , a side horizontal component 16 , a frontal curved component 17 and a lower curved component 20 . A footrest 19 is mounted at the frontal extremity of the lower curved component 20 of the frame 14 . First and second caster wheels 21 are pivotally mounted toward the frontal extremity of the lower curved component 20 of the frame 14 . The manual wheelchair 10 is symmetrical about a centre line and the opposed side is identical to the side visible in FIG. 1 . Thus, when the first and second of numbered items are referred to without the second item being shown, it can be appreciated that the second numbered item is identical to the first but on the opposite side of the wheelchair.
First and second caliper brakes 18 are mounted to extension plates (not shown) which are in turn mounted to the frame 14 . The caliper brakes 18 are positioned to clamp onto first and second disks 22 (see FIGS. 1 and 4 ). In the preferred embodiment of this invention, the first and second caliper brakes 18 are manufactured by Hayes/HMX, model number BR3920. However, numerous other cable actuated caliper brakes are available on the market and can be used in this invention. The first and second wheelchair wheels 24 can be detached without removal of the first and second disks 22 or the first and second caliper brakes 18 .
Referring to FIGS. 2A through 2E , the first and second disks 22 are concentrically mounted to the inner face 83 first and second disk hubs 23 by means of a plurality of screws 29 passing through radially spaced interiorly threaded, aligned holes 51 in the first and second disk hubs 23 and the first and second disks 22 . In the preferred embodiment, as shown in FIGS. 2A , 2 B, and 2 C, the screws 29 are Allen screws where the heads 33 of the screws 29 extend from the outer vertical faces 27 of the first and second disk hubs 23 and are secured on the opposite end by nuts 38 . In a second preferred embodiment, as shown in FIGS. 2D and 2E , the screws 29 are of a length insufficient to extend beyond the outer vertical faces 27 of the first and second disk hubs 23 .
The first and second disk hub 23 and disk 22 assemblies are concentrically mounted to outer ends of first and second detachable axle pieces 80 and rotate thereon. The first and second detachable axle pieces 80 are tubular with a smooth surface portion 82 at their outer end and a exteriorly threaded portion 84 at their inner end. The smooth surface portion 82 and the exteriorly threaded portion 84 are divided by a flange 86 .
The first and second detachable axle pieces 80 are mounted to the frame 14 of the wheelchair 10 (see FIG. 1 ) by screwing the exteriorly threaded portion 84 into a tubular axle 25 . As shown in FIG. 3 , the tubular axle 25 is clamped to the first and second lower curved components 20 of the frame 14 (See FIG. 1 ) at its rear extremity by first and second frame clamps 72 .
Referring again to FIGS. 2A through 2E , the outer ends of the tubular axle 25 have mounting heads 88 . Each mounting head 88 has a threaded bore 90 with a diameter sufficient to accept and secure the exteriorly threaded portion 84 of the first and second detachable axle pieces 80 therein. The first and second detachable axle pieces 80 are mounted to the tubular axle 25 by screwing the exteriorly threaded portion 84 into the threaded bore 90 .
The first and second disk hub 23 and disk 22 assemblies are secured to the first and second detachable axle pieces 80 by means of a clip ring 39 . The clip ring 39 is spring biased to close around and fit in to a circumferential groove 78 cut into the smooth surface portion 82 of the first and second detachable axle pieces 80 at their extreme outer end. In order to allow the first and second disk hub 23 and disk 22 assemblies to rotate on the first and second detachable axle pieces 80 , the smooth surface portion 82 of the first and second detachable axle pieces 80 extend axially through a tubular opening 92 at the center of the first and second disk hubs 23 and the outer face of flange 86 abuts a concentric circular shoulder 87 (see FIGS. 2C and 2D ) on the inner face 83 of the first and second disk hubs 23 with a spacer ring 94 between. The spacer ring 94 prevents frictional contact between the outer face of flange 86 and the circular shoulder 87 on the inner face of the first and second disk hubs 23 . In the preferred embodiment, the spacer ring 94 is a Delrin washer. However it is anticipated that other smooth, durable material can be substituted.
Referring to FIGS. 2A , 2 B, and 2 E, the outer vertical face 27 of the first and second disk hub have a concentric circular recessed portion 93 surrounding the tubular opening 92 . The horizontal length of the smooth surface portion 82 of the detachable axle piece 80 is sufficient to allow the smooth surface portion 82 to extend through the tubular opening 92 of the first and second disk hubs 23 and expose the circumferential groove 78 on the opposite side of the first and second disk hubs 23 with minimal clearance at the concentric circular recessed portion 93 . This allows the clip ring 39 to close around circumferential groove 78 within the concentric circular recessed portion 93 .
As shown in FIGS. 2A through 2C , the first and second wheelchair wheels 24 are concentrically mounted on the first and second wheel hubs 37 . The inner surface 57 of the first and second wheelchair wheels 24 (See FIG. 2C ) is mounted flush against the outer vertical surface 70 (See FIG. 2E ) of the flanged inner portion 31 of the first and second wheel hubs 37 and are secured to the first and second wheel hubs 37 by first and second nuts 45 , which screw onto exteriorly threaded outer ends 75 of the first and second wheel hubs 37 . The first and second wheel hubs 37 have a tubular opening 43 through their center. As shown in FIGS. 2A and 2B , an outer circular bearing assembly 61 is pressed fit into the tubular opening 43 towards the outer end of the first and second wheel hubs 37 .
As shown in FIGS. 2B , 2 C, and 2 D, an inner circular bearing assembly 79 is pressed fit into the tubular opening 43 at the inner end of the first and second wheel hubs 37 . The outer bearing assembly 61 and inner bearing assembly 79 have inner rings 63 which turn within the bearing assemblies. The inner diameter of the inner rings 63 is equal to the inner diameter of first and second detachable axle pieces 80 . In the preferred embodiment, the outer circular bearing assembly 61 and inner circular bearing assembly 79 are manufactured by NICE, Model No. 1616 DC TN or KYK, Model No. R-8-DDHA1(IB). However, it is anticipated that other similar bearings could be used.
Referring again to FIGS. 2A through 2E , when the first and second wheelchair wheels 24 are mounted to the wheel hub 37 and in turn mounted to the wheelchair 10 (See FIG. 1 ), the outer vertical faces 27 of the first and second disk hubs 23 interlock with inner faces 77 of the flanged inner portion 31 of the first and second wheel hubs 37 . In the preferred embodiment, as shown in FIGS. 2A , 2 B, and 2 C, the inner faces 77 of the flanged inner portion 31 of the first and second wheel hubs 37 are flat with a plurality of radially spaced holes 96 shown in FIG. 2C . The heads 33 of the plurality of screws 29 fit snugly into the corresponding radially spaced circular holes 96 in the flanged inner portion 31 of the first and second wheel hubs 37 . In an alternate embodiment, as shown in FIGS. 2D and 2E , the inner face 77 of the flanged inner portion 31 of the first and second wheel hubs 37 have a raised surface 98 extending from the inner face 77 . The raised surface 98 is centered on the inner face 77 with parallel sides 100 extending to the circumference of the inner face 77 . The parallel sides 100 extend perpendicularly from the inner face. In this alternate embodiment, the outer vertical faces 27 of the first and second disk hubs 23 have a channel 102 . The placement and dimensions of the channel 102 are to allow the raised surface 98 to fit snugly into the channel 102 with minimal clearance at all contiguous surfaces when the first and second wheel hubs 37 are interlocked with the first and second disk hubs 23 .
In the preferred embodiment, as shown in FIGS. 2A , 2 B, and 2 C, the interlocking of heads 33 within the radially spaced circular holes 96 cause the first and second wheelchair wheels 24 and the first and second disks 22 to rotate together. In another alternate embodiment, as shown in FIGS. 2D and 2E , the interlocking of the raised surface 98 on the inner face 77 of the first and second wheel hubs 37 with the channel 102 in the outer vertical faces 27 of the first and second disk hubs 23 cause the first and second wheelchair wheels 24 (See FIG. 1 ) and the fist and second disks 22 to rotate together.
Still referring to FIGS. 2A through 2E , in order to hold the first and second disk hubs and the first and second wheel hubs together when interlocked, first or second locking pins 35 a and 35 b (see FIGS. 2A and 2B ) extend axially through the center of the first and second wheel hubs 37 , the first and second disk hubs 23 , and into the first and second detachable axle pieces 80 . The first or second locking pins 35 a and 35 b have a diameter which allows the first or second locking pins 35 a and 35 b to slide through the inner rings 63 of the outer circular bearing assembly 61 (See FIGS. 2A and 2B ) and the inner circular bearing assembly 79 (See FIGS. 2C and 2D ) and into the first and second detachable axle pieces 80 with minimal clearance.
The first and second wheelchair wheels 24 can be detached from the wheelchair 10 (See FIG. 1 ) without removing the first and second disks 22 or disturbing the first and second caliper brakes 18 by removing the first and second locking pins 35 a or 35 b and separating the first and second wheel hubs 37 from the first and second disk hubs 23 .
In the preferred embodiment of the invention (see FIGS. 2A , 2 C, 2 D, and 2 E), the first and second locking pins 35 a have a push button 47 , a rod 49 , an adjusting nut 53 , and a set of retractable nipples 55 . The push button 47 is spring biased in the released position, causing the retractable nipples 55 to extend from the rod 49 . When the push button 47 is depressed, the retractable nipples 55 retract into the rod 49 . The first and second locking pins 35 a can be inserted through the inner ring 63 of the outer circular bearing assembly 61 and into the tubular openings 43 of the first and second wheel hubs 37 by depressing the push button 47 and thereby causing the retractable nipples 55 to retract. When the first and second locking pins 35 a are further inserted through the first and second disk hubs 23 and into the first and second detachable axle pieces 80 and the push button 47 is released, the retractable nipples 55 extend into grooves (not shown) circumferentially cut into the tubular interior surface (not shown) of the first and second detachable axle piece 80 . The grooves (not shown) are of sufficient depth and width to allow the retractable nipples 55 to extend into the grooves (not shown) with minimal clearance. The grooves (not shown) are positioned in the first and second detachable axle pieces 80 to allow the retractable nipples 55 to extend into the first and second grooves (not shown) when the first and second locking pins 35 a are fully inserted into the first and second wheel hubs 37 such that the adjustable nut 53 contacts the outer surface of the outer circular bearing assembly 61 . In the preferred embodiment, the first and second locking pins 35 a are QRP Quick Release Push Button (large/small) Axle, Model No. 21QRP11CDASN.
In an alternate embodiment of the invention, the length of the exteriorly threaded portion 84 of the first and second detachable axle pieces 80 is sufficient to allow the position of the retractable nipples 55 on the first and second locking pins 35 a to extend beyond the inner lip 85 of the first and second detachable axle pieces 80 when the first and second locking pins 35 a are fully inserted into the first and second wheel hubs 37 such that the adjustable nut 53 contacts the outer surface of the outer circular bearing assembly 61 . Thus, when the first and second locking pins 35 a are fully inserted and the push button 47 is released, the retractable nipples 55 extend adjacent to the inner lip 85 of the first and second detachable axle pieces 80 with minimal clearance and thereby holding the first and second locking pins 35 a in place. In this embodiment, the first and second locking pins 35 a are, once again, QRP, Quick Release Push Button (large/small), Axle Model No. 21QRP11CDASN.
In yet another embodiment of the invention (see FIG. 2B ), the first and second locking pins 35 b have a release lever 65 at one end of a rod 67 , a spacer joint 69 between the release lever 65 and the rod 67 , an expandable tip 71 attached to the other end of the rod 67 , and a wedging cap 73 attached to the expandable tip 71 opposite the rod 67 . When the release lever 65 is rotated to the released position so that it extends parallel with the rod 67 , the diameter of the expandable tip 71 is not expanded and is equal to the diameter of the rod 67 . When the release lever 65 is rotated perpendicular to the rod 67 , the wedging cap 73 is pulled toward the release lever 65 causing the expandable tip 71 to expand to a diameter greater than the diameter of the rod 67 . When the release lever 65 is in the released position, the first and second locking pins 35 b can be inserted through the inner ring 63 of the outer circular bearing assembly 61 and into the tubular opening 43 of the first and second wheel hubs 37 . When the first and second locking pins 35 b are inserted through the first and second wheel hubs 37 , and into the first and second detachable axle pieces 80 and the release lever 65 is then rotated perpendicular to the rod 67 , the expandable tip 71 expands into and makes frictional contact with the interior surface (not shown) of the first and second detachable axle pieces 80 . The frictional force created is great enough to hold the first and second locking pins 35 b in place. The diameter of the spacer joint 69 is greater than the inner diameter of the inner ring 63 of the outer circular bearing assembly 61 , such that when the first and second locking pins 35 b are fully inserted, the spacer joint 69 contacts the outer face of the outer circular bearing assembly 61 . In this preferred embodiment, the locking pin 35 b is the Ultra Axle, 0.50″ O.D. manufactured by Rousson Chamoux.
The first and second caliper brakes 18 are activated by pulling a cable wire 26 (See FIGS. 4 and 5 ) attached to the caliper brakes 18 at first and second ends of the cable wire 26 . The first and second ends of the cable wire 26 are directed to the first and second caliper brakes 18 through a cable wire housing 28 which is attached to a nozzle 30 on the first and second caliper brakes 18 . The first and second ends of the cable wire 26 are attached to the first and second caliper brakes 18 , respectively, in typical fashion. The cable wire 26 passes through the nozzle 30 of the first and second caliper brakes 18 and into the cable wire housing 28 . The cable wire housing 28 directs the cable wire 26 to a mounting bracket 32 (See FIG. 5 ). The mounting bracket 32 has a vertical portion, and an upper horizontal portion. The mounting bracket 32 is mounted to the bottom of the solid seat base 11 by two screws (not shown) passing through interiorly threaded aligned holes in the solid seat base 11 and upper horizontal portion of the mounting bracket 32 .
The cable wire housing 28 is connected to the mounting bracket 32 by means of first and second hollow connectors 34 . The first ends of the first and second hollow connectors 34 fit snugly within first and second circular openings (not shown) in the mounting bracket 32 and the second ends of the first and second hollow connectors 34 fit snugly around the cable wire housing 28 . The centers of said first and second circular openings (not shown) are equidistant from the upper horizontal portion of the mounting bracket 32 and are horizontally spaced a distance equal to the diameter of the pulley 36 . The diameter of the first and second circular openings (not shown) is sufficient to allow the first and second hollow connectors 34 to fit snugly and the cable wire 26 to pass through first and second circular openings (not shown) within the first and second hollow connectors 34 . The cable wire 26 passes through the circular openings in the mounting bracket 32 within the first and second hollow connectors 34 and then passes around the pulley 36 .
The pulley 36 and cable wire 26 assembly is covered with a circular pulley cap 40 . The inner diameter of the circular pulley cap 40 is of sufficient dimension to cover the pulley 36 and wire cable 26 assembly with minimal clearance. The vertical side of the pulley cap 40 has first and second openings 41 spaced to allow the cable wire 26 to pass into the pulley cap 40 and around the pulley 36 . In the preferred embodiment of this invention, the segments of the cable wire 26 on opposite sides of the pulley 36 between the pulley 36 and mounting bracket 32 are parallel. Both segments of the cable wire 26 are perpendicular to the vertical side of the mounting bracket 32 .
The pulley cap 40 , pulley 36 , and wire cable 26 are connected to an actuator rod 42 of a DC linear actuator 50 (See FIG. 3 ) by means of a coupling bracket 44 . The pulley cap 40 , pulley 36 , and wire cable 26 are connected to the coupling bracket 44 by a bolt and nut combination 46 passing through holes vertically aligned with the axis of the pulley cap 40 and pulley 36 . The actuator rod 42 is connected to the coupling bracket 44 by a bolt and nut combination 48 passing through holes horizontally aligned through the coupling bracket 44 and through the center of the outer end of the actuator rod 42 .
The DC linear actuator 50 , as shown in FIG. 3 , is mounted to the solid seat base 11 by means of a mounting flange 56 and an actuator mounting piece 52 . The actuator mounting piece 52 is mounted to the solid seat base 11 by two nut and bolt combinations. The mounting flange 56 is mounted to the actuator mounting piece 52 by a nut and bolt combination passing through horizontally aligned holes in the mounting flange 56 and first and second vertical portions 54 of the actuator mounting piece 52 . The DC linear actuator is positioned so that displacement of the actuator rod 42 is in a direction perpendicular to the vertical portion of the mounting bracket 32 and centered between the first and second circular openings (not shown) in the vertical portion of the mounting bracket 32 . In the preferred embodiment, the DC linear actuator 50 is manufactured by Warner Electric, model number DE12Q17W41-02FHM3HN.
The DC linear actuator 50 is powered by a twelve-volt rechargeable battery 58 mounted to the bottom of the solid seat base 11 . In the preferred embodiment of this invention, the twelve volt rechargeable battery 58 is mounted to the solid seat base 11 by first and second Velcro straps 59 . Each of the first and second Velcro straps 59 pass through two slits (not shown) in the solid seat base 11 such that each of the first and second Velcro straps 59 pass through the first slit (not shown) to the top of the solid seat base 11 and back through the second slit (not shown) and around the twelve volt rechargeable battery 58 . In the preferred embodiment of this invention, the twelve volt rechargeable battery 58 is a sealed, non-spillable, lead battery manufactured by CSB Battery Company, Ltd.
A recharger outlet 68 is mounted to the frame 14 and is wired across the positive and negative leads of the twelve volt rechargeable battery 58 . In the preferred embodiment of this invention, the recharger outlet 68 is mounted to the rear of the solid seat base 11 . However, the recharger outlet 68 can be mounted generally to any part of the frame 14 where it is convenient and accessible.
As shown in FIGS. 3 and 8 , the battery power is controlled by a double throw toggle switch 60 which is mounted to the frame 14 . In the preferred embodiment of this invention, the double throw toggle switch 60 is mounted to vertical component 15 of the frame 14 . (See FIG. 1 .) However, the double throw toggle switch 60 can be mounted generally to any part of the frame 14 where it is convenient and accessible to the wheelchair user. The double throw toggle switch 60 is wired into the electrical circuit, as shown in FIG. 7 , across the positive and negative leads of the twelve volt rechargeable battery 58 . The double throw toggle switch 60 can be thrown in a first direction 74 or a second direction 76 . If the double throw toggle switch 60 is thrown in the first direction 74 , it closes the circuit and powers the motion of DC linear actuator 50 and causes the actuator rod 42 to retract. The retraction of the actuator rod 42 pulls the pulley 36 and cable wire 26 assembly causing the displacement of the cable wire 26 within the cable wire housing 28 in a direction away from the first and second caliper brakes 18 (See FIGS. 4 , 5 , and 6 in combination). The displacement of the cable wire 26 away from the first and second caliper brakes 18 causes equal tension in the cable wire 26 on opposite sides of the pulley 36 and activates the first and second caliper brakes 18 with equal braking force.
If the double throw toggle switch 60 is thrown in the second direction 76 , it closes the circuit and the polarity and direction of current flow through the DC linear actuator 50 is reversed. This powers the motor of the DC linear actuator 50 in the reverse direction and causes the actuator rod 42 to extend. The extension of the actuator rod 42 displaces the pulley 36 and causes the cable wire 26 to move within the cable wire housing 28 toward the first and second caliper brakes 18 . This in turn releases the tension in the cable wire 26 created by retracting the activator rod and deactivates the first and second caliper brakes 18 . The first and second caliper brakes 18 are spring biased (not shown) toward the deactivated position which retains tension in the cable wire 26 while the actuator rod 42 is extending and prevents bunching of the cable wire 26 .
In order to control the tension in the cable wire 26 when the actuator rod 42 is retracting, a motion limit switch 62 is placed in the electrical circuit, as shown in FIG. 7 , between the positive lead of double throw toggle switch 60 . When the double throw toggle switch 60 is thrown in the first direction 74 , the motion limit switch 62 limits movement of the DC linear actuator 50 . The motion limit switch 62 is equipped with a motion arm 64 as shown in FIGS. 3 , 6 , 7 , and 8 . The motion arm 64 is spring biased to contact and press against an actuating pin 66 as shown in FIGS. 3 , 6 , 7 , and 8 . The actuating pin 66 extends from, and is a part of, the coupling bracket 44 as more clearly illustrated in FIG. 6 . The motion limit switch 62 is normally closed. Retraction of the actuator rod 42 causes displacement of the coupling bracket 44 and actuating pin 66 , which in turn displaces the motion arm 64 . Sufficient displacement of the motion arm 64 throws the motion limit switch 62 opening the circuit and preventing further retraction of the actuator rod 42 . The displacement of the motion arm 64 required to throw the motion limit switch 62 is adjustable to allow for control and selection of the tension in the cable wire 26 and the resulting braking force.
In the normal operation of the wheelchair 10 , it is desirable to have brakes activated during the transfer in and out of the wheelchair 10 . If the wheelchair user intends to transfer out of the wheelchair, he will throw the toggle switch 60 in the first direction 74 which causes the actuator rod 42 to retract and activates the first and second caliper brakes 18 . The wheelchair user should hold the toggle switch 60 in the first direction 74 , thereby increasing the braking force applied by the first and second caliper brakes 18 until the motion limit switch 62 is thrown and opens the circuit which stops the retraction of the actuator rod 42 . The user should then release the toggle switch 60 which is spring biased to the center, OFF position. The motor of the DC linear actuator 50 locks the actuator rod 42 in position when there is no power to the DC linear actuator 50 . Thus, the first and second caliper brakes 18 will remain activated and hold the wheelchair 10 in position while the wheelchair user transfers out of the chair. The first and second caliper brakes 18 will remain activated until the toggle switch 60 is thrown and held in the second direction 76 and thereby allowing the actuator rod 42 to extend a sufficient amount to deactivate the first and second caliper brakes 18 and allow the first and second wheelchair wheels 24 to rotate freely. The toggle switch 60 is then released allowing it to spring back to the center OFF position which opens the circuit and stops the flow of power to the DC linear actuator 50 .
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limited sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the inventions will become apparent to persons skilled in the art upon the reference to the description of the invention. It is, therefore, contemplated that the appended claims will cover such modifications that fall within the scope of the invention. | A quick release detachable wheel hub assembly is shown for a lightweight manual wheelchair. The wheelchair wheels mount on exterior hubs and rotate therewith. The inner face out of each of the exterior hubs mates with an opposing outer face of interior hubs. One of the opposing faces on the hubs has a projection or a plurality of projections which fit snugly into corresponding openings on the opposing face of the other hub when the opposing faces of the hubs are mated. The interior hubs are mounted and rotate on detachable axles which screw into the wheelchair frame. A quick release, removable locking pin is inserted through the center of the hubs and into detachable axle and locked in place and thereby causing the hubs to be locked and rotate together. The wheels are quickly detached by simply removing the locking pins and pulling apart the hubs. | 0 |
This application claims benefit of 60/962,739, filed Jul. 31, 2007.
BACKGROUND OF THE INVENTION
Aldehydes and ketones are valuable building blocks for chemical industry. Reductive amination is a fundamental chemistry process that dramatically expands the application of aldehydes and ketones by transforming them into amines. The Leuckart reaction is a unique one step method of reductive amination. It is a remarkably simple process that includes only two components: the carbonyl compound and formamide. The reaction is completed simply by heating the components at 160° C. to 185° C. for 6 to 25 hours [1]. The long processing time seemed to be the only shortcoming of the reaction. However, it is associated with a number of serious practical problems.
First, the prolonged exposure of the reaction mixture to high temperatures inevitably leads to significant thermal decomposition of the components, and, consequently, to lower yields of the products and difficulties with their isolation and purification. Second, maintaining high temperatures for a long period of time means high consumption of energy and increasing production costs which make the Leuckart reaction unattractive to chemical industry. Third, long processing times per se are unattractive to fast paced modern synthetic applications, such as combinatorial chemistry and automated parallel synthesis. Thus, the Leuckart reaction as a unique one step method of reductive amination became almost completely abandoned in modern synthetic chemistry.
Most of the current reductive amination procedures are currently performed as two step combinations of the separate amination and reduction reactions. These two step procedures can often take as much time as the traditional Leuckart reaction [2]. They are also quite expensive because they require either the use of custom complex hydrides, or precious metal catalysts and high pressure equipment. Their only advantage over the one step Leuckart reaction is that they are not accompanied by thermal decomposition and as a result produce cleaner products.
Therefore, it is evident that there is a compelling need for a fast and inexpensive method of reductive amination of aldehydes and ketones equally attractive to industrial and laboratory practices.
SUMMARY OF THE INVENTION
An improved method for the synthesis of substituted formylamines via an accelerated Leuckart reaction. The method may also include an accelerated hydrolysis of the substituted formylamines to substituted amines. The accelerated Leuckart reaction is conducted by reacting formamide or N-alkylformamide, formic acid and an aldehyde or a ketone at a specific molar ratio and a specific temperature. The accelerated Leuckart reaction is completed within minutes or seconds instead of hours. The accelerated hydrolysis is conducted in the presence of a specific acid and a specific solvent at an elevated temperature. The accelerated hydrolysis is also completed within seconds.
DETAILED DESCRIPTION OF INVENTION
The improved method of reductive amination of aldehydes and ketones via an accelerated Leuckart reaction is an unanticipated discovery. The Leuckart reaction was first described in the XIX century, and since that time remained one of the slowest reactions in organic chemistry. Many attempts were made to improve the reaction by using various additives, most commonly formic acid. However, the only area of improvement appeared to be the yield of the product, not the processing time.
In 1996 a significantly shorter reaction time of 30 minutes was achieved through the use of microwave heating [3]. However, the technique was successfully applied only to a very narrow group of compounds. In addition, the current technical solutions for microwave assisted synthesis do not allow for processing large-scale reactions and therefore cannot be used in industry.
In the present invention using the Leuckart reaction it was unexpectedly discovered that the reaction time can be dramatically decreased by decreasing the concentration of the aldehyde or a ketone used in the reaction. Certain specific molar ratios of the aldehyde (ketone), formic acid, and formamide (alkylformamide) the reaction time can be reduced to 30 minutes or lower without the use of microwave assistance. Surprisingly it was found, that in many cases the reaction becomes instant i.e. fully completed at the moment when it reaches the usual reaction temperature of 160-185° C. The accelerated Leuckart reaction is equally successful if it is conducted with conventional or microwave heating.
The unique molar ratio of formamide (N-alkylformamide) to an aldehyde or a ketone is between 150:1 to 5:1 and most preferably between 100:1 to 10:1. The specific molar ratio of formamide (N-alkylformamide) to formic acid is between 20:1 to 6:1 and most preferably 10:1.
The specific temperature of the accelerated Leuckart reaction is between 150-200° C., and most preferably 180-190° C., if the reaction is conducted in an open system. It was found that the specific temperature of the accelerated Leuckart reaction is between 150 to 250° C., most preferably 190-210° C., if the reaction is conducted in a sealed system.
This accelerated Leuckart reaction can be successfully applied to the areas where the traditional Leuckart reaction was not successful. Specifically, it was believed that the Leuckart reaction does not work on substituted benzaldehydes, and that the substituted benzylamines cannot be obtained from the respective benzaldehydes via the Leuckart reaction [1]. Further the accelerated Leuckart reaction does work on substituted benzaldehydes and that practically any substituted benzylamine can be prepared via the accelerated Leuckart reaction. Specifically, it was found that the reductive amination of vanillin (4-hydroxy-3-methoxybenzaldehyde) can be completed instantly via the accelerated Leuckart reaction. Vanillylamine is an important industrial chemical that is used for the synthesis of safe natural painkillers, such as capsaicin and analogs. The new accelerated Leuckart reaction comprises the new method of the synthesis of vanillylamine. Further, it was also discovered that the accelerated Leuckart reaction can be successfully applied to α,β-unsaturated aldehydes and ketones, thus comprising a new method of obtaining substituted allylamines.
The improved increased reaction rate prevents any substantial thermal deterioration of the reaction mixture. As a result, the filtrates obtained after the separation of the reaction products can be repeatedly used as solvents for the next rounds of the reaction. The accelerated Leuckart reaction allows for the recycling of the reaction filtrates thus leading to quantitative yields of the products and minimal amounts of wastes.
As a complementary process, it was shown that substituted formylamines that are obtained as a result of the Leuckart reaction can be hydrolyzed to substituted amines via an accelerated (instant) hydrolysis. Normally, the hydrolysis step that follows the Leuckart reaction is a relatively slow step that takes about an hour. Surprisingly, in the presence of a specific solvent the hydrolysis step also becomes an instant procedure. As a result, the entire process of obtaining amines from aldehydes and ketones becomes a combination of two accelerated (instant) reactions, an accelerated (instant) Leuckart reaction and accelerated (instant) hydrolysis.
The present invention is illustrated by the following examples herein.
EXAMPLE 1
Reductive Amination of Vanillin (I)
The multi-mode MARS 5 reaction system (CEM Corporation) with GreenChem reaction vessels was used for the synthesis of vanillylformamide (II). 1.52 g (10 mmol) of I, 20 ml of formamide, and 1 ml of formic acid were placed in the GreenChem reaction vessel. The GreenChem reaction vessel was placed into the MARS 5 reaction system and the reaction mixture was quickly heated to 200° C. The reaction mixture was kept at 200° C. for 3 minutes and then cooled to 100° C. The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TLC showed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated. The residue was purified by column chromatography (silica gel, CH 2 Cl 2 :CH 3 OH 20:1 v/v) and yielded 1.37 g (75%) of N-vanillylformamide (II), m.p. 83.5° C. (benzene). 1 H NMR (D6-acetone): 8.21 s (1H, HC═O), 7.60 s (1H, NH), 7.55 br.s. (1H, OH), 6.93 s (1H, aromatic), 6.76 s (2H, aromatic), 4.32 d (2H, CH 2 ), 3.80 s (3H, CH 3 ). 13 C NMR (D6-acetone): 161.9 (C═O), 148.7, 147.1, 131.7, 121.6, 116.1, 112.6 (aromatic carbons), 56.6 (CH 3 ), 42.3 (CH 2 ). IR (neat crystals, ATR, cm −1 ): 3296 (NH), 3213 (OH), 1643 (C═O). C 9 H 11 NO 3 , calculated, %: C, 59.66; H, 6.12; N, 7.73. Found, %: C 59.90, 59.89; H 6.13, 6.12; N 7.74, 7.73.
The reaction was repeated with 4.56 g (30 mmol) of vanillin and a reaction time of 1 min. TLC showed that the reaction was complete. The reaction mixture was extracted and purified the same way producing 3.29 g (60%) of N-vanillylformamide (II).
The reaction was repeated with 1.52 g (10 mmol) of vanillin and conventional heating at 190° C. for 1 minute. The reaction mixture was extracted and purified the same way producing 1.46 g (80%) of N-vanillylformamide (II).
EXAMPLE 2
Instant Reductive Amination of 4-hydroxybenzaldehyde (III)
4-hydroxybenzaldehyde (1.22 g or 10 mmol), formamide (22.72 g or 20.03 mL) and formic acid (2.43 g or 2 mL) were placed into a 50 mL round bottom flask equipped with a thermometer, a reflux condenser, a magnetic stirrer and a heating mantle. The reaction mixture was heated to 189° C. The heating was immediately turned off; the reaction flask was quickly raised from the heating mantle and allowed to cool to room temperature. The TLC conducted on the cold reaction mixture confirmed that the reaction was complete. The reaction mixture was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried with sodium sulfate and the solvent was evaporated to produce 1.17 g (77.1%) of 4-hydroxybenzylformamide (IV).
EXAMPLE 3
Reductive Amination of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-one (V)
One g (3.9 mmol) of V, 2 ml of formic acid, and 20 ml of formamide were placed in a round bottom flask equipped with thermometer, reflux condenser, and a heating mantle. The reaction mixture was heated to 188-190° C. and maintained at this temperature for 10 minutes. The reaction mixture was left to cool to room temperature overnight. The precipitated crystals were separated by filtration, rinsed with water, and dried with vacuum, producing 70% of N-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]-formamide (VI).
EXAMPLE 4
Reductive Amination of Benzophenone (VII)
The reaction procedure for V was repeated with 5 g of benzophenone and the reaction time of 15 minutes. The reaction produced 95% of benzhydrylformamide (VIII) (isolated yield).
EXAMPLE 5
Instant Hydrolysis of N-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]formamide (VI)
One g of VI, 10 ml of concentrated hydrochloric acid, and 10 ml of methanol were placed in the GreenChem reaction vessel. The GreenChem reaction vessel was placed into the MARS 5 reaction system and the reaction mixture was quickly heated to 120° C. The microwave heating was immediately turned off and the reaction mixture was quickly cooled to 60° C. The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature; the precipitated crystals were separated by filtration. The filtrate was dried with vacuum and produced an additional amount of the product. The yield of N-[1-(2,4-dichlorophenyl)-4,4-dimethyl-1-propen-3-yl]-amine hydrochloride (IX) is quantitative.
EXAMPLE 6
Instant Hydrolysis of Benzhydrylformamide (VIII)
The reaction procedure for VI was repeated with 1 g of VIII and produced quantitative yield of benzhydrylamine hydrochloride (X).
EXAMPLE 7
Instant Hydrolysis of Vanillylformamide (II)
The reaction procedure for VI was repeated with 1 g of II and produced quantitative yield of vanillylamine hydrochloride (Xi).
EXAMPLE 8
Reductive Amination of 2,4,6-trimethoxybenzaldehyde (XII) with Recycling of the Filtrate
1.96 g (10 mmol) of XII, 20 ml of formamide, and 2 ml of formic acid were placed in the GreenChem reaction vessel. The GreenChem reaction vessel was placed into the MARS-5 reaction system and the reaction mixture was quickly heated to 200° C. The reaction mixture was kept at 200° C. for 3 minutes and then cooled to 100° C. The GreenChem reaction vessel was removed from the MARS 5 system, the residual pressure was released, and the reaction vessel was opened. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature; the precipitated crystals were separated by filtration, rinsed with water and dried with vacuum. The filtrate was used as solvent in the next reaction. The reaction was repeated 10 times. The total of 9.6492 g of formic acid, and 34.5680 g of formamide were added to the reaction mixture over the ten cycles to compensate the losses. The total yield of 2,4,6-trimethoxybenzylformamide (XIII) is quantitative.
Other Embodiments
The description of the specific embodiments of the invention is presented for the purpose of illustration. It is not intended to be exhaustive nor to limit the scope of the invention to the specific forms described herein. Although the invention has been described with reference to several embodiments, it will be understood by one of ordinary skill in the art that various modifications can be made without departing from the spirit and the scope of the invention, as set forth in the claims. All patents, patent applications and publications referenced herein are hereby incorporated by reference.
Other embodiments are within the claims. | An improved method for the synthesis of substituted formylamines and substituted amines via an accelerated Leuckart reaction. The Leuckart reaction is accelerated by reacting formamide or N-alkylformamide and formic acid with an aldehyde or a ketone at a preferred molar ratio that accelerates the reaction. The improved method is applicable to various substituted aldehydes and ketones, including substituted benzaldehydes. An accelerated method for the hydrolysis of substituted formylamines into substituted amines using acid or base and a solvent at an elevated temperature. The improved method is useful for the accelerated synthesis of agrochemicals and pharmaceuticals such as vanillylamine, amphetamine and its analogs, and formamide fungicides. | 2 |
BACKGROUND OF THE INVENTION
This invention relates to a bracket and tooth assembly for a planting implement.
In commercial planting implements, such as corn planters or the like, a herbicide is typically applied to the furrow at the same time that the seeds are being planted. Liquid fertilizers are also being used more and more by farmers, and are sometimes applied during the planting operation. However, if the liquid fertilizer is applied directly to the seeds, the seeds may be damaged or killed.
It is therefore a general object of this invention to provide a novel bracket and tooth assembly which may be readily mounted on a planter type implement, and which is operable to form a shallow furrow closely adjacent the seed furrow for receiving liquid fertilizer therein.
It is another object of this invention to provide a bracket and tooth assembly for a planter type implement which effectively discharges the liquid fertilizer closely adjacent the seed furrow, but preventing discharge of the fertilizer from the seeds. These and other objects of the invention are more fully described in the following specification.
FIGURES OF THE DRAWING
FIG. 1 is a perspective view of a corn planter implement incorporating the novel bracket and tooth assembly;
FIG. 2 is a rear view of the corn planter implement incorporating the novel bracket and tooth assembly;
FIG. 3 is a fragmentary exploded perspective view illustrating the novel bracket and tooth assembly mounted on the tool bar of a planter implement;
FIG. 4 is a perspective view of a modified form of the bracket and tooth assembly; and
FIG. 5 is a perspective view of a further modification of the bracket and tooth assembly.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings and more specifically to FIG. 1, it will be seen that my novel bracket and tooth assembly designated generally by the reference numeral 9 is advantageously incorporated on a conventional commercial planter implement, such as the corn planter 10. It is pointed out that my novel bracket and tooth assembly 9 may be used with any planter implement and that the planter implement 10 is merely illustrative of a planter implement with which the bracket and tooth assembly have been illustrated. The planter implement 10 includes a frame 11 having ground engaging wheels 12 to permit the planting implement to be towed by a tractor or the like. The planter implement 10 is provided with a plurality of planter devices including seed boxes 13 mounted on the frame and arranged in side-by-side relation. Each planter device has a discharge tube through which the seed is discharged. The planter implement 10 may also include a plurality of herbicide receptacles 14 which contain a powdered herbicide and each have an outlet conduit through which the herbicide is discharged. The corn planter includes a plurality of furrowing discs 15 for forming the furrows into which the seeds are discharged. A plurality of closing discs 16 are also provided for closing the furrow in a well-known manner.
Referring now to FIG. 3, it will be seen that the novel bracket and tooth assembly 9 is mounted on the transverse frame member 17 of the frame 11 and is positioned forwardly of the planter 13. The bracket and tooth assembly 9 includes a bracket assembly 18 and a Danish-type furrowing tooth 19. The furrowing tooth 19 includes an upper arcuate portion 20 which terminates in a flat attachment tab 21 having an opening 22 therewith. The upper arcuate portion 20 of the tooth 19 is integral with an intermediate portion 23 that extends rearwardly and downwardly therefrom. The intermediate portion 23 is integral with a lower portion 24 that extends downwardly and forwardly therefrom. The lower forward end of the lower portion 24 is provided with a spark shovel 25 which is secured thereto. The furrowing tooth 19 is adapted to form the planting furrow during the planting operation.
In this regard, a fertilizer discharge tube 26 is secured to the rear surface of the lower portion 24 of the furrowing tooth, as best seen in FIG. 2. The upper end portion of the discharge tube 26 is connected to the conduit 16 so that the fertilizer is discharged into the furrow formed by the furrowing tooth.
The bracket device 18 is secured to the furrowing tooth 19 and mounts the latter on the tool bar 17 of the frame 11. The bracket device includes a generally rectangular-shaped front plate 28 and a generally rectangular-shaped rear plate 29. The front plate 28 includes upper and lower straight substantially parallel transverse edges 30 and opposed vertical edges 31. A plurality of openings 32 are formed in the front plate 28 and are arranged in rows, each row being located adjacent one end of the vertical edges 31.
The rear plate 29 also has upper and lower straight substantially parallel transverse edges 33 and opposed vertical edges 34. Rear plate 29 also has a plurality of openings 25 therethrough and has openings also arranged in a pair of rows, each row being located adjacent one of the vertical edges 34. Bolts 36 extend through the openings in the front and rear plates and are secured in place by suitable nuts 37. In this regard, the front plate 28 is positioned against the front surface of the transverse tool bar 17 and the rear plate 29 is clamped against the rear surface thereof.
The rear surface 38 and rear plate 29 has an L-shaped support arm 39 extending outwardly and horizontally therefrom. An L-shaped support arm 39 includes a longitudinally extending arm element 40 which is of rectangular cross-sectional configuration and an arm element 41 which is integral with the arm element 40 and extends at right angles thereto. It will also be noted that the arm element 41 is also a hollow rectangular cross-sectional configuration. The arm element 41 has an opening 42 through the upper wall surface 42a thereof which communicates with the interior of the arm element 41.
The bracket and tooth assembly 9 also includes an L-shaped bracket 43 including a substantially flat horizontal bracket element 44 and a depending bracket element 45 which is integral with the bracket element 44 and extends downwardly at substantially right angles thereto. The horizontal bracket element 44 has an opening 46 therethrough and the depending bracket element 45 has a transverse slide 47 therethrough. The bracket element 43 is positioned so that the horizontal element 42 is positioned against the upper surface 42a of the arm element 41 and the opening 46 and the L-shaped bracket is exposed in registering relation with the opening 42 in the upper surface of the arm element 41. The attachment tab 21 of the furrowing tooth extends through the slot 47 in the depending bracket element 45 and a bolt 48 extends through the opening 22 in the attachment tab and the registering openings in the L-shaped bracket 43 and the arm element 41. A suitable nut and washer 49 secure the bolt 48 in connected relation with the arm element 41.
Referring now to FIG. 2, it will be seen that the shallow furrow made by the tooth 19 is laterally offset with respect to the seed furrow. In the embodiment shown, the furrow made by the tooth 19 is offset approximately one to three inches from the seed furrow. With this arrangement, the liquid fertilizer will be discharged closely adjacent the seed furrow, but will not be discharged directly into the seed furrow. Therefore, there is little, if any, danger of damaging the seeds with the liquid fertilizer. The bracket and tooth assembly 9 may be shifted laterally to move the furrowing tooth 19 towards or away from the seed furrow, depending on the kind and condition of the soil.
Referring now to FIG. 4, it will be seen that a different embodiment of a bracket and tooth assembly, designated generally by the reference numeral 99, is thereshown. The bracket and tooth assembly include a tooth (not shown) and is identical in all respects to the furrowing tooth 19, illustrated in the embodiments of FIGS. 1 and 2. The tooth (not shown) is provided with a fertilizer discharge tube (not shown) and is mounted on the bracket device 103 by an L-shaped bracket 102, which is also identical in construction to the L-shaped bracket 43 in the embodiment illustrated in FIGS. 1 to 3.
The bracket device 103 includes a generally rectangular shaped elongate vertically disposed clamping plate 104 having a plurality of openings 105 therethrough. The bracket device 103 also includes an L-shaped support member 106 including an elongate vertical arm 107 and a shorter horizontal arm 108, which is integral with the vertical arm and projects at substantially right angles thereto. The vertical and horizontal arms 107 are of a rectangular cross-sectional configuration and the vertical arm 107 is provided with spaced apart openings 109 therethrough for accommodating bolts 110 that also project through the openings 105 and the clamping plate 104. It will be noted that the clamping plate 104 is positioned against one vertical surface of the tool bar 17 and the vertical arm 107 of the L-shaped support member 106 is positioned against the other vertical surface. Suitable nuts 111 engage the threaded ends of the bolts 103 to secure the latter in clamped relation with respect to the tool bar.
The bracket device 103 also includes a generally rectangularly shaped clamping plate 112 and a generally rectangular shaped clamping plate 113, which is slightly larger in size than clamping plate 112. Clamping plate 112 has a plurality of openings 114 therethrough and the clamping plate 113 has a plurality of openings 115 therethrough. The clamping plates 112 and 113 are positioned against opposed surfaces of the horizontal arm 108 and are secured thereagainst by suitable bolt and nut units 116. In the embodiment shown, the horizontal arm 108 projects forwardly of the vertical arm 107 and the clamping plates 112 and 113 are disposed in vertical relation with respect to the horizontal arm 108. The clamping plate 113 has an arm 117 integral therewith and projecting laterally therefrom. The arm 117 is horizontally disposed and is of a generally rectangular cross-sectional configuration. In the embodiment shown, the arm 117 is disposed in parallel relation with respect to the tool bar 17.
The bracket 102 is positioned so that the horizontal arm 102a engages the upper surface of the transverse arm 117 and the vertical bracket element 102b engages the rear surface of the transverse arm 117. The tooth (not shown) projects through the slot 102c of the L-shaped bracket 102, and a nut and bolt assembly extend through an opening in the horizontal bracket element 102a through the opening in the attachment tab of the tooth (not shown). The bolt is secured in place by a suitable nut 119.
Referring now to FIG. 5, it will be seen that a further embodiment of the novel bracket and tooth assembly, designated generally by reference numeral 199, is thereshown. The bracket and tooth assembly include a tooth (not shown) and a bracket device 201. The tooth (not shown) is identical to the tooth 19 illustrated in the embodiments of FIGS. 1 to 3. Thus, the tooth is provided with a fertilizer discharge tube (not shown) which is clamped to the rear surface thereof in the identical manner of the earlier described embodiments.
The bracket device 201 includes a generally rectangular shaped clamping plate 202 having openings 203 therethrough. The bracket device also includes a second rectangular shaped clamping plate 204 having openings 205 therethrough arranged in longitudinal rows adjacent the longitudinal side edges of the clamping plate 204. It will be noted that the clamping plate 204 is substantially larger in size than the clamping plate 202. Suitable bolts 206 extend through the openings 205 in the clamping plate 204 and the openings 203 in the clamping plate 202. Each bolt 206 is provided with a nut 207 to secure the clamping plates in clamped relation on the tool bar 17 of a planter-type implement. In the embodiment shown, the tool bar 17 extends in a fore and aft direction and the clamping plates 202 and 204 engage vertical surfaces of the tool bar and are disposed in vertical relation relative thereto.
The clamping plate 204 is provided with an elongate arm 208 which is rigidly affixed thereto and which projects outwardly therefrom. It will be noted that the arm 208 is a generally rectangular hollow configuration and extends laterally and horizontally relative to the tool bar 17 when the bracket and tooth assembly are mounted on the tool bar. The tooth 200 is mounted on the arm 208 of the bracket device 201 by means of an L-shaped bracket 209 which is identical in construction to the L-shaped brackets used to mount the tooth on the previously described embodiments. In this regard, the bracket 209 is provided with a slot therein through which the attachment tab of the furrowing tooth projects. The horizontal bracket element of the L-shaped bracket 43 engages the upper surface of the arm 208 and a bolt 210 extends through an opening in the horizontal bracket element and through an opening in the attachment tab of the tooth and is secured in place by means of a suitable nut 211.
The bracket and tooth assembly of FIG. 5 function in the same manner as the previously described embodiments.
From the foregoing description, it will be seen that the bracket and tooth assembly permits efficient application of fertilizer in close but safe proximity to the seed furrow during the planting operation.
Thus, it will be seen that I have provided a novel and improved bracket and tooth assembly, which is not only of simple and inexpensive construction, but one which operates in a more efficient manner than any heretofore known comparable device. | A bracket and tooth assembly for a planter type implement includes a bracket having mounting means adjustably engaging the implement tool bar. The bracket includes an arm which supports the furrowing tooth to position the latter laterally but closely adjacent the planting furrow to permit effective dumping of liquid fertilizer from a conventional dispensing tube carried by the furrowing tooth. | 0 |
DESCRIPTION
The present invention relates to an apparatus for connection between a floating or semi-submerged structure, particularly a hydrocarbon loading or pumping buoy, and a riser pipe or conduit for raising hydrocarbons from the sea floor.
The development of the production of hydrocarbons starting with deposits found under bodies of water, particularly undersea, has led to the development of processes and apparatus permitting the extraction and then the raising to the surface for ultimately loading or distributing the hydrocarbon products.
Applicant's assignee has for example already described in French Pat. Nos. 72.32438, 72.39657, 76.28030, 76.33086 apparatus for collecting hydrocarbon products starting at the sea floor. Such apparatus generally use flexible tubular pipes or conduits having very high resistance to traction and to crushing, and are products of very great length which are made by applicant's assignee.
Certain problems are presented by ascending pipes or "risers", formed particularly advantageously by a flexible tubular pipe which is attached at its lower end to a well head or base on the sea floor, and which at the level of its upper end should be attached to a floating or semi-submerged structure usually constituted of a loading buoy which may be moored to a support ship or a tanker to which can be transferred the hydrocarbons supplied by the riser pipe from the sea floor. In effect, the surface structure or loading buoy will be subjected to displacements because of the wave motion of the water surface and the relative movements of the ships connected to it. The ascending pipe being attached by its lower end, it is necessary to provide a rotatable or swivel connection between the upper end of the pipe and the loading buoy. This rotatable connection is advantageously realized by a roller bearing assembly placed inside the loading buoy to assure relative rotation between the loading structure and the riser pipe or other members fixed to it, the riser pipe being inserted into the interior of the loading buoy through an opening made in the lower portion of the buoy.
During operation, it can become necessary to obtain access to or intervene for maintenance, repair, and replacement of the roller bearing assembly, or at the region or level of the connector which is attached to the upper end of the riser pipe.
The present invention has as a purpose, to provide an apparatus permitting easy accomplishment of such maintenance or intervention operations during the course of the buoy operation, this apparatus being particularly simple and reliable.
The apparatus according to the invention is characterized by the fact that it comprises at least one locking element located inside the loading structure and able to engage a member attached to the riser pipe, the locking element being movable between a first position out of engagement with the member attached to the riser pipe and in which the loading structure is rotatable with respect to the riser piper by means of an assembly of roller bearings and a position of engagement in which the loading structure is fixed to the riser piper and in which the roller bearing assembly no longer provides the connection between the loading structure and the riser pipe.
It will be understood that the use of the locking element or elements for fixing the loading structure and the riser pipe, permits the roller bearing assembly to be "disconnected" or removed, allowing all the necessary interventions inside the loading structure.
Preferably, the locking element or elements are arranged to cause, during their displacement between the disengagement and the engagement positions, a relative vertical movement of the loading structure and the riser pipe.
In one particular embodiment, the or each of the locking elements has a part in the shape of a wedge connected to the shaft or rod of a hydraulic cylinder or screw jack mounted in the loading structure and able to engage in an annular groove having an inclined flank formed in a member fixed to the riser pipe.
In order to make the invention better understood, one embodiment will now be described by way of non-limiting example with reference to the attached drawings in which:
FIG. 1 is a vertical sectional view of the apparatus according to the invention in normal operating position;
FIG. 2 shows the apparatus of FIG. 1 with the locking elements in their engaged positions;
The drawings show the lower portion of a semi-submerged structure such as a loading buoy designated overall by 1, which is basically cylindrical in shape, and has at its lower portion an axial opening 2 through which enters the end of a riser pipe 3 furnished with a peripheral sheath 4. Riser pipe 4 has a connector 5 at its upper end.
A trumpet or funnel shaped element 6 is fixed to riser pipe 3, this piece 6 itself being connected to an annular casing 7.
In the normal operating position, shown on FIG. 1, the loading buoy 1 is capable of relative rotation with respect to the assembly comprised of the riser pipe 3 and elements 6 and 7 connected to it by the intermediary of a roller bearing assembly 8 mounted coaxially with respect to the riser pipe 3 near its end having connector 5, this assembly of roller bearings being disposed between casing 7 connected to the riser pipe, and an annular element 9 fixed to the loading buoy 1.
Casing 7 has an annular groove 10 whose upper face 11 is inclined upwardly.
Above this groove 10 casing 7 has a flange 12 having an upwardly inclined upper face. Annular element 9, fixed to loading buoy 1 has an annular groove 13 with an inclined surface, flange 12 having shape corresponding to the shape of groove 13.
The apparatus according to the invention has screw jacks or hydraulic cylinders 14 connected to loading buoy 1 and whose shaft or rod has at its end a piece in the shape of a wedge 15 having an upper inclined surface 16 whose slope corresponds to the slope of face 11 of annular groove 10.
When, for example, to attain access to the roller bearing assembly 8, screw jacks 14 are operated, the upper faces 16 of wedges 15 engage against the inclined face 11 of groove 10, this causes a slight downward movement of piece 9 and the buoy assembly 1 relative to the riser pipe 3 and annular casing 7, to the full locking position shown on FIG. 2.
Where there is sufficient slack in riser pipe 3, the pipe and annular casing 7 will be lifted relative to the buoy.
In this position the loading buoy 1 is wholly fixed and rigid with the riser pipe or column 3, the roller bearing assembly 8 being in an unloaded or disconnected condition which allows access or intervention at this level, especially repair or replacement as required.
The apparatus according to the invention also includes seals or packing especially at 17 at the level of opening 2 and at 18 at the upper and lower portions of the roller assembly 8 to prevent entry of outside sea water to the inside of the loading buoy, and especially at the level of the roller bearing assembly.
With the wedges 15 extended, as shown at FIG. 2, bearing assembly 8 is unloaded or disconnected and annular casing 7 is rigidly clamped or secured to the buoy. The bearing assembly 8 can then easily be serviced or replaced without danger to personel, and without danger of disconnection of riser pipe 3.
In the embodiment shown, the bearing assembly 8 and annular casing 7 are so constructed, relative to each other, that after support ring 19 is removed from the upper end of casing 7, the entire bearing assembly 8 can be lifted axially for replacement or maintenance operations, such as replacement of rollers or seals. After the bearing assembly is replaced, support ring 19 is installed, and wedges 15 are withdrawn to the FIG. 1 position in which the annular casing 7 to which riser pipe 3 is connected, is again supported on bearing assembly 8, so that the buoy can swivel relative to the riser pipe.
Although the invention has been described in connection with one particular embodiment, it is of course evident that it is in no way thereby limited and that it may undergo numerous variations and modifications without exceeding either its scope or its spirit. In particular, it is clear that although the invention has been described as applied to the connection of a riser pipe for hydrocarbons, to a floating or semi-submerged loading buoy, it is in no way thereby limited and may be used in other applications such as, for example, the connection of a pipe to a floating beacon, torch, or platform. | A hydrocarbon loading buoy has a connection element rotatable in a bearing supported by the buoy. When a riser pipe or conduit is connected to the connection element the pipe and element can rotate or swivel relative to the buoy. A lock mechanism on the buoy is operable to lock the connection element to the buoy so that the connection element is supported independently of the bearing. With the connection element locked the bearing can be serviced, or removed, while the buoy is in operation. In a preferred form, the lock mechanism includes wedges which move radially and engage a sloping surface of the connection element to move it axially into clamping engagement with the buoy. | 1 |
FIELD OF THE INVENTION
This invention relates to new compositions of matter and more particularly to bisphosphine oxide monomers and polycarbonates derived therefrom. The resulting polycarbonates unexpectedly retain high glass transition temperatures, high impact resistances and flame retardancy.
BACKGROUND OF THE INVENTION
Polycarbonates are a well known class of high impact resistant thermoplastic resins characterized by optical clarity, high ductility as well as other advantageous properties. They are frequently employed as lenses and windows as a result of their transparency. Bisphenol A polycarbonate (BPA) is the predominant commercially available resin of this type. It is derived from 2,2-bis(4-hydroxyphenyl)propane, and ordinarily has a glass transition temperature of about 150° C.
It is of increasing interest to prepare polycarbonates which, while retaining the ductility of bisphenol A polycarbonates, have higher glass transition temperatures and are therefore more resistant to softening when heated. Moreover, there is need for polycarbonates which possess flame retardant properties since they are, for instance, conventionally used in the automotive and aircraft industries. Several flame retardant agents have been utilized in an attempt to produce flame retardant polycarbonates. For example, alkali metal salts of strong sulfonic acids are commonly used. However, when incorporated into the polycarbonate, the resulting polymer is hydrolytically sensitive. Further, when using these salts, it is also necessary to employ drip inhibitors or gas phase flame retardant agents. This is not ideal since drip inhibitors destroy the clarity of the polymer and gas phase retardants are often halogenated which creates problems with corrosion and toxicity. As an alternative to the above, phosphorus containing compounds such as triphenylphosphate have been used. When blended with a base polycarbonate, some flame retardant properties are observed. However, the resulting polymer blends are not desirable since they possess low glass transition temperatures (Tg) and low impact resistance when compared to the base resin.
The present invention is based on the discovery of bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone and homologs thereof, and their incorporation into polycarbonates. The resulting bisphosphine oxide substituted polycarbonates are expected to exhibit improved flame retardancy since they possess phosphine oxide groups which increase polycarbonate limiting oxygen index values. Additionally, they are expected to retain high Tg values and impact resistances when compared to the base resin devoid of the bisphosphine oxide comonomer.
DESCRIPTION OF THE PRIOR ART
Accordingly, attempts have been made to prepare polycarbonates that possess high glass transition temperatures in addition to clarity and high ductility. In commonly assigned, copending applications, Ser. Nos. 07/989,309 and 07/989,310, it is disclosed that polycarbonates prepared from 1,3-bis(4-hydroxyphenyl)-1,3-dialkylcyclohexanes and bis[4'-4-(hydroxyphenyl)phenyl]alkanes, respectively, display glass transition temperatures on the order of about 10° C. to about 45° C. higher when compared to conventionally used polymers. Moreover, in commonly assigned, copending application Ser. No. 07/989,316, it is disclosed that polycarbonates prepared from heterocyclic bis(4-hydroxyphenyl)cycloalkanes possess glass transition temperatures on the order of about 35° C. to about 84° C. higher when compared to the typical resins. However, the polycarbonates of the present invention are distinguishable from the above polycarbonates since, among other reasons, the latter fail to consider flame retardancy by incorporation of phosphine oxide comonomers.
Other investigators have focused their attention on the flame retardancy of polycarbonates. As previously stated, attempts have been made to incorporate phosphorus containing additives in a flame retardant polymer formulation; however, the results have been unfavorable since glass transition temperatures and impact resistances have been adversely affected.
In commonly assigned U.S. Pat. No. 5,194,564, mono-phosphine oxide copolymers, which possess flame retardant properties as well as favorable Tg values, are disclosed. Nonetheless, the instant polycarbonates are distinguishable from the above mono-phosphine oxide copolymers since, among other reasons, they employ bisphosphine oxide comonomers in lieu of the well known mono-phosphine oxide comonomers mentioned above. The purpose is to achieve improved flame retardancy while maintaining base polymer stability.
Efforts to produce polycarbonates either ignore the important benefits which can be obtained by producing polycarbonates possessing high Tg values, polymer stability and flame retardancy or fail to simultaneously achieve them all.
SUMMARY OF THE INVENTION
The principal object of the present invention therefore is the discovery of a bisphosphine oxide monomer and a bisphosphine oxide substituted polycarbonate comprising the structural units of the formula ##STR1## wherein A 1 is a tetravalent substituted or unsubstituted aromatic radical and A 2 and A 3 each are independently selected from aromatic radicals. Generally, 0.5-25 mole percent of the units of formula I are present in the bisphosphine oxide substituted polycarbonate, and preferably 2.5-10 mole percent of the total polymer consists of the units of formula I.
Additionally, the polycarbonates of the present invention can further comprise structural units of the formula ##STR2## wherein A 4 is a divalent substituted or unsubstituted aromatic radical.
When employing the mono-phosphine oxide comonomer discussed in U.S. Pat. No. 5,194,564, greater amounts of the comonomer are required to produce the desired copolymer displaying favorable flame retardancy. This can cause a decrease in base polymer stability.
Characteristically, phosphorus monomers used to prepare polyesters and polycarbonates cause hydrolytically unstable phosphorus oxygen bonds to form which leads to inferior base polymer properties as well as molecular weight degradation. These unstable phosphorus oxygen bonds are less prevalent when utilizing a bisphosphine oxide. When producing the desired conventional phosphine oxide substituted polycarbonate, a greater mole percent of the mono-phosphine comonomer is required when compared to the bisphosphine oxide comonomer of the instant invention. This is true because the former possesses a much lower weight percent of phosphorus in comparison to its bisphosphine oxide counterpart. Thus, in order to obtain the Tg values and flame retardancy of the polycarbonates of the instant invention, greater amounts of the mono-phosphine oxide comonomer would have to be incorporated into the base polymer chain resulting in poor base polymer stabilities and molecular weight degradation.
The additional features and advantages of the invention will be made evident upon reference to the following detailed description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Polycarbonates are generally formed by the reaction of a dihydroxyaromatic compound and a carbonate source.
One reactant for formation of the polycarbonates of this invention is a dihydroxyaryldiphosphine oxide (bisphosphine oxide monomer) of the formula ##STR3## wherein A 1 , A 2 and A 3 are as previously described. Specifically, A 1 can be ##STR4## wherein R 1 and R 2 are hydrogen, halogens, alkyl or aryl radicals and preferably para to each other. A 2 and A 3 may be any unsubstituted aromatic radical or substituted derivatives thereof. Suitable substituents include alkyl, alkenyl, halo, nitro, alkoxy and the like. Unsubstituted phenyl radicals are preferred. The hydroxy groups of formula III are preferably para to each other.
Bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone may be prepared by the reaction of a quinone and a phosphine oxide or a suitably treated chlorophosphine. The formation of the instant bisphosphine oxide monomer was discovered during the synthesis of a dihydroxyarylphosphine oxide via a process similar to the one mentioned in U.S. Pat. No. 5,003,029. Illustrative quinones include parabenzoquinone, 1,4-naphthoquinone, 1,4-anthraquinone, methyl-p-benzoquinone and dimethyl-p-benzoquinone. The preferred quinone is p-benzoquinone. Suitable phosphine oxides or chlorophosphine include diphenyl phosphine oxide or diphenyl chlorophosphine.
Additionally, the synthesis of mono-phosphine oxide monomers is described in Zh Obshch. Khim, 1972, 42 (11), 2415-18, Chem Comm., 1966 (15), 505-6 and USSR patents 302 and 346.
The preferred bisphosphine oxide monomer of the instant invention is bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone and can be prepared as disclosed by the examples which follow.
EXAMPLE 1
Into a 50 cc single-neck round bottom flask equipped with a magnetic stir bar reflux condenser and N 2 bypass was placed 0.5 g (55 mmols) of p-benzoquinone along with 1.0 g (5 mmols) of diphenyl phosphine oxide and 10 mL of 2-ethoxyethanol. The reaction mixture was stirred at 125° C. and after about 15 minutes a precipitate began to form. After 2 hours, the reaction mixture was cooled and filtered. The yellow product obtained was washed with a small amount of 2-ethoxyethanol and dried. The product weighed 0.67 g and melted at 253°-254° C. An H 1 NMR (d 6 -DMSO) analysis showed that a 50/50 mixture of 2,5-dihydroxyphenyldiphenylphosphine oxide and bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone was formed. The latter bisphenol was concentrated to one-third volume by treating with acetone. The concentrated product was then recrystallized from ethanol/water to produce the desired product. The structure was confirmed by 1 H and 13 C NMR (d 6 -DMSO) testing.
EXAMPLE 2
Into a 100 cc single-neck round bottom flask equipped with a magnetic stir bar was placed 4.5 g (14.5 mmols) of 2,5-dihydroxyphenyldiphenylphosphine oxide along with 6.0 g of sodium sulfate, 3.6 g (15.5 moles) of silver oxide and 60 mL of acetone. The reaction mixture was stirred at room temperature for 17 hours, followed by filtration and removal of the acetone to give 4.5 g of a brown sticky solid. 1 H NMR (CDCl 3 ) study showed that 2-diphenylphosphine oxide-1,4-benzoquinone was formed. To 1.54 g (5 mmols) of the benzoquinone above, in raw form, was added 1.0 g (5 mmols) of diphenylphosphine oxide dissolved in 20 mL of toluene. After stirring for about 5 minutes at room temperature, a tan precipitate was formed. Stirring was continued for 1.5 hours at which time the product was filtered and washed with toluene and dried to produce 2.12 g of bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone which was shown to be pure by 1 H NMR study.
Homologs of the bisphosphine oxide monomers prepared above may be prepared from additional precursor quinones. They too would make suitable comonomers for flame retardant polycarbonates and polyesters thereof.
Moreover, the above bisphosphine oxide monomers and homologs thereof would be useful for flame retardant strategy and stabilization in polymer systems other than polyesters and polycarbonates.
The phosphine oxide containing polycarbonates above may be formed by any method conventional in the art. Examples of methods to prepare phosphine oxide containing polycarbonates include an interfacial process, a transesterification process and a bishaloformate process.
The preferred method of forming the phosphine oxide substituted polycarbonates is interfacially, that is, in a mixed aqueous-organic system which results in recovery of the polycarbonate in the organic phase. A carbonate precursor is used in the interfacial reaction and is preferably phosgene. When using an interfacial process it is also standard practice to use a catalyst system well known in the synthesis of polycarbonates and copolyestercarbonates. Suitable catalysts include tertiary amines. Tertiary amines include aliphatic amines such as triethylamine, tri-n-propylamine, diethyl-n-propylamine, and tri-n-butylamine, and highly nucleophilic heterocyclic amines such as 4-dimethylaminopyridine. Such amines generally contain at least about 6 and preferably about 6-14 carbon atoms. The most useful amines are trialkylamines containing no branching on the carbon atoms in the 1- and 2-positions. Triethylamine is the most preferred.
A chain terminating agent to control the molecular weight of the polymers is usually present. Suitable chain termination agents are those commonly employed for polycarbonate formation, including monohydroxyaromatic compounds such as phenol, p-t-butylphenyl and p-cumylphenol. Phenol is preferred. Quantities of chain terminating agents can range from about 0.5 to about 7 mole percent based on the total amount of non-phosphorus dihydroxyaromatic compound employed.
Another method of preparing polycarbonates is by transesterification with a bisphenol of a carbonate ester such as diphenyl carbonate or a bis-polyfluoroalkyl carbonate. U.S. Pat. Nos. 4,217,438, 4,310,656 and 4,330,664 describe the formation of polycarbonates by a transesterification method and are hereby incorporated by reference.
Still another method of polycarbonate formation is the reaction of bishaloformates with alkali metal hydroxides and various amines. One method for reaction bishaloformates with dihydroxy compounds is disclosed in U.S. Pat. 4,737,573 which is hereby incorporated by reference. Generally bischloroformate oligomer compositions are prepared by passing phosgene into a heterogeneous aqueous-organic mixture containing at least one dihydroxyaromatic compound. The reaction is a condensation reaction that typically takes place interfacially.
The polycarbonates of the present invention can include both homo- and copolycarbonates. The copolycarbonates preferably contain about 0.5 mole percent to about 25 mole percent dihydroxyarylbisphosphine oxide units and more preferably contain about 2.5 mole percent to about 10 mole percent units.
The non-phosphorus dihydroxyaromatic compounds useful for forming copolycarbonates may be any such compound known to the art. The material represented by the formula
HO-A.sup.4 -OH V
is the source of the structural units of formula II above. Illustrative non-limiting examples of non-phosphorus dihydroxyaromatic compounds include:
2,2-bis(4-hydroxyphenyl-propane (bisphenol A);
2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane;
2,2-bis(3,5-dimethyl-4-hydroxyphenyl)propane;
1,1-bis(4-hydroxyphenyl)cyclohexane;
1,1-bis(3,5-dimethyl-4-hydroxyphenyl)cyclohexane;
1,1-bis(4-hydroxyphenyl)decane;
1,4-bis(4-hydroxyphenyl)propane;
1,1-bis(4-hydroxyphenyl)cyclododecane;
1,1-bis(3,5-dimethyl-4-hydroxyphenyl)cyclododecane;
4,4-dihydroxydiphenyl ether;
4,4-thiodiphenol;
4,4-dihydroxy-3,3-dichlorodiphenyl ether; and
4,4-dihydroxy-3,3-dihydroxydiphenyl ether.
Other useful non-phosphorus dihydroxyaromatic compounds which are also suitable for use in the preparation of the above polycarbonates are disclosed in U.S. Pat. Nos. 2,999,835; 3,028,365; 3,334,154 and 4,131,575, all of which are incorporated herein by reference. The preferred bisphenol is 2,2-bis(4-hydroxyphenyl)propane (bisphenol A).
The following example depicts the formation of the bisphosphine oxide substituted copolycarbonate of the instant invention.
EXAMPLE 3
The phosphine oxide containing copolycarbonate was prepared by interfacial phosgenation of a mixture of 21.7 g of BPA, 2.55 g of 2,5-(diphenylphosphine oxide)-1,4-hydroquinone (5 mole % compared to BPA), 0.32 g of p-cumylphenol chainstopper and 0.2 g of triethylamine in 125 mL of methylene chloride and 100 mL of water. To the vigorously stirred emulsion was added 15.2 g of phosgene over a 0.5 hour period. Once the reaction was complete, the phases were separated and the polymer solution (methylene chloride layer) was washed two times with 300 mL of 0.1N HCL followed by five times with 300 mL of distilled water. The polymer solution was precipitated into 1 L of methanol in a blender. The white powder obtained was isolated and dried at 120° C. GPC analysis of the polymer shows an Mn=15,000. 1 H and 31 P NMR analysis confirmed the incorporation of 2,5-(diphenylphosphine oxide)-1,4-hydroquinone into the polymer. The copolymer gave a strong, clear, colorless solvent cast film and the Tg of the copolymer determined by DSC is 150° C. | Bisphosphine oxide monomers and homologs thereof may be incorporated into polycarbonates in order to obtain a flame retardant polymer. More particularly, bis[2,5-(diphenylphosphine oxide)]-1,4-hydroquinone and homologs thereof may be used to prepare flame retardant polycarbonates that retain high glass transition temperature and high impact resistances. | 2 |
FIELD OF THE INVENTION
[0001] This invention concerns a waterboiler system with apparatus for removing solids from the boiler water for the purpose of conditioning the water without the use of water softeners or other chemical agents to reduce or eliminate the water's tendency to deposit precipitates onto heat transfer surfaces of the boiler system.
BACKGROUND OF THE INVENTION
[0002] Precipitation of dissolved solids from water is a result of the water reaching supersaturation, and many dissolved solids become less soluble at higher temperatures. Solids that behave in this manner are referred to as “inversely soluble”. The primary force inducing particle precipitation out of solution in water boilers is water temperature. Other parameters that contribute to particle precipitation include water hardness, conductivity, pH, water velocity, and alkalinity. These other parameters play a lesser role in boilers than they do in other systems due to the dramatic temperature increase. Of the many inversely soluble minerals that precipitate out of solution, the first is usually calcium carbonate. In untreated water, the initiation of particle precipitation is nucleation which occurs on surfaces of the boiler internal components, gradually producing an insulating scale that greatly reduces boiler efficiency.
[0003] To reduce or eliminate the build up of scale on boiler surfaces, a common practice is to treat the boiler water with water softeners to reduce the tendency for mineral precipitation and/or with other chemical agents to form compounds with increased solubility or other chemical complexes with the minerals dissolved in the boiler water to form precipitates in the boiler water, rather than on the boiler surfaces, which precipitates then settle by gravity to a low point of the boiler structure which then are periodically removed from the boiler, as by a “blowdown” procedure.
[0004] Another known way of causing precipitates to occur in the boiler water rather than on the boiler surfaces, is to treat the boiler water with oscillating electromagnetic flux, as for example with use of a device such as described in U.S. Pat. No. 6,063,267, owned by the Assignee of this application, which device is referred to as the “Dolphin” water treatment device and available from the Assignee of this application, namely Clearwater Systems, LLC of Essex, Conn., USA. Such exposure of the boiler water to oscillating electromagnetic flux causes nucleation of dissolved minerals to occur in the boiler water, which nucleation is then followed by an agglomeration of a nucleated particles into more massive and heavy precipitates which again settle by gravity to a low point in the boiler system and can be removed by periodic “blowdown” procedures.
[0005] The use of alternating electromagnetic flux for the treatment of boiler water has the advantage over chemical treatment of the water in that expensive chemicals and procedures and apparatus for adding the chemicals to the water are not required. On the other hand, both the chemical treatment and the treatment with a alternating electromagnetic flux have a common disadvantage in that the periodic boiler blowdowns required to remove the settled precipitates from the boiler system release significant amounts of hot water and therefore decrease the boiler efficiency.
[0006] A general aim of this invention is therefore to provide an apparatus for use with boiler systems to remove dissolved minerals from the boiler water before they form scale on boiler surfaces, which apparatus does not require the use of water softeners or other chemical agents and which apparatus greatly reduces the number of boiler blowdowns required over a given period of time.
[0007] In keeping with the above object, a further general object is to provide a water treatment apparatus for a boiler system which apparatus allows the boiler system to be operated continuously over long periods of time without blowdown and with a reduced need for manual supervision and maintenance.
SUMMARY OF THE INVENTION
[0008] The above objects are solved in accordance with the invention in that in an otherwise conventional boiler system, the water in the boiler system is treated by oscillating electromagnetic flux, by a device such as the above-mentioned Dolphin device, with the device preferably being located in the feed water supply line feeding water to the boiler. At the bottom or other low point of the boiler at which precipitated particles accumulate by gravity, water with entrained particles, is removed from the boiler by a pump and supplied under pressure to a mechanical solids separator, such as a centrifuge, to separate the drained water into solids and cleansed water, with the cleansed water flowing continuously from the separator and with the separated particles being collected in a sump of the separator. By means of a timer controlled valve, the collected particles are periodically drained from the separator; and the continuous outflow of cleansed water is returned to the boiler structure while still at a temperature close to that of its temperature at the point of drainage from the boiler.
[0009] Further, particularly in the case of the boiler structure being that of a firetube boiler, the cleansed water from the mechanical separator is preferably injected into the boiler as a jet or jets near the bottom of the boiler structure so as to keep the boiler water in the bottom of the boiler structure in a stirred or riled condition inhibiting the settling of the precipitated particles into compact masses which might otherwise become difficult to remove from the boiler.
[0010] More particularly, in the use of the apparatus of the invention, agglomerated free floating particles nucleated in the bulk water solution as induced by the electromagnetic flux and which would otherwise become scale are prevented from settling on surfaces or accumulating in low flow areas by providing a pump assisted flow on a continuous basis from the boiler to a mechanical separator that is performance enhanced by the nature of the agglomerated particles and which in turn is periodically drained to produce a concentrated mineral discharge to drain that saves energy by minimizing hot water loss from the system. The continuous flow of cleansed water from the separator is redirected back into the boiler in locations where internal boiler geometry promotes low water flow and enhances particulate settling. Thus, stirring these low flow areas to allow otherwise settled particles to enter the recirculating piping loop including the pump and the mechanical separator.
[0011] Other features and advantages of the invention will become apparent from the following detailed description of the preferred embodiments of the invention and from the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 . is a schematic view of a firetube boiler system and boiler water treatment apparatus embodying the invention.
[0013] FIG. 2 is a schematic view of a watertube boiler system and boiler water treatment apparatus comprising another embodiment of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] In the case of conventional boiler systems, bottom blowdown is the method used for solids removal from a boiler. The industry standard procedure for bottom blowdown is to have it almost always operated manually with the involved valves typically being opened for about fifteen seconds every eight hour shift. The standard bottom blowdown frequency varies depending upon the water and operating conditions of the individual boiler. In the use of chemical treatment, where the goal is to keep solids in solution by water softening and other means, this bottom blowdown method is usually sufficient to prevent excessive solids accumulation in the bottom of the boiler.
[0015] Referring to the drawings, FIG. 1 shows a boiler system embodying the invention wherein the boiler, indicated generally at 10 , is that of a conventional firetube boiler 12 with conventional piping which has been modified to adapt it to the present invention. External parts of the system are shown in solid line, and parts inside of the boiler are shown in broken line.
[0016] The boiler 12 of FIG. 1 is nearly completely filled with a body of water 14 . Inside the boiler 12 are a number of firetubes 16 through which hot gases produced by a burner 17 flow to an exhaust stack 18 as indicated by the arrows 20 . The water 14 thus surrounds the firetubes 16 and becomes heated by the hot gases flowing through the firetubes. The boiler shown is taken to be a steam boiler and has an outlet pipe 22 through which steam is removed from the boiler for whatever use to which it is put. It should be understood, however, that in keeping with the invention, the boiler need not be a steam boiler and in some instances may be a boiler for producing hot water in which case hot water rather than steam is removed from the boiler.
[0017] The conventional piping associated with the boiler 12 includes a feed water supply tank 24 which contains a supply of feed water and to which water is added by both a return pipe 26 and a raw water pipe 28 . Water supplied through the pipe 26 is condensate or other water originally removed as steam or hot water from the boiler through the outlet pipe 22 ; and the water added by the pipe 28 is raw water to make up for water lost in the use of the steam or hot water passing from the outlet pipe 22 .
[0018] Water is fed to the boiler 12 from the feed water supply tank 24 through a supply line or conduit 30 through which the flow of the water is controlled by a suitably controlled flow control valve 32 and through a check valve 34 . In the illustrated piping system, valves which are normally open are shown in non-solid form and valves which are normally closed are shown in solid form. Valves 36 , 38 , and 40 are conventional isolation valves provided for maintenance purposes. The water flowing to the boiler through the supply line 30 is shown in FIG. 1 to enter the boiler 12 at the point 42 after passing through open valve 44 .
[0019] The conventional blowdown piping for the boiler 12 of FIG. 1 includes two normally closed valves 45 and 46 connected in parallel with one another between the bottom of the boiler 12 and a drain line 48 , with the drain line including a normally closed valve 50 and a check valve 52 . Thus, for a conventional blowdown of the boiler 12 , the valve 50 is manually open and then each valve 45 and 46 is individually opened for the required amount of time and then re-shut to remove water with accumulated solids from the boiler.
[0020] In keeping with the invention, the conventional boiler system components described above for FIG. 1 , which may be taken to be intended for chemical treatment of the water, are modified by adding to the feed water supply line 30 a device 54 , which device 54 is preferably one such as shown by U.S. Pat. No. 6,063,267, the content of which is incorporated herein by reference, which applies electromagnetic flux, in the form of repetitive bursts of ringing electromagnetic flux, to the feed water passing through the line 30 to the boiler 12 .
[0021] The conventional components of the system shown in FIG. 1 are further supplemented by a pump 56 receiving water and solids from the drain line 48 , a mechanical separator 58 , preferably a centrifuge, receiving water and solids from the pump 56 , a timer controlled valve 60 connected between the solids outlet at the bottom end of the separator 58 and the drain line 48 , and a return line 62 connected with the upper cleansed water outlet of the separator 58 , with the return line 62 having two parallel branches which supply the cleansed water from the separator 58 through two check valves 64 and 66 respectively to two inlet points 68 and 70 of the boiler, with the inlet points 68 and 70 preferably being so located as shown in the bottom portion of the boiler 12 that the cleansed water enters the boiler bottom at relatively high jet like velocities to maintain the water in the bottom of the boiler 12 in a stirred condition to inhibit compacting of solid particulates which might otherwise impede the drainage of the solids through the drain line 48 .
[0022] Having described the components of the system shown in FIG. 1 , it's operation may be further described as follows. The separator 58 is designed to centrifugally separate solids from the drain water and its operating effectiveness (in terms of size and percentage of particles captured) is closely related to the pressure drop through the separator. The pressure drop through the separator (about 9 psig) is controlled by mass flow through the separator. Thus, the size and operating design parameters of the separator dictates the size of the pump 56 to be used. The standard separator size to be used is expected to be between 100-200gpn. The pump further is one, which has the necessary seals, and is otherwise designed, to withstand the relatively high operating temperatures of the handled water. With the existing manual blowdown valve 50 closed and valves 45 and 46 open, the illustrated system is allowed to operate continuously as solids accumulate in the bottom of the separator 58 and clean water is continuously sent back to the boiler through the top of the separator and the two branches of the return line 62 . The timer controlled valve 60 connected to the solids discharge bottom end of the separator 58 opens for about five seconds every day (depending upon water conditions and solids accumulation) to flush the separated solids from the separator. Cleansed water exiting the top of the separator 58 is directed to the front and rear bottom portions of the boiler 12 by the two branches 62 a, 62 b of the return line 62 . Partition walls inside the boiler at these locations can be used to promote solids accumulation and the continuous flow of cleansed water to these areas helps to keep the solids stirred up. A nozzle or adductor arrangement at each of the points of the discharge of the cleansed water from the two branches 62 a and 62 b of the return line may be used to further promote the stirring effect.
[0023] The system shown in FIG. 1 also includes an alternate line 72 extending from the feed line 30 through a valve 74 to the line 76 connecting the pump 56 to the separator 54 . With the valve of the system conditioned as shown in FIG. 1 , the feed water moving through the supply line 30 is added to the water 14 already in the boiler by passing through the open valve 44 and by entering the boiler at the point 42 . As an alternative to this, the feed water can instead be added to the water supplied to the separator 58 , as can be achieved in FIG. 1 by closing the valve 44 and opening the valve 74 . The benefits of this are twofold: first, the nucleation of particles precipitating out of solution would occur prior to reaching the separator 58 . This would remove some quantity of solids before they ever enter the boiler 12 and would thereby reduce the potential for solids accumulation in the boiler. Second, the combination of water streams from the pump 56 and the boiler feed water line 30 increases the overall flow to the separator providing additional pressure drop across it if needed. This can be important because separators sometimes fail to achieve the necessary pressure drop to operate at maximum effectiveness.
[0024] FIG. 2 shows a boiler system embodying the invention which embodiment is in many ways similar to that shown in FIG. 1 except for the boiler comprising a watertube boiler 80 instead of the firetube boiler 12 . Parts of the FIG. 2 system which are similar to those of the FIG. 1 system in FIG. 2 have been given the same reference numbers as in FIG. 1 and need not be redescribed.
[0025] The watertube boiler of FIG. 2 has an upper steam drum 82 and a lower mud drum 84 collectively containing the body of water 14 and connected to one another by generally vertically extending watertubes 86 which are so arranged that heated gases from the associated burner (not shown) as indicated by the arrow 88 pass over the watertubes 86 and supply heat to the water contained in the tubes.
[0026] In the case of the system shown in FIG. 2 , the water from the feed water supply line 30 enters the steam drum 82 through what may be an existing chemical feed pipe 90 , which is converted to this function since the use of chemicals has been eliminated by the use of the electromagnetic treatment device 54 . This pipe 90 typically has holes running its length to evenly disperse the supply water into the steam drum 82 . Because a certain amount of subcooling is required to promote natural circulation (the result of water density variations in different generating banks of watertubes 86 as a result of differences in the amount of heat picked up by various tubes) and to minimize bubble entrainment in the downcomer tubes of the tube bank (downcomer tubes are ones wherein the water flow is downward, as opposed to riser tubes where the flow of water is upward), the relatively cold feed water preferably enters the steam drum 82 and not the mud drum 84 . Water in the mud drum 84 is cooler than the water in the steam drum 82 , and the recirculated water from the mud drum may assist in the subcooling. Since the industry standard design location for feed water entering the boiler is being maintained, there is no swirling effect to dislodge accumulated deposits in the mud drum of the watertube boiler 80 . However, water velocities in a watertube boiler are usually much greater than in a firetube boiler so that in a case of a watertube boiler, the potential benefit of swirling the water in the bottom of the mud drum 84 would not be as significant as in the firetube boiler. Also in FIG. 2 the illustrated system differs from that of FIG. 1 in that the option provided in FIG. 1 of directing the feed water to the separator 58 rather than to the body of water 14 in the boiler, as made possible by the line 72 and valve 74 of FIG. 1 , is not included in the system of FIG. 2 . This alternate possibility is not shown in FIG. 2 since it could possibly effect the steam drum subcooling if the feed water temperature were to be significantly increased prior to entering the steam drum 82 .
[0027] In summary, in systems embodying the invention an electromagnetic flux water treatment device is used to promote the precipitation of solids from the boiler water and a mechanical apparatus is used to supplement the removal of the precipitated solids to prevent their accumulating through gravitational settling into the lower areas of the steam boilers and/or hot water boilers. This mechanical apparatus is a centrifugal separator/pump system installed as an addition to the existing piping previously designed for intermittent operation and solids removal, with the added components providing a continuous flushing and removal of solids, thereby allowing mineral loading incurred through the use of the electromagnetic flux device to be managed without the need for water softeners or other chemical agents. This is accomplished by adding a pump assisted recirculating loop from the existing periodic flushing, or blowdown, system through a mechanical separator and back into the boiler. The continuous flow of water from the from the bottom flush of the boiler, or blowdown, allows the solids to accumulate in the separator while the “cleaned” water is reverted back to the boiler. The separator is then periodically flushed to remove a much denser concentration of solids from the boiler than previously capable, thus allowing for much less hot water to be disposed down the drain, resulting in energy savings. The agglomerated nature of particle formation induced by the electromagnetic flux water treatment device further enhances the effectiveness of the separator and subsequent removal of particulate matter from the boiler, in addition to allowing for the aforementioned elimination of water softening chemicals and equipment. Also, the continuous nature of the water directed into the boiler that might otherwise only experience periodic inflows of water allows this recirculated water to be injected into the boiler in such a manner that it promotes dispersion of solids that otherwise would be allowed to settle in low flow areas. A secondary effect of the system may be to provide continuous water movement in the boiler, such that heat transfer effectiveness would increase and the boiler would be more responsive to variations in load demand, as well as reducing the time necessary to bring the boiler on line from a cold start. The system of the invention is particularly viable to augment the water treatment provided by an electromagnetic flux treatment device such as that shown in U.S. Pat. No. 6,063,267 that produces particle nucleation sites to produce free floating precipitated particles and subsequent benign water properties associated with equilibrium of non-chemically treated water.
[0028] Basic benefits of a boiler system in accordance with the invention are:
1. Eliminates water softening requirements while effectively removing the particles induced to precipitate in the bulk solution before they grow large enough to settle. 2. Takes advantage of the particle agglomerating principles of operating of the electromagnetic flux treatment device to make the mechanical separator more effective in removing the boiler solids. 3. Minimizes the effects of particulate settling in low flow areas of the boiler. 4. Reduces the amount of hot blowdown water to drain in order to increase boiler heat rate. 5. In the case of firetube boilers, provides an option for creating an alternative nucleation site by having the initial feed water temperature occur at the separator inlet as opposed to the boiler inlet, thus preventing many precipitated solids from ever entering the boiler. 6. In the case of a firetube boiler, increases the boiler responsiveness to load changes by providing greater forced convention and therefore higher heat transfer rates and lower boiler tube metal temperatures and stresses.
[0035] 7. In the case of a watertube boiler, enhances steam drum water temperature uniformity through better mixing—this providing smaller water density differentials in the watertube bank and thereby lower tube metal temperature and stresses. | A water boiler system for producing steam or hot water includes an apparatus for removing dissolved minerals from the boiler water without the use of water softeners or other chemical treatment agents. An electromagnetic flux producing device first treats water of the boiler system with alternating electromagnetic flux to cause nucleation of dissolved minerals in the bulk boiler water, rather than on boiler surfaces, with nucleated particles then accumulating into particulates which settle by gravity to a low area of the boiler. Water is continuously drained from the low area of the boiler and fed by a pump to a mechanical separator which continuously separates solids from the drain water and continuously passes cleansed water at a high temperature back to the boiler. In the return of the cleansed water to the boiler, it may be directed at high velocity toward the low area of the boiler to stir the boiler water to inhibit compact settling of the precipitated particles and/or to enhance the heat transfer efficiency of the boiler. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. patent application Ser. No. 09/348,776, filed on Jul. 7, 1999, the specification of which is hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present description generally relates to medical tools and methods, and more particularly, a percutaneous transluminal ablation catheter holding tool and method of use.
BACKGROUND
[0003] Percutaneous transluminal ablation (PTA) catheters for tissue ablation are available for the treatment of many conditions of the heart, including atrial fibrillation, atrial and ventricular arrhythmias or dysfunction, as well as others. The PTA catheters are long, slender, and flexible such that they can be inserted through a small incision through the skin into a blood vessel, such as an artery or vein, and advanced to the treatment site near to or inside the heart. Once positioned, the PTA catheter is used to selectively ablate or “burn” selected tissue which results in a change in the physiology of the treatment site. Such treatments may be used to block electrical conduction to correct abnormal cardiac rhythm that interferes with proper organ function.
[0004] Since its initial description in 1982, catheter ablation has evolved from a highly experimental technique to its present role as first-line therapy for most supraventricular arrhythmias, including atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, focal atrial tachycardia, and atrial flutter. Over the past five years, increasing attention has been focused on the development of catheter ablation techniques and ablation systems to cure atrial fibrillation. J. F. Swartz, et al., is credited with being the first to demonstrate that chronic atrial fibrillation can be cured using catheter ablation techniques (Swartz J F, Perrersels G, Silvers J, Patten L, Cervantez D., A Catheter Based Curative Approach to Atrial Fibrillation in Humans, Circulation. 1994; 90 (suppl 1): 1-335). These authors reported that creation of linear lesions in the right and left atrium results in a progressive increase in the organization of atrial activity until sinus rhythm is restored. M. Haissaguerre, et al., reported successful ablation of atrial fibrillation in a patient with paroxysmal atrial fibrillation by the creation of three linear lesions in the right atrium, two longitudinal and one transverse, that connected the two longitudinal lesions using a specially designed catheter (Haissaguerre M, Gencel L, Fischer B, Metayer P L, Poquet F, Marcus FI, Clementy J., Successful Catheter Ablation of Atrial Fibrillation, J Cardiovasc Electrophysiol 1994;5:1045-1052).
[0005] Currently available ablation systems are limited because they can only create singular spot lesions or short drag lesions, requiring a significant amount of time to perform biatrial lesions. Systems that can create linear lesions are currently undergoing investigation at this time and hold exciting promise for the future. One such system currently under clinical investigation is the Guidant's Heart Rhythm Technology's (HRT; Guidant Corporation, Cardiac Rhythm Management Group, St. Paul, Minn.) Linear Phased Radio Frequency Ablation System consisting of a 7 Fr., 5-mm tipped quadripolar deflectable electrode catheter and multiple pre-shaped steerable linear catheters which incorporate 12-3-mm platinum band electrodes with an inter-electrode spacing of 4 mm. Thermocouples are positioned on the outside curvature of the catheter to allow for temperature monitoring during radio frequency (RF) delivery. A variety of 3-dimensional catheter shapes, are designed to be used in conjunction with sheaths to achieve specific linear lesions within the right and left atria. The pre-shaped steerable linear catheters are created by means of a pre-shaped Nitinol stylet embedded within the shaft. These catheters are used in conjunction with the Guidant HRT Linear Phased RF Ablation Generator, which is a multi-channel RF generator capable of delivering phased RF energy at a frequency of 540 kHz to selected electrodes, in order to modify the lesion length, from localized, spot lesions to lesions which are 8 cm in length. When using the multi-electrode catheters, by delivering RF energy at adjacent electrodes out of phase with each other, a voltage gradient is created between electrodes and also to the back plate. This results in current paths both between electrodes and also to the return electrode (back plate), thereby creating a continuous linear lesion. The generator has the ability to continuously monitor the impedance and temperature of each active band electrode. Power output for pre-shaped linear catheters can be varied from 0 to 20 Watts per electrode. Power delivery is in the form of a duty cycle with a constant output amplifier with power variability controlled by varying the amount of time energy is delivered. This approach to power delivery allows for electrode cooling during the off cycle. Adjustments in the power output can be made to all electrodes at once or in three zones of four electrodes each. The generator incorporates additional safety features if excessive temperature or impedance is detected. The generator automatically shuts down power delivery to any band electrode if the impedance of that circuit exceeds a pre-set limit, or if the temperature exceeds a preset value. For the 5-mm tip ablation catheter, the RF generator will deliver RF energy with a maximal power output of 50 Watts to the tip only, while continuously monitoring the impedance and temperature of the tip electrode. Ablation duration can be adjusted from 5 seconds to 5 minutes.
[0006] Successful ablation therapy is defined as a return to normal sinus rhythm. To achieve this, lesions need to be continuous, transmural, and connected with other lesions or anatomical structures that cause blockage of atrial conduction. The seven recommended lesions are as follows: 1) right atrial isthmus ablation: linear lesion applied to the right atrium between the tricuspid annulus and the eustachian ridge, 2) right atrial inter-caval ablation: linear lesion applied along the posterior wall of the right atrium, between the superior vena cava and the inferior vena cava, 3) right pulmonary vein ablation (RPV): linear lesion applied to the left atrium, beginning below Bachmann's bundle, across the right superior pulmonary vein (RSPV) to the right inferior pulmonary vein (RIPV) and adjoining the mitral annulus, 4) left pulmonary vein ablation (LPV): linear lesion applied to the left atrium, beginning below Bachmann's bundle, across the left superior pulmonary vein (LSPV) to the left inferior pulmonary vein (LIPV) and reaching the mitral annulus, 5) superior pulmonary vein ablation (SPV): linear lesion applied to the left atrium, across the right superior pulmonary vein to the left superior pulmonary vein, 6) left atrial roof ablation (ROOF): linear lesion applied from the trigone, across the roof of the left atrium, to the left superior pulmonary vein, and 7) left atrial septal ablation (SEP): linear lesion applied to the foramen ovale to the right superior pulmonary vein. During creation of the right atrial inter-caval line, pacing is performed from each pair of electrodes at high output to assure the absence of diaphragmatic stimulation.
[0007] PTA catheters use any of a number of methods to deliver ablative energy to the tissue. Some of these methods include electric heating, microwave radiation, ultrasound radiation, and cryogenics. The energy delivery component of the PTA catheter, sometimes referred to as an electrode, is located either at the distal tip or along a portion of the distal end of the PTA catheter. When the PTA catheter is advanced through the blood vessel to the treatment site, either the tip or the side of the PTA catheter, depending on electrode type, is pressed against the tissue to be ablated.
[0008] There is a need to have the capability to apply ablation therapy non-transluminally, such as during open heart surgery, on either epicardium or endocardium. For example, some patients having surgery for the treatment of atrioventricular valve disease would benefit from ablation therapy in order to correct cardiac arrhythmias of the atria or ventricle. Up to 40% of patients requiring mitral valve replacement have concurrent atrial fibrillation (fast atrial arrhythmia) which can be treated by creation of long linear ablation lines in the atria. Since PTA catheters are currently available, there is a need to use PTA catheters non-transluminally.
SUMMARY
[0009] In general, the present tool and methods embody a percutaneous transluminal ablation (PTA) catheter manipulation tool for holding and positioning a PTA catheter, comprising a handle portion and a PTA catheter support structure. The PTA catheter is securely held in the PTA catheter support structure and the user holds the handle portion to position the PTA catheter against the treatment site. In one embodiment, the tool is made from a rigid material. In another embodiment, the PTA catheter support structure and/or the handle portion are made from a malleable material to facilitate forming to a desired shape. After treating one site, the tool may then be bent to a new desired configuration to treat the same or additional sites. In another embodiment, the PTA catheter manipulation tool incorporates, either internally or externally, a fluid delivery system that provides fluid to cool the PTA catheter support structure and/or the treatment site. In another embodiment, the support structure is pivotally mounted such that when pressed against the treatment site, the support structure will automatically position itself flush with the surface being treated.
[0010] This summary is a brief overview of some embodiments of the tool and methods of using a PTA catheter manipulation tool for holding and positioning a PTA catheter and is not intended to be exclusive or limiting and the scope of the invention is provided by the attached claims and their equivalents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] [0011]FIG. 1 is a perspective view of one embodiment of an ablation PTA catheter manipulation tool.
[0012] [0012]FIG. 2 is a perspective view of one embodiment of an ablation PTA catheter manipulation tool with PTA catheter attached.
[0013] [0013]FIG. 3A is a cross-sectional view of one embodiment of an PTA catheter manipulation tool PTA catheter support structure with PTA catheter attached.
[0014] [0014]FIG. 3B is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with cooling capability, with PTA catheter attached.
[0015] [0015]FIG. 3C is a perspective view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with cooling capability.
[0016] [0016]FIG. 4A is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with PTA catheter attached.
[0017] [0017]FIG. 4B is an end view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure.
[0018] [0018]FIG. 4C is cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with suturable lips.
[0019] [0019]FIG. 4D is cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down members and loops.
[0020] [0020]FIG. 4E is a perspective view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down members.
[0021] [0021]FIG. 4F is a perspective view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down member.
[0022] [0022]FIG. 5A is an end view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down latches.
[0023] [0023]FIG. 5B is cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down clips.
[0024] [0024]FIG. 5C is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with hold-down bands.
[0025] [0025]FIG. 6A is an end view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with attached PTA catheter.
[0026] [0026]FIG. 6B is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with cooling capability and attached PTA catheter.
[0027] [0027]FIG. 6C is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with cooling capability.
[0028] [0028]FIG. 6D is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with shaft attachment means.
[0029] [0029]FIG. 7 is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure.
[0030] [0030]FIG. 8A is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with PTA catheter.
[0031] [0031]FIG. 8B is a cross-sectional view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with cooling capability and PTA catheter.
[0032] [0032]FIG. 8C is a top view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with PTA catheter.
[0033] [0033]FIG. 8D is a top view of one embodiment of a PTA catheter manipulation tool PTA catheter support structure with PTA catheter.
[0034] [0034]FIG. 9 is prospective view of one embodiment of a PTA catheter manipulation tool.
[0035] [0035]FIG. 10 is a partial cross-sectional perspective view of one embodiment of an ablation PTA catheter manipulation tool with cooling capability.
[0036] [0036]FIG. 11 is a perspective view of one embodiment of a PTA catheter manipulation tool with cooling capability.
[0037] [0037]FIG. 12 is a perspective view of one embodiment of a PTA catheter manipulation tool with cooling capability.
[0038] [0038]FIG. 13A is an exploded top view of one embodiment of a PTA catheter manipulation tool.
[0039] [0039]FIG. 13B is a side view of one embodiment of a PTA catheter manipulation tool with PTA catheter.
[0040] [0040]FIG. 14 is a top view of one embodiment of a PTA catheter manipulation tool.
DETAILED DESCRIPTION
[0041] In the following detailed description, reference is made to the accompanying drawings, which are not necessarily to scale, which form a part hereof, and in which is shown by way of illustrating specific embodiments in which the device may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the device, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural changes may be made without departing from the spirit and scope. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined by the appended claims and their equivalents. In the drawings, like numerals describe substantially similar components throughout the several views.
[0042] The present apparatus and methods will be described in applications involving biomedical applications. However, it is understood that the present apparatus and methods may be employed in other environments and uses.
[0043] [0043]FIG. 1 is a perspective view of an embodiment of a PTA catheter manipulation tool 110 illustrating generally, by way of example, but not by way of limitation, one embodiment of a PTA catheter manipulation tool. More in particular, the tool 110 comprises a PTA catheter support structure 130 and a handle portion 120 . The PTA catheter support structure 130 is shaped to accept a PTA catheter. In the embodiment shown, the support structure 130 is in the form of a concave channel. Generally, support structure 130 comprises an elongated shape since PTA catheters are usually elongated in shape.
[0044] In one embodiment, PTA catheter support structure 130 is a relatively stiff member that is manufactured into a desired shape. The desired shape is dependent on its use such that the PTA catheter is held to create the desired lesion shape and that the handle portion facilitates access to the treatment site. In another embodiment, PTA catheter support structure 130 and/or handle portion 120 are made from a relatively malleable material or have malleable properties to facilitate bending into a desired shape, such as a curve or straight position, and retain that shape during use. In some embodiments, the malleability feature of support structure 130 and/or handle portion 120 is a property of the material that it is made. In other embodiments, the malleability feature of support structure 130 and/or handle portion 120 is facilitated by imbedding a spine of malleable material (such as a wire, rod or sheet) into flexible material that makes up the bulk of support structure 130 . In another embodiment, the support structure 130 may consist of a material that can be trimmed, such as with a scalpel or scissors, to a desired length.
[0045] The handle portion 120 is of any shape that would facilitate the grasping and using the tool 110 . The handle portion 120 and the PTA catheter support structure 130 may be one integral unit. In another embodiment, the handle portion 120 is detachable from the support structure 130 .
[0046] [0046]FIG. 2 is a perspective view of an embodiment of a PTA catheter manipulation tool 210 illustrating generally, by way of example, but not by way of limitation, one embodiment of a PTA catheter manipulation tool having a PTA catheter attached. More in particular, FIG. 2 shows an embodiment of the tool 210 consisting of a handle portion 220 , two shafts 222 and a PTA catheter support structure 230 . A PTA catheter 290 is shown mounted to support structure 230 in such a way that the PTA catheter electrodes 292 are held within the support structure 230 . In use, the user would hold the tool 210 by grasping the handle portion 220 and pressing the PTA catheter 290 against the treatment site.
[0047] The handle portion 220 is of any shape that would facilitate the holding and using the tool 210 . In some embodiments, the handle portion 220 is connected to the PTA catheter support structure 230 with more than one shaft 222 . The handle portion 220 , the one or more shafts 222 , and the support structure 230 may be formed as a single unit, or one or more of the entities may be detachable.
[0048] In embodiments where the support structure 230 and/or the one or more shafts 222 are made from rigid material, one shaft 222 may be sufficient to effectively transmit force applied on the handle portion 220 to the support structure 230 . The one or more shafts 222 and/or the support structure 230 may be of a material that is relatively malleable to facilitate bending the tool 210 to a desired shape. If the support structure 230 and/or the one or more shafts 222 are made from a relatively flexible or malleable material, more shafts 222 may be needed to uniformly transfer force from the handle portion 220 to the support structure 230 . The one or more shafts 222 may be made from a shape memory material that, upon the application of heat, such as with autoclaving, the one or more shafts 222 return to their manufactured shape. This would facilitate the reuse of tool 210 . The detachability of the one or more shafts 222 from the support structure 230 allows for disposal of the support structure 230 , or separate processing, such as sterilization.
[0049] The PTA catheter support structure 230 is shaped to accept a PTA catheter 290 . In the embodiment shown in FIG. 2, the support structure 230 is in the form of an elongated concave channel. Depending on the type of PTA catheter used, the support structure 230 may need to possess thermal, electrical, or both thermal and electrical insulating properties.
[0050] In one embodiment, the support structure 230 is pivotally mounted to the one or more shafts 222 which allows the support structure 230 to self align when pressed against the treatment site.
[0051] FIGS. 3 A-C are views, illustrating generally, by way of example, but not by way of limitation, of embodiments of portions of the PTA catheter support structure. These embodiments may also incorporate fluid channels and orifices to allow cooling of the treatment site. More in particular, FIG. 3A shows a cross-sectional view of a support structure 332 . The PTA catheter support structure 332 comprises a concave channel having a base 331 , spaced lips 333 extending from one side of the base 331 forming a cavity 338 , each lip having a free end, 335 and 337 respectively. In one embodiment, cavity 338 has a substantially circular cross section substantially conforming to and engaging a major portion of the outer surface of the PTA catheter 390 . The lips 333 , extending from the base 331 , partially overlap the PTA catheter 390 in order to retain the PTA catheter 390 with in the cavity 338 . A portion of the PTA catheter 390 , when placed within the cavity 338 , is exposed beyond the lips 333 . In one embodiment, the support structure 332 is made from a relatively rigid material and the PTA catheter 390 is slidably inserted into the cavity 338 . The PTA catheter 390 is held in place by friction or other means.
[0052] In another embodiment, lips 333 are made from a relatively resilient material which allows for the flexing or opening of the lips 333 away from each other to allow the PTA catheter 390 to be inserted into the cavity 338 , and once the flexing force is released, to allow the lips 333 to close in around the PTA catheter 390 to hold it in place.
[0053] The PTA catheter support structure 334 may incorporate a fluid delivery capability. This fluid delivery capability comprises one or more fluid passages in fluid communication with one or more fluid orifices. FIG. 3B shows a cross-sectional view of an embodiment of a support structure 334 , which incorporates fluid orifices 340 in fluid communication with internal fluid passages 342 which allow cooling fluid to exit the support structure 334 near the PTA catheter 390 to provide for cooling of the treatment site. FIG. 3C shows a top view of an embodiment of a cooled support structure 336 , which incorporates fluid orifices 341 along the length which allows cooling fluid to exit the support structure 336 to provide for cooling the treatment site.
[0054] FIGS. 4 A-F are views, illustrating generally, by way of example, but not by way of limitation, of embodiments of portions of the PTA catheter holding support structure. These embodiments may also incorporate fluid orifices to allow cooling of the treatment site. More in particular, FIG. 4A shows a cross-sectional view of a support structure 430 . The PTA catheter support structure 430 comprises a concave channel having a base 431 , spaced lips 433 extending from one side of the base 431 forming a cavity 438 . In one embodiment, cavity 438 has a substantially circular cross section substantially conforming to and engaging a portion of the outer surface of the PTA catheter 490 . The lips 433 , extending from the base 431 , partially surrounds the PTA catheter 490 . PTA catheter 490 may be held in cavity 438 with an adhesive means.
[0055] [0055]FIG. 4B shows a cross-sectional view of support structure 432 further comprising a gripping surface 435 , within cavity 438 , which is provided to engage and frictionally grip the PTA catheter. This gripping surface 435 may consist of a plurality of resilient ridges or bumps 439 provided to “grab hold” of the PTA catheter 490 when inserted into the cavity 438 of the support structure 430 . In one embodiment, the support structure 432 is be made from a resilient material, such that lips 433 may be flexed or opened up away from each other to allow the insertion of the PTA catheter 490 . Once inserted, the expansion force would be relieved and the bumps or ridges 439 would “grasp” the PTA catheter 490 while the lips 433 are closed around it.
[0056] [0056]FIG. 4C is a cross-sectional view showing an embodiment of support structure 434 where the lip free ends 441 have the ability to be sutured into, such that suture 450 could be used to form hold-downs 450 that would hold the PTA catheter 490 onto the cavity 438 . FIG. 4D is a cross-sectional view showing an embodiment of PTA catheter support structure 436 where the lips 437 incorporate suture loops 460 to facilitate the use of suture or other hold-down material to form hold-downs 452 . FIG. 4E shows a top view of a portion of the support structure 434 with multiple single suture hold-downs 450 . FIG. 4F shows a top view of a portion of the support structure 434 with a single running lace hold-down 454 .
[0057] FIGS. 5 A-E are views, illustrating generally, by way of example, but not by way of limitation, of embodiments of portions of the PTA catheter holding support structure. These embodiments may also incorporate fluid orifices to allow cooling of the treatment site. FIG. 5A is an end view of an embodiment of PTA catheter support structure 530 having one or more clips 554 . IN this embodiment, the PTA catheter is attached to support structure 530 by clips 554 . Clips 554 may incorporate a hinge means 551 attaching clips 554 to the other lip 537 . Clips 554 may incorporate a latch means 553 which engages a catch means 555 on lip 535 . Clips 554 may be made from a rigid material or a resilient material. Clips 554 and support structure 530 may be made as a single unit or as separate entities.
[0058] [0058]FIG. 5B is a cross-sectional view of an embodiment of a PTA catheter support structure 534 that has one or more clips 542 . In this embodiment, the PTA catheter is attached to support structure 534 by one or more clips 542 that are shaped to substantially conform to the shape of the PTA catheter. In one embodiment, one or more clips 542 is slidably inserted over the support structure 534 . In another embodiment the one or more clips 542 are resilient or spring-like to allow flexing or opening up such that it can be placed over the PTA catheter 540 and support structure 534 and “clamped” around the support structure 534 holding the PTA catheter to the support structure 534 . In one embodiment, lips 545 have an attachment means 565 that engages attachment means 567 on the one or more clips 542 .
[0059] [0059]FIG. 5C is a cross-sectional view of another embodiment of the PTA catheter support structure 536 . In this embodiment, PTA catheter 590 is held to the support structure 536 by use of one or more resilient bands 544 .
[0060] FIGS. 6 A-D are views, illustrating generally, by way of example, but not by way of limitation, of embodiments of portions of the PTA catheter holding support structure. These embodiments may also incorporate fluid orifices to allow cooling of the treatment site. FIG. 6A is a end view of an embodiment of the support structure 630 comprising a V cup having a base 631 , spaced lips 633 extending from one side of the base 631 forming a cavity 638 . Cavity 638 provides that the support structure 630 can accommodate various sizes (i.e., diameters) of PTA catheters 690 . A portion of the PTA catheter 690 , when placed within the cavity 638 , is exposed above the lips 633 . In one embodiment, the support structure 630 is made from a relatively rigid material. In one embodiment, the support structure 630 is malleable.
[0061] In one embodiment, the resilient force of the support structure 630 clamping down or squeezing is enough to hold the PTA catheter 690 in place. Hold-downs 490 , 450 , 452 , 444 , 554 , 542 , and 544 like the ones in FIGS. 4C, 4D, 4 E, 4 F, SA, 5 B and 5 C respectively, may also be used as well as the use of bumps or ridges 439 as shown in FIG. 4B.
[0062] [0062]FIG. 6B shows a cross-sectional view of another embodiment of the support structure 632 that incorporates one or more fluid orifices 640 and one or more fluid passages 632 . FIG. 6C shows a cross-sectional view of another embodiment of the support structure 634 that incorporates fluid orifices 642 . FIG. 6D shows a cross-sectional view of another embodiment of the support structure 636 that shows how removable or permanent attachment means of shaft 622 may be made; on the support structure side 637 and/or the support structure back 639 .
[0063] [0063]FIG. 7 is a cross-sectional view, illustrating generally, by way of example, but not by way of limitation, of an embodiment of a portion of the PTA catheter holding support structure. This embodiment may also incorporate fluid orifices to allow cooling of the treatment site. FIG. 7 show a cross-sectional view of an embodiment of support structure 730 that has one or more malleable members 770 . One or more malleable members 770 , or substructure, are made from a material, and are sized and numbered, such that they impart a bend and stay property to the support structure 730 which would be made from a complementary material that allows the support structure 730 to be bendable. One or more malleable members 770 may be wires, rods, and flat sheet, among others. The one or more malleable members 770 are used in PTA catheter holding support structures of any shape; including those having a circular, V-shaped, and rectangular cross section.
[0064] FIGS. 8 A-D are views, illustrating generally, by way of example, but not by way of limitation, of embodiments of portions of the PTA catheter holding support structure. These embodiments may also incorporate fluid orifices to allow cooling of the treatment site. FIG. 8A is a cross-sectional view of an embodiment that has a flat-shaped support structure 830 . The PTA catheter 890 is held onto the support structure 830 with the use of one or more hold-downs 850 , such as suture, clips, bands, and the like. In one embodiment, the hold-downs 850 are integrally molded loops or rings that the PTA catheter is threaded through. In other embodiments, elastic loops, adhesive, and the like may be used to attach the PTA catheter 890 to the support structure 830 . In one embodiment, the hold-downs 850 pass through the support structure 830 and are tied-off, or first passed through pledget 852 and then tied off. The pledget 852 helps to reinforce and resist suture-knot pull-out. FIG. 8B shows a cross-section of PTA catheter support structure 832 further comprising one or more fluid orifices 840 and one or more fluid passages 842 .
[0065] [0065]FIG. 8C and D are top views showing an embodiment of a flat-shaped support structure 832 having notch features 838 which facilitates the support structure 832 to be straight (FIG. 8C) or bent (FIG. 8D). PTA catheter 890 may be held onto the support structure 890 by the use of elastic bands, suture ties, and other hold-downs 853 , wrapping the PTA catheter 890 and the support structure 832 in the notch feature 838 . In one embodiment, the hold-downs 853 are one continuous piece wrapped around at least one notch feature 838 and the PTA catheter 890 . In other embodiments, singular hold-downs 853 at each notch feature 838 and PTA catheter 890 location are used.
[0066] [0066]FIG. 9 is a perspective view of an embodiment of an PTA catheter manipulation tool 910 illustrating generally, by way of example, but not by way of limitation, one embodiment of an PTA catheter manipulation tool. More in particular, FIG. 9 shows an embodiment of the tool 910 consisting of a handle portion 920 , two shafts 922 and a PTA catheter support structure 930 . Support structure 930 further comprises loops 956 forming a substantially tubular shape through which a PTA catheter may be slidably inserted. A PTA catheter would be mounted to support structure 230 in such a way that the PTA catheter electrodes are exposed between the loops 956 . In use, the user would hold the tool 910 by grasping the handle portion 920 and pressing the attached PTA catheter 990 against the treatment site.
[0067] [0067]FIG. 10 is a top view, illustrating generally, by way of example, but not by way of limitation, of an embodiment of portions of the PTA catheter manipulation tool. In particular FIG. 10 shows an embodiment of a PTA catheter manipulation tool 1010 that has cooling capability. Fluid is supplied to the support structure 1030 from a fluid supply system 1059 via a fluid supply line 1050 that attaches to the handle portion 1020 that has an internal fluid channel 1052 in fluid communication with internal support structure fluid channels in fluid communication with a plurality of orifices 1056 which allow the cooling fluid to exit the orifices 1056 and drench the PTA catheter 1090 and the surrounding area.
[0068] [0068]FIG. 11 is a top view, illustrating generally, by way of example, but not by way of limitation, of an embodiment of portions of the PTA catheter manipulation tool. In particular FIG. 11 shows an embodiment of a PTA catheter manipulation tool 1110 that has cooling capability. The fluid is supplied to the support structure 1130 from a fluid supply system 1159 via a fluid supply line 1150 that may or may not attach to the handle portion 1120 . The fluid supply line 1150 attaches to a connection means 1153 on the support structure 1130 . The fluid line 1150 is in fluid communication with internal passages in the support structure 1130 . The passages in the support structure 1130 are in fluid communication with a return fluid line 1151 that returns fluid to the supply system 1159 in a recirculating manner. The fluid flowing through the passages cools the support structure 1130 during use.
[0069] [0069]FIG. 12 is a top view, illustrating generally, by way of example, but not by way of limitation, of an embodiment of portions of the PTA catheter manipulation tool. In particular FIG. 12 shows an embodiment of a PTA catheter manipulation tool 1210 that has cooling capability. The fluid is supplied to the support structure 1230 from a fluid supply system 1259 via a fluid supply line 1250 that may or may not attach to the handle portion 1220 . The fluid supply line 1250 attaches to a connection means 1253 on the support structure 1230 . The fluid line 1250 is in fluid communication with internal passages in the support structure 1230 . The passages in the support structure 1230 are in fluid communication with orifices 1256 which allow the cooling fluid to exit the orifices 1256 and drench the PTA catheter and the surrounding area.
[0070] [0070]FIGS. 13A and 13B present a top and side view, respectively, illustrating generally, by way of example, but not by way of limitation, embodiments of the PTA catheter manipulation tool. In particular FIGS. 13A and B are exploded views showing an embodiment of the PTA catheter manipulation tool 1310 having multiple shafts 1322 , handle portion 1320 , and a PTA catheter holding support structure 1330 . Attachment means 1324 on the shafts 1322 interrelate with attachment means 1328 on the support structure 1330 for a temporary or permanent connection. Attachment means 1324 and 1328 is a snap fitting, a screw fitting, a ratchet fitting, or any other means to temporarily or permanently connect the shafts 1322 to the support structure 1330 . FIG. 13B shows a side view of the embodiment in FIG. 13A with the addition of PTA catheter 1390 . PTA catheter 1390 may or may not be attached to the handle portion 1320 for support.
[0071] [0071]FIG. 14 presents a top view illustrating generally, by way of example, but not by way of limitation, embodiments of the PTA catheter manipulation tool. In particular FIG. 14 shows an embodiment of the PTA catheter manipulation tool 1410 having a handle portion 1420 , multiple independently bendable and adjustable shafts 1422 , each shaft 1422 having a PTA catheter holding support structure 1430 . The PTA catheter holding support structures 1430 may incorporate clips 1424 , such as those shown in FIG. 5, for a temporary or permanent connection of a PTA catheter to the holding support structure 1430 .
[0072] Operation and use of an embodiment of a PTA catheter manipulation tool can now be briefly described as follows. This example is not intended to be exclusive or limiting and the scope of the invention is provided by the attached claims and their equivalents. Let it be assumed that it is desired to introduce radio frequency energy into the wall forming a chamber of the heart to cause ablation of the myocardium. Also let it be assumed that the tool is introduced into the chamber of the heart in a human being in a conventional open heart procedure. By using operator experience and preference, the tool is bent and formed into a desired shape to allow convenient assess to the ablation site by the PTA catheter and to produce a lesion of the desired shape. The PTA catheter is attached to the PTA catheter holding support structure. The support structure is pressed against the tissue such that the PTA catheter is touching the tissue. Radio frequency is applied to the electrode which ablates the tissue. Fluid flows from the fluid supply system through the supply line and out the orifices in the support structure effectively cooling the surrounding tissue to minimize collateral tissue damage.
[0073] It is to be understood that the above description is intended to be illustrative, and not restrictive. Many other embodiments will be apparent to those of skill in the art upon reviewing the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. | The present tool and methods embody a percutaneous transluminal ablation (PTA) catheter manipulation tool for holding and positioning a PTA catheter, comprising a handle portion and a PTA catheter support structure. The PTA catheter is securely held in the PTA catheter support structure and the user holds the handle portion to position the PTA catheter against the treatment site. In one embodiment, the tool is made from a rigid material. In another embodiment, the PTA catheter support structure and/or the handle portion are made from a malleable material to facilitate forming to a desired shape. After treating one site, the tool may then be bent to a new desired configuration to treat the same or additional sites. In another embodiment, the PTA catheter manipulation tool incorporates, either internally or externally, a fluid delivery system that provides fluid to cool the PTA catheter support structure and/or the treatment site. In another embodiment, the support structure is pivotally mounted such that when pressed against the treatment site, the support structure will automatically position itself flush with the surface being treated. | 0 |
BACKGROUND
[0001] The present invention concerns an air diffuser for a vehicle, in particular for ventilation, heating and/or air conditioning of the passenger compartment.
[0002] Air diffuser are known for use in vehicles of various kinds. They allow a entry of fresh air, heated and/or colled air into a vehicle interior. Usually, anticipated air diffusers have an air outlet element with passage ways and which is rotatable around one or several axes. By orienting the air outlet element the direction of the air stream can be selected.
[0003] From patent DE 19721831A1 an air diffuser for the interior of a vehicle is known where the air outlet element features a partial area for a diffuse air exit and a partial area for an unrestricted air exit over a larger area, and where the manner of the air exit can be selected by turning the air exit element.
[0004] From patent DE 4338099C2 is also known an instrument panel with a large-surface perforated air exit surface covering an airduct on one side, for diffuse air distribution.
[0005] Here the large-surface perforated air exit area forms the top side of the instrument panel facing the windshield. The air exit area is connected to an air distributor box which has a perforated ventilation damper for controling the airstream. Additional air supply devices for the vehicle interior which allow diffuse ventilation, are for instance known from patents DE 3908541C2, DE 1530615 and DE 1909519.
[0006] Anticipated air outlets are generally adjusted manually. There are however air outlets in the luxury class that are driven by an actuator.
[0007] From patent DE 3717676 A1 a vehicle air conditioning unit is known which has a bimetallic tab which effects a commutation at a channel branching, depending on the airstream temperature, the airstream intensity or according to a time function.
[0008] A disadvantage of anticipated air outlets for producing a diffuse flow field is the flow field is not adequately diffuse, i.e., that it is still distinguishable as a directed flow field and/or that the constructive expenditure for obtaining the diffuse flow field is relatively high.
[0009] Furthermore it is also known from the state of the art, to provide a vehicle seat with ventilation. In the so-called “climate seat” of the BMW 7 vehicles multistage fans are imbedded in the upholstery of seat and back which circulate air from the vehicle interior through the seat upholstery. By means of balance control heat distribution between the seat are and the seatback can be adjusted individually. Here again it is disadvantageous that the constructive expenditure for making such a ventilated seat is relatively high.
[0010] The invention is therefore based on the objective to create an improved air outlet for a vehicle, as well an an improved instrument panel, a headliner and interior covering with a ventilating function, as well as a vehicle seat with integrated ventilation.
[0011] The objective the invention is based on is being solved with the characteristics of the individual patent claims. According to invention an actuator for the air outflow is used which features a temperature-inducible deformation effect. Furthermore, means are provided for inciting the deformation effect, in order to achieve a desired setting of the airstream.
[0012] According to a preferred design of the invention the actuator is in the form of a flexible strip. When for instance a current is applied to the actuator the actuator gets hot and bends so that an air exit opening is unblocked more or less. Alternatively the deformation effect of the actuator is induced by heating the actuator with a controllable radiation source.
[0013] According to another preferred design of the invention the actuator is formed for the arching of an interior covering. For this purpose, several adjacent actuators are for inprovided which each featuring a deformation effect in the opposite direction. Through temperature induction of the de formation effect this results in the formation of air exit openings of varying size.
[0014] According to another preferred design of the invention the actuators are arranged on a meander-shaped support. The deformation effect causes a deformation of the support which consequently unblocks a air exit opening.
[0015] According to another preferred design of the invention the actuator is supported solidly one one side and detachably on an opposite side. The detachable support may for instance be realized with electromagnetic means.
[0016] According to another preferred design of the invention each actuator can be controlled separately, or groupd of actuators are formed with the individual groups being each separately controllable.
[0017] According to a preferred design of the invention a large-surface air exit area is realized in the area of the instrument panel, the headliner or another interior covering component. For this purpose several actuators are distributed over the air exit area.
[0018] According to another preferred design of the invention one or several actuators are provided in a vehicle seat for supplying the airstream through the seat surface.
[0019] For the realization of the temperature-inducible deformation effect of the actuator several suitable technologies may be applied. An actuator may for instance be realized by sandwiching materials of different thermal expansion coefficients; when different metallic materials are used, such an arrangement is called a bimetall strip.
[0020] According to a preferred design of the invention the temperature-inducible deformation effect is achieved by using materials with a shape-memory effect. Appropriate alloys are also called Shape-Memory-Alloys (SMA). Examples for this are the NiPi- and NiTiPb alloys. Additional shape-memory alloys are known from “Alloys with Shape-Memory”, Dieter Stöckel, Erhard Hornbogen, Expert-Verlag, 1988, ISBN 3-8169-0323-1. Alternatively or additionally conductive synthetic materials as they are known in the field of polyelectronics may be used.
[0021] The deformation effect is a reversible effect. For this one may use a one-way effect with an additional mechanic readjusting device. This reversible effect is based on the fact that so-called memory-alloys are considerably less solid in the martensitic state than in the high-temperature phase. It is therefore by heating that the deformation of the actuator into the high-temperature form is achieved, for instance through the supply of an electrical current. After the current is switched off the actuator does not automatically resume its original shape, but it is returned ot its original shape by a force produced by appropriate mechanical means.
[0022] Alternatively, a material is used that features a two-way effect. With the two-way effect the material “remembers” both the high-temperature and a low-temperature form. As a special case of the two-way effect one may also use materials featuring an all-round effect.
[0023] Use of materials with shape-memory effect for automotive technology is as such known from “Alloys wwith shape-memory”, chapter 3.8.2, page 92 to 94, and notably for fog lights with protective lamella against stones with a nickel-titanium spring as memory element and also for temperature-dependent actuating functions for engines, transmissions and chassis, as for instance for fan clutches of engines, throttling devices of injection pumps as well as for vehicle transmissions with enhanced shifting behavior. From patent CA 2346260A1 one is also familiar with the use of shape-memory alloys for the setting/adjusting of a rearview mirror.
SUMMARY OF THE INVENTION
[0024] The present invention allows the advantageous use of materials with shape-memory effects for realizing an air outlet for a vehicle. Through the use of materials with shape-memory it is possible to create a large-surface diffused flow field which vehicle occupants find to be especially pleasant.
[0025] According to a preferred version of the invention an appropriately large-surfaced air outlet is integrated into the instrument panel. Alternatively or additionally the air outlet may also be integrated into the headliner or another interior covering element. And it is also possible to integrate an air outlet according to invention into a vehicle seat.
[0026] In the following some preferred versions of the invention are explained in detail with reference being made to the drawing.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 a first version of an air outlet in its closed state.
[0028] FIG. 2 the air outlet of FIG. 1 in the opened state,
[0029] FIG. 3 a second version of an air outlet in its closed state,
[0030] FIG. 4 the air outlet per FIG. 3 after driving it to direct the airstream into a first direction,
[0031] FIG. 5 the air outlet per FIG. 3 after driving it to direct the airstream into a second direction,
[0032] FIG. 6 a cross section of an air outlet in closed condition that is integrated into an interior covering element,
[0033] FIG. 7 the interior covering element of FIG. 6 in its opened condition,
[0034] FIG. 8 an interior covering element with a lamellar, parallel arrangement of actuators in the closed condition,
[0035] FIG. 9 the interior covering element of FIG. 8 in the opened condition,
[0036] FIG. 10 an interior covering element with a meander-shaped support in the closed condition,
[0037] FIG. 11 the interior covering element of FIG. 10 in the opened condition,
[0038] FIG. 12 a perspective view of an instrument panel with integrated large-surfaced outlet and
[0039] FIG. 13 the instrument panel of FIG. 12 with the outlet in the opened condition.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0040] FIG. 1 shows an interior covering element 100 of a vehicle. Integrated into the interior covering element 100 is an outlet which features several actuators 102 . Each actuator 102 has a material layer 104 of a material with a temperature-inducible deformation effect.
[0041] The material is for instance a shape-memory alloy, i.e., a so-called Shape-Memory-Alloy (SMA). The material layer 104 is in the form of strips and fastened at its one end on the support 106 .
[0042] On the surface of the material layer 104 is an additional layer 108 . The layer 108 may be a decorative layer or it may be another functional layer. In the latter case the layer 108 may be of the same material as the layer 104 , with the material in layer 108 being in a different phase, i.e. for instance in the material layer 104 in the austenitic phase and in the material layer 108 in the martensitic phase or vice versa.
[0043] FIG. 1 shows the condition of the interior covering element 100 in its closed state. In this state the actuators 102 are in their low temperature shape.
[0044] By applying a voltage or other induction of current into the material layer 104 the temperature is increased by several degrees Kelvin. Alternatively one may also use a radiation source below the actuators 102 to increase the temperature. The temperature change causes the actuators 102 to “remember” their high temperature shape and to transition to it, as shown in FIG. 2 . Through the transition to the high temperature shape the actuators 102 unblock air exit openings 110 through which air 112 can stream from a fan into the passenger compartment.
[0045] When a Shape-Memory-alloys with two-way effect is used for the material layer 104 , the actuator 102 resumes, after the current or the radiation source is shut off and due to the cooling caused thereby, its low-temperature shape shown in FIG. 1 . By selecting the current or radiation intensity and thereby the associated temperature it is possible to regulate the bending of the actuators 102 and thereby the size of the air exit opening 110 .
[0046] When using a Shape-Memory-Alloy with one-way effect the layer 108 may serve for the application of a mechanical restoring force to the material layer 104 . After cooling of the material layer 104 this layer retransitions to the martensitic phase and is restored to its original position by the layer 108 above it, which has been elastically deformed by the high-temperature shape of the material layer 104 .
[0047] Here is is particularly advantageous that the interior covering element 100 with integrated air outlet can be made from a small number of individual components and that the air outlet can be controlled by an electrical current for instance without requiring an otherwise usual servomotor.
[0048] These advantages come together with a lower weight. An additional particular advantage is that a large-surface air stream from the interior covering element 100 can be realized with little constructive expenditure.
[0049] FIG. 3 shows an interior covering element 300 . Similar to the interior covering element 100 of FIGS. 1 and 2 the interior covering element 300 of FIG. 3 does also have actuators 302 . Furthermore the interior covering element 300 has actuators 303 which are built in mirror image to the actuators 302 .
[0050] FIG. 3 shows the interior covering element 300 with closed actuators 302 and 303 , when the actuators 302 , 303 are in their low temperature form. If the temperature of only the actuators 302 is being increased, e.g. by applying a voltage or inducing a current or through external radiation, these actuators 302 assume their high temperature shape shown in FIG. 4 . Thereby air exit openings 310 are unblocked, in order to direct the airstream of the fan for instance for de-icing of the windshield of the vehicle. The actuators 303 remain in their low temperature shape.
[0051] If, on the other hand, voltage for instance is applied only to actuators 303 so their temperature increases, the actuators 303 assume their high temperature shape as shown in FIG. 5 . This unblocks air exit openings 311 in order to direct the fan air for instance into the direction of the vehicle occupants.
[0052] With the shape of actuators 102 of FIG. 1 or with the shape of actuators 302 , 303 of FIG. 3 respectively, it may be the low temperature shape or also the high temperature shape. In this case an increased temperature must be present to achieve the clsoed condition of the interior covering element 100 or of the interior covering element 300 respectively. To realize air exit openings 110 or 310 or 311 respectively the voltage applied to each must be reduced appropriately or shut off, to let the desired actuators transition to the low temperature shape.
[0053] FIG. 6 shows an interior covering element 600 with several actuators 602 which are held in place by supports 604 . The actuators 602 consists of a shape-memory alloy with a high temperature and a low temperature shape. The shape of the actuators 602 shown in FIG. 6 for instance is the low temperature shape.
[0054] The low temperature shape of actuators 602 is essentially level. The actuators 602 carry a decorative layer 606 . This may be for instance a casting skin made of polyurethane or PVC, a so-called slush skin or a spray skin. Alternatively or additionally the decorative layer 606 may also feature a fabric layer. The decorative material visible from the outside of the decorative layer 606 may for instance be applied to a layer consisting of polypropylene foam.
[0055] By applying a voltage to the actuators 602 a current is produced which heats the actuator 602 so that they assume their high temperature shape, as shown in FIG. 7 . In their high temperature shape these actuators 602 are curved upwards. This deformation of actuators 602 changes the shape of the flexible decorative layer 606 . This deformation unblocks air exit openings 610 through which air can stream into the passenger compartment in a diffuse manner.
[0056] FIG. 8 show a perspective view of the interior covering element 600 . The decorative layer 606 has incisions along the lines 614 resulting in several strips 616 and 618 . As shown in FIGS. 6 and 7 the area of strip 616 is built up. In the area of strip 618 the actuators 612 located there undergo during increased temperature a deformation that is opposite in direction to the deformation of actuators 602 , i.e., the actuators 612 are curved downward in their high temperature shape.
[0057] The interior covering element 600 may feature a multitude of lamella-like strips 616 and 618 arranged side by side with the strips 616 and 618 succeeding each other alternatingly. If no control signal is applied, all actuators 602 and 612 are in their low temperature shape thereby creating an essentially closed surface of the interior covering element 600 .
[0058] Through induction of the deformation effect the actuators 602 transition to their upward-bent high temperature shape while the actuators 612 transition to their downward-bent high temperature shape. This causes the creation, in the area of strips 616 and 618 convexity in opposite directions of the surface of the interior covering element 600 . Where adjacent strips 616 and 618 border on each other, the opposing convexities serve to unblock the air exit openings 610 (compare to FIG. 9 ).
[0059] FIG. 10 shows an interior covering element 700 with a meander-shaped support 702 for actuators 704 made of a shape-memory alloy. Actuators 704 are each arranged on parallel opposing sections of the meander-shaped support 702 . The intermediate sections 708 of the meander-shaped support 702 do not bear any actuators 704 . The sections 706 of the meander-shaped support 702 are solidly connected to the interior covering element 700 . Along the remaining sections of the meander-shaped support 702 there are incisions into the surface of the interior covering element 700 .
[0060] Through induction of the deformation effect the actuators 704 transition from their low temperature shape into their upward-bent high temperature shape, as shown in FIG. 11 . This causes the actuators 704 and the sections 708 of the interior covering element 700 opposite the sections 706 to unblock air exit openings on the surface of the interior covering element 700 .
[0061] FIG. 12 shows an instrument panel 800 on the upper part of which strips 616 , 618 are arranged in alternating sequence. On principle these are constructed as explained above with reference to FIGS. 6 to 9 . Preferably the entire surface of the instrument panel 800 is essentially subdivided into strips 616 and 618 .
[0062] FIG. 12 shows the strips 616 , 618 in closed condition so that an essentially smooth surface is created on the upper side of the instrument panel 800 . By appropriate triggering of the actuators arranged on the strips 616 , 618 the upper side of the instrument panel assumes an undulatory structure (compare FIG. 9 ). This creates a multitude of air exit openings 610 on the upper side of the instrument panel 800 as shown in FIG. 13 . This results in a large-surface diffuse airstream field which the occupants find to be very pleasant.
[0063] Alternatively the upper side of the instrument panel 800 may be equipped with meander-shaped supports (compare meander-shaped supports 702 of FIGS. 10 and 11 ), in order to realize air exit openings by exploiting the shape-memory effect.
[0064] Instead of on the upper side of the instrument panel 800 it is possible in this manner to create large-surface outlets also in other vehicle parts for the creation of a diffused ventilation. For instance the headliner as well as side covering elements, seat covering elements and covering elements of the center console may be used for this purpose.
LIST OF REFERENCE MARKS
[0000]
Interior covering element 100
Actuator 102
Material layer 104
Support 106
Layer 108
air exit opening 110
air 112
Interior covering element 300
Actuator 302
Actuators 303
air exit opening 310
air exit opening 311
Interior covering element 600
Actuator 602
Support 604
Decorative layer 606
Air exit opening 610
Stellelement 612
Linie 614
Streifen 616
Streifen 618
Innenverkleidungsteil 700
meander-shaped support 702
Stellelemente 704
Abschnitt 706
Instrumententafel 800 | The invention concerns an air outlet for a vehicle with an actuator for an air outflow, with the actuator featuring a temperature-inducible deformation effect, and means to trigger the deformation effect. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent application Ser. No. 11/737,364, filed Apr. 19, 2007, which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates generally to a vehicle auxiliary light, and more particularly, to techniques for controlling the operation of the auxiliary light.
BACKGROUND
[0003] Automotive vehicles, such as light trucks and sport utility vehicles, commonly include various types of auxiliary lights, such as fog lights and off-road utility lights. Off-road lights are typically mounted to the front or roof of a vehicle, whereas fog lights are generally mounted to the lower front region of the vehicle. In addition to providing light, fog and off-road utility lights are considered decorative with respect to the vehicle. Auxiliary lights are available as an aftermarket accessory and as original equipment on certain model vehicles.
[0004] Various regulations, such as California Vehicle Code §24499-24411 govern the use of off-road lights. Many states, for example, require auxiliary lights to be physically capped when the vehicle is operated on public streets. Regulations also require that auxiliary lights not be operated on public streets.
[0005] Capping auxiliary lights when not in use is also desirable because it protects the light from being damaged by debris, such as stones, that can be kicked up from the road. However, it is desirable that auxiliary lights not be operated with the cap installed. Certain high powered lights, particularly off-road utility lights, can generate significant heat when operated. If the auxiliary light were operated with the cap installed, the heat could damage the cap. It has generally been left up to the user to ensure that the cap is removed prior to operating the auxiliary light. This creates a risk that the user will inadvertently fail to remove the cap prior to activating the auxiliary light. It has also generally been left up to the user to ensure that the cap is replaced prior to operating the vehicle on public roads. This creates a risk that the user will inadvertently fail to replace the cap and will operate the vehicle in a manner not fully complying with applicable regulations.
SUMMARY
[0006] A system is provided for controlling an auxiliary light for a vehicle. The system includes a user-operated actuator to activate the auxiliary light, the user-operated actuator having at least an “on” state and an “off” state; a first sensor operable to generate a signal indicating when a cover is installed on the auxiliary light; a warning indicator; and a controller adapted to activate the warning indicator in response to the signal generated by the first sensor.
[0007] In some embodiments, a system is provided for controlling an auxiliary light for a vehicle. The system includes a user-operated actuator to activate the auxiliary light, the user-operated actuator having at least an “on” state and an “off” state; a switch adapted to couple and decouple the auxiliary light to a power source, based on the state of the user-operated actuator; a first sensor adapted to detect the existence of at least one predetermined vehicle condition other than the installation of a cover on the auxiliary light; and a controller responsive to the first sensor to disable activation of the auxiliary light when the predetermined vehicle condition exists.
[0008] In other embodiments, a method is provided for operating an auxiliary light for a vehicle. The method includes detecting the whether the auxiliary light is in a cover-on condition or a cover-off condition; detecting the state of a user-operated auxiliary light switch; and activating a warning indicator in response to the detected state of the auxiliary light switch and the detected condition of the auxiliary light.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The description herein makes reference to the accompanying drawings, wherein like reference numerals refer to like parts throughout the several views, and wherein:
[0010] FIG. 1 is fragmentary top perspective view of a vehicle showing a pair of auxiliary lights mounted to a roof of the vehicle;
[0011] FIG. 2 a schematic diagram of a first embodiment a vehicle lighting system;
[0012] FIG. 3 is schematic diagram of a second embodiment of a vehicle lighting system;
[0013] FIG. 4 is a flow chart illustrating the operation of the embodiment of FIG. 3 ;
[0014] FIG. 5 is a state table illustrating the operation of the embodiment of FIG. 3 ; and
[0015] FIG. 6 is a flow chart further illustrating the operation of the embodiment of FIG. 3 .
DETAILED DESCRIPTION
[0016] Other applications of the present invention will become apparent to those skilled in the art when the following description of the best mode contemplated for practicing the invention is read in conjunction with the accompanying drawings. The following description of the embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
[0017] To avoid damaging the caps that are used on auxiliary lights, it is desirable to develop a device that can disable the utility light to prevent it from being operated when the cap is installed on the light. It is also desirable to prevent drivers from operating vehicles on public roads when auxiliary lights are not capped.
[0018] Referring to FIG. 1 , an auxiliary lighting system 10 is shown to have at least one auxiliary light 12 for generating a beam of visible light. Auxiliary light 12 can be mounted to a vehicle 14 at various locations depending on the lighting requirement of the particular application. Off-road utility lights, for example, can be mounted to a roof 16 of the vehicle, as shown in FIG. 1 , for casting visible radiant light in a direction forward of the vehicle to illuminate objects in front of the vehicle. Auxiliary light 12 can alternatively be mounted on the vehicle another suitable location. For esthetic, as well as performance reasons, it can be desirable to integrate auxiliary light 12 with the vehicle's surrounding exterior structure. For example, the auxiliary light can be integrated with an air deflector 18 to produce a custom look to meet consumer styling preferences, while at the same time minimizing the turbulence and wind noise created by air flowing over the auxiliary light.
[0019] Referring to FIG. 2 , auxiliary light 12 can include a housing 20 for enclosing a lamp 22 . Applying an electric current to lamp 22 causes the lamp to generate a beam of visible radiant light. Lamp 22 can include various devices for producing visible radiant light, including but not limited to, an incandescent lamp, a xenon lamp, and a halogen lamp.
[0020] Radiant visible light produced by lamp 22 can exit housing 20 through an aperture 24 defined in a forward end 26 of housing 20 . A lens 28 for focusing and directing the radiant light can be positioned within the aperture 24 . An outer circumference of lens 28 can be suitably attached to housing 20 to prevent water, dirt, and other environmental contaminants from entering the housing.
[0021] Auxiliary light 12 can include a cap 30 that detachably engages front portion 26 of housing 20 . Cap 30 can protect the auxiliary light from damage caused by stones and other debris that can be kicked up form the road. Cap 30 can also be required to comply with various regulations requiring auxiliary lights, such as off-road utility lights, to be capped when operating the vehicle on a public road. Cap 30 overlays at least a portion of aperture 24 , and can be removed from housing 20 (the detached cap is shown in phantom in FIGS. 2 and 3 ) prior to activating lamp 22 . Although a simple, genetically configured cap 30 is depicted in FIGS. 2 and 3 , it shall nevertheless be appreciated that the cap can have a wide variety of other configurations depending on the stylistic and functional requirements of the particular application.
[0022] Electric current for operating lamp 22 can be supplied by a power supply 32 , which can be electrically connected to lamp 22 . Power supply 32 can include, without limitation, an alternator, generator, battery, fuel cell, or any other similar device capable of generating electric current and can be controlled by the placing the vehicle key to the ING position for example. The flow of electrical current from power supply 32 to lamp 22 can be further controlled by a relay 34 electrically connected to power supply 32 by means of an electrical conductor 36 . Operation of relay 34 can be controlled by means of a cockpit switch 38 located within a passenger compartment of vehicle 14 and accessible to a vehicle operator. Cockpit switch 38 can be a lever, button or other suitable user-operated actuator that has at least an “on” state and an “off” state to control the operation of lamp 22 . A second conductor 40 can connect relay 34 to a switch 42 , which is responsive to a sensor (in this case a plunger 46 as described below) to break the electrical connection between power supply 32 and lamp 22 when cap 30 is attached to auxiliary light 12 . A third conductor 44 can electrically connect switch 42 to lamp 22 .
[0023] Switch 42 can included any of a variety of mechanical and electronic switches operable to selectively open and close the electrical circuit between power supply 32 and lamp 22 . One non-limiting example of mechanical switch can include a plunger 46 , which extends from a switch housing 48 . As explained below, a plunger 46 operates as a sensor to detect the presence of cap 30 on housing 28 .
[0024] Plunger 46 can be slid axially along its axis within housing 48 , between and extended position (depicted in phantom in FIG. 2 ) and a depressed position, thereby functioning as a sensor for detecting the presence of cap 30 on housing 28 . Plunger 46 is preferably biased toward the extended position. Positioning plunger 46 in the extended position closes the electrical circuit between relay 34 and lamp 22 , thereby allowing electric current to flow from power supply 32 and lamp 22 when the auxiliary light is activated. Conversely, depressing plunger 46 opens the electrical circuit between relay 34 and lamp 22 , thereby preventing electric current from flowing between power supply 32 and lamp 22 when relay 34 is operated to activate the auxiliary light.
[0025] An end 50 of plunger 46 engages cap 30 when the cap is attached to auxiliary light 12 . Attaching cap 30 to auxiliary light 12 depresses plunger 46 and opens the electrical circuit between power supply 32 and lamp 22 , thereby preventing electric current from flowing between the two components so that lamp 22 is not illuminated when the auxiliary light 12 is activated. Removing cap 30 from auxiliary light 12 releases plunger 46 and closes the electrical circuit between power supply 32 and lamp 22 , thereby allowing electric current to pass between the two components and thus illuminate lamp 22 when auxiliary light 12 is activated. Persons skilled in the art will appreciate that this is merely one example of the wide variety of mechanical switches that can be employed with the present invention, and that various other types of mechanical and electronic switches can be satisfactorily employed.
[0026] Referring to FIG. 3 , auxiliary light system 10 can include a controller 52 for controlling operation of relay 34 in response to various input signals received by the controller. The operation of controller 52 as described below can be performed in one processor or if desired distributed among more than one processor. For ease of illustration, the disclosed embodiment shows the controller functions in a single processor. Although controller 52 and relay 34 are shown as separate components in FIG. 3 , it is contemplated that the two devices can nevertheless be combined as a single device.
[0027] Controller 52 can receive a signal from cockpit switch 38 signaling that the vehicle operator has actuated cockpit switch 38 to activate auxiliary lights 12 . Cockpit switch 38 can be located within the vehicle passenger compartment so as to be accessible by the vehicle operator.
[0028] Controller 52 can be adapted to receive a signal from a sensor 54 operable for detecting whether cap 30 is attached or installed to auxiliary light 12 or is removed from auxiliary light 12 . A non-limiting example of one such sensor is a Hall effect sensor having a circuit that can vary its output voltage in response to changes in magnetic field density. A Hall effect sensor can be employed in the present invention by attaching a magnetic 56 to cap 30 . A circuit 58 capable of sensing the magnetic field density of magnet 56 can be located so as to be positioned adjacent the magnet 56 when the cap is attached to auxiliary light 12 . The output voltage of circuit 58 will vary depending on whether cap 30 is attached to auxiliary light 12 and this output voltage can be transmitted to controller 52 as an output signal of sensor 54 indicative of the presence of cap 30 on light 12 . Alternatively, cap 30 can include a different type of signal emitter, such as an RFID chip.
[0029] Controller 52 will either enable of disable activation of lamp 22 depending on whether the output signal of sensor 54 indicates that cap 30 is attached to auxiliary light 12 . For example, in response to a signal received from cockpit switch 38 indicating that auxiliary lights 12 have been activated, if the output of sensor 54 indicates that cap 30 is not attached to auxiliary light 12 , then controller 52 can send a signal to relay 34 causing relay 34 to close the electrical circuit between power supply 32 and lamp 22 and thus power lamp 22 . If on the other hand, controller 52 determines from the output of sensor 54 that cap 30 is attached to auxiliary light 12 , then controller 52 causes relay 34 to remain open, and thus disable operation of lamp 22 by interrupting the supply of power to lamp 22 , even though the controller has received a signal from cockpit switch 38 to activate auxiliary light 12 . Thus, once the cockpit switch 38 is activated, controller 52 will allow auxiliary light 12 to be activated if receives a signal from sensor 54 indicating that the cap has been removed. It will be appreciated that controller 52 and relay 34 act in combination as a switch to control auxiliary light 12 .
[0030] Controller 52 can also, if desired, enable and disable lamp 22 in response to a signal received from a vehicle sensor 62 . Vehicle sensor 62 detects a predetermined condition of the vehicle. Even in cap 30 is removed from auxiliary light 12 and even if the operator of the vehicle has actuated cockpit switch 38 to turn on auxiliary light, controller 52 can cause relay 34 to remain open to prevent power from reaching lamp 22 if the output of vehicle sensor 62 indicates the existence of one or more predetermined conditions. Examples of such conditions can include, the high beams lights are off, the vehicle speed exceeds a predetermined threshold (such as 25-45 mph), the vehicle key is not in the ING position, whether the vehicle is operating in two-wheel drive, the vehicle is operating on a public road, oncoming headlights are detected, or the amount of ambient light outside the vehicle exceeds a predetermined threshold. Each of these exemplary conditions is indicative of a circumstance in which auxiliary lights 12 should not be operated. Vehicle sensor 62 can detect one or more of these or other suitable conditions. It will be appreciated that although vehicle sensor 62 and sensor 54 are shown as separate components, the two sensors could be integrated into a single physical component, and references herein to “first” and “second” are hereby defined to cover this as well as the more typical deployment where the sensors 54 and 62 would be in separate components.
[0031] For example, if the vehicle speed exceeds a predetermined threshold (such as 25-45 mph) or if the vehicle is in two-wheel drive, the vehicle is probably not in an environment where off-road lighting is appropriate. If ambient light is detected above a predetermined level or if the light of oncoming vehicles is detected, the auxiliary lighting system can be disabled by opening relay 34 based on the assumption that the lights are not required or appropriate in daylight or if there are oncoming vehicles.
[0032] Whether the vehicle is operating on a road can be detected by a number of methods. For example, sensor 62 can track the vehicle's location using a GPS unit (not shown), which in conjunction with a geographic database (not shown) determines if the vehicle is on a public road. Alternatively, a vision recognition system can be used to detect the markers of a road (such as curbs, lane dividers and the movement of oncoming traffic). Alternatively, a rate indicator can be used to detect the whether the vehicle in a straight line for a predetermined distance or on even terrain indicative of pavement. Each of these methods individually or in combination with others can be used to determine whether the vehicle is on a public road. For example, if it can be judged that a vehicle is on the public roads if it travels in a straight line for a predetermined distance (such as 100 to 200 yards) at a speed of over 25-45 mph. Other suitable criteria can be selected for establishing that the vehicle is on a public road.
[0033] A cap warning indicator 60 for notifying the vehicle operator that cap 30 is attached to auxiliary light 12 can be provided. Warning indicator 60 can be suitably located within the passenger compartment of the vehicle. Warning indicator 60 can be operably connected to controller 52 and configured to emit an audible or visual warning signal notifying the vehicle operator that cap 30 is attached to auxiliary light 12 in response to a signal received from controller 52 . In an alternative embodiment, controller 52 can activate warning indicator 60 when auxiliary light 12 is on and cap 30 is detected without disabling the operation of auxiliary light 12 (that is, without opening relay 34 ).
[0034] In alternative embodiments, cap warning indicator 60 can have two warning modes, one mode indicating that the cap is on when auxiliary light 12 is in operation, and the second mode indicating that the cap is off when the vehicle is on public roads. Controller 52 can cause warning indicator 60 to indicate the first warning mode in response to sensor 54 indicating the presence of cap 30 . Controller 52 can cause warning indicator 60 to indicate the second warning mode in response to sensor 54 indicating the absence of cap 30 and vehicle sensor 62 indicating that the vehicle is operating on a public road (as described above).
[0035] Referring to FIG. 4 , the operation of the embodiment of FIG. 3 is illustrated. Control initiates at decision block 64 , where a controller 52 determines whether the signal received from cockpit switch 38 indicates that the vehicle operator has actuated cockpit switch 38 to turn on auxiliary lights 12 . If cockpit switch 38 has not been actuated, control moves to block 66 where controller 52 causes relay 34 to remain open (thus cutting off power to auxiliary lights 12 ). If cockpit switch 38 has been actuated, then control moves to block 68 , where controller 52 determines whether the signal received from sensors 54 is indicative of cap 30 being detected on either of lights 12 . If cap 30 is detected, then control moves to block 70 , where controller 52 causes indicator 60 to indicate that cap 30 is detected. Control then moves to block 64 where controller 52 causes relay 34 to remain open (thus cutting off power to auxiliary lights 12 ). If cap 30 is not detected, then control moves to block 72 .
[0036] At block 72 , controller 52 determines whether the input signal received form vehicle sensor 62 is indicative of other vehicle conditions that require auxiliary light 12 to be disabled. If any of these other vehicle conditions are met, then control moves to block 64 , where controller 52 causes relay 34 to remain open (thus cutting off power to auxiliary lights 12 ). If other vehicle conditions are met, then control moves to block 74 , where controller 52 causes relay 34 to close, thus providing power to auxiliary lights 12 . Controller 52 can repeat the operations FIG. 4 periodically.
[0037] Another condition to permit activation of auxiliary lights 12 is the vehicle key being in the ING position. This can provides power to power supply 32 and sensor 54 so that no power is provided to auxiliary lights 12 if key is not in the ING position, regardless of whether the user actuates cockpit switch 38 . The state table of FIG. 5 illustrates operation of auxiliary lights 12 in relation to the state of the key being in the ING position.
[0038] Referring to FIG. 6 , controller 52 can also activate indictor 60 to alert the driver when one of caps 30 is removed from one of the auxiliary lights 12 while the vehicle is operating on a public road. Beginning at block 76 , controller 52 determines if the auxiliary lights 12 are on (that is, relay 34 is closed). If the auxiliary lights 12 are on, then processing occurs periodically as described in FIG. 4 . If the auxiliary lights 12 are off, then control moves to a block 78 , where controller 54 determines whether the signal received form vehicle sensor 62 is indicative of the vehicle being on the public road. Techniques for making this determination are described above, and one or more criteria can be applied to judge that vehicle 14 is on a public road. If the signal received from sensor 62 indicates that vehicle 14 is not on a road, then processing terminates. Otherwise, if the signal received from sensor 62 indicates that vehicle 14 is on a public road, then control moves to block 80 , where controller 52 determines whether the signal received from sensors 54 is indicative of cap 30 being detected on either of auxiliary lights 12 . If caps 30 are detected on both auxiliary lights 12 , then processing terminates. If caps 30 are not detected on both auxiliary lights 12 , then control moves to a block 82 , where controller 52 activates indicator 82 to warn the operator that caps 30 are removed while vehicle is on a public road. Such warning may be audible or visual or both.
[0039] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiments but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims, which scope is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent structures as is permitted under the law. | A system controls an auxiliary light for a vehicle. The system includes a cockpit button to activate the auxiliary light, a Hall sensor operable to detect the installation and removal of a magnetized cover for the auxiliary light; a warning indicator; and a controller. The controller activates the warning indicator in response to the output of the sensor and the on/off state of the cockpit button. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Application No. 60/795,278, entitled “All-in-one Climate Control Hat/Flap and Accessories (CCH)” and filed on Sep. 18, 2006, which is specifically incorporated herein by reference for all that it discloses and teaches.
TECHNICAL FIELD
[0002] The invention relates generally to articles of manufacture worn about the head and neck and more particularly to a system of components worn about the head and neck that allow the wearer to better control his or her environment.
BACKGROUND
[0003] Hats, scarves, facemasks, and other head and neck garments have been utilized by mankind for millennia. Originally, head and neck garments were primarily functional items that served to protect the wearer from the vagaries of a changing environment—from the pre-dawn chill, to the blistering noon-day sun, to the evening downpour. Later, style and design became important considerations in such garments as well. However, regardless of whether a garment is worn because of its ‘look’ or because of its utility and functionality, the person wearing the garment often finds that he or she must constantly add, remove, change, or replace head and neck garments as weather conditions and other environmental factors change. For example, a standard baseball-style cap can be extremely useful to reduce the glare and sunburn that can be caused by bright sunshine. However, if clouds suddenly move in and an unexpected rain shower occurs, the baseball cap may have no waterproofing or other features which would allow it to protect the wearer from the rain. Similarly, a waterproof hat is little help once a rain ends and swarms of mosquitoes appear.
[0004] Currently, such changing environmental conditions require the savvy outdoors-person to carry a number of different head and neck garments. For example, a hunter may need a baseball cap to keep the sun out of his eyes in the morning and a head-net to keep the pestering insects at bay after noon. Climbing up and down the mountains pursuing game can cause a lot of heat to build-up and the hunter needs something to help keep him cool, so he might don a neck pouch containing a cooling gel packet. Then, later in the evening, a warm scarf and knit hat may be necessary to protect the hunter's head and neck as a cold front moves into the area.
[0005] Clearly, constantly carting around even the small sampling of head and neck garments mentioned above is impractical. Thus, there is a need for a garment system that allows a garment wearer to control the environment around his or her head and neck without carrying a large number of differing head and neck garments at all times.
SUMMARY
[0006] Embodiments described and claimed herein address the foregoing problems by providing a complete system of head and neck garments that allows the wearer to control the environment around his or her head and neck. The system requires that the wearer carry minimal additional gear while providing the wearer with the ability to cool, warm, waterproof, camouflage, and protect his or her head and neck areas against wind, rain, snow, insects, blowing sand, etc.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The aforementioned and other features and objects of the present invention and the manner of attaining them will become more apparent and the invention itself will be best understood by reference to the following description of a preferred embodiment and other embodiments taken in conjunction with the accompanying drawings, wherein:
[0008] FIG. 1 illustrates a left side perspective view of an exemplary embodiment of an environment control system for the head and neck as it could be worn by a person.
[0009] FIG. 2 provides a left side perspective view of an exemplary embodiment of a climate control flap component of an environment control system for the head and neck as it could be worn by a person.
[0010] FIG. 3 illustrates a front view of an exemplary embodiment of a climate control flap component of an environment control system for the head and neck.
[0011] FIG. 4 illustrates a rear view of an exemplary embodiment of a climate control flap component of an environment control system for the head and neck.
[0012] FIG. 5 illustrates a front view of an exemplary embodiment of an all-weather flap component of an environment control system for the head and neck.
[0013] FIG. 6 illustrates a left side perspective view of an exemplary embodiment of an all weather flap component of an environment control system for the head and neck.
[0014] FIG. 7 illustrates a rear view of an exemplary embodiment of a face protector component of an environment control system for the head and neck.
DETAILED DESCRIPTION
[0015] In one embodiment, an environment control system (hereafter, “ECS”) can be utilized with a standard baseball-style cap. The cap is modified in order to allow attachment of the various components of an ECS. In alternate embodiments, an ECS can be utilized with a variety of other hat types and styles. Furthermore, an ECS can include one or more hats (of similar or varying styles) as component(s) of the system or an ECS can be added to an existing hat. The term “hat” as used herein can refer to any piece of headgear or other item that is worn, suspended, or otherwise held in close proximity to a person's head. Examples include, but are not limited to, baseball caps, cowboy hats, straw hats, helmets, visors, etc. In addition, the term “cap” can be interchangeably used for the term “hat”, and vice versa.
[0016] FIG. 1 illustrates an exemplary embodiment of an ECS 100 . The illustration shows three primary components: a climate control flap (hereafter, “CCF”) 110 , an all-weather flap (hereafter, “AWF”) 130 , and a face protector (hereafter, “FP”) 150 . Also shown in FIG. 1 are a baseball-style cap 170 and a person 190 wearing components of an ECS. As mentioned above, the cap 170 can be included in an ECS 100 .
[0017] A CCF 110 can be attached to a cap 170 by a myriad of means, including, but not limited to: hook-and-loop material (e.g., those sold under the trademark VELCRO®), snaps, buttons, zippers, magnets, ties, etc. As shown in the embodiment of FIG. 1 , the top edge of the CCF 110 can be placed inside the cap 170 . In alternate embodiments, only the attaching means (such as two flaps extending out from the top of a CCF 110 , each flap having a zipper to attach to corresponding zippers on the cap 170 ) actually contacts the cap 170 .
[0018] In addition to the attachment means described above, a CCF 110 can have a belt loop 111 . In the embodiment utilizing a baseball-style cap, the cap 170 has an adjustment band 171 . The adjustment band 171 can be threaded through the belt loop 111 to provide an additional means of attachment and minimize movement of the CCF 110 relative to the cap 170 .
[0019] As shown in the left side perspective view in FIG. 1 , the CCF 110 has a left horizontal attachment means 112 . A right horizontal attachment means is also contemplated, but not sown in FIG. 1 . The horizontal attachment means 112 shown in FIG. 1 is a hook-and-loop material, other attachment means are contemplated. The CCF's 110 horizontal attachment means 112 is placed so as to accept the AWF's 130 horizontal attachment means 132 . The AWF's 130 left side horizontal attachment means 132 is shown using dashed lines as the exemplary hook-and-loop attachment means is on the inside front face of the AWF 130 and so is not visible on the rear surface of the AWF 130 , as displayed in FIG. 1 . Furthermore, the AWF's 130 left side horizontal attachment means 132 has a twin right side horizontal attachment means, not shown.
[0020] The AWF's 130 left side vertical attachment means 133 is shown using dashed lines as the exemplary hook-and-loop attachment means is also on the inside front face of the AWF 130 , and so is not otherwise visible in FIG. 1 . The AWF's 130 left side vertical attachment means 133 has a twin right side vertical attachment means, not shown. Furthermore, the AWF's 130 vertical attachment means 133 attaches to the corresponding CCF's 110 vertical attachment means 113 .
[0021] The CCF 110 has a drawstring 115 and a push-button clasp 114 . The drawstring 115 serves multiple purposes. As shown in FIG. 1 , the drawstring 115 is attached to the bottom pair of three eyelet pairs. This configuration allows the person 190 wearing the ECS 100 to draw up the sides of the CCF 110 to form a channel-like opening between the person's 190 neck and the CCF 110 . This “air-channel” provides airflow and facilitates the cooling effect that can be garnered from the CCF 110 . Alternatively, the drawstring 115 can be attached to the middle or upper eyelet pairs in order to draw the CCF 110 closer to the wearer's neck, which is helpful when the wearer wishes to minimize drafts and increase the warming effect of the ECS 100 . The push-button clasp 114 is used to quickly and easily loosen or tighten the drawstring 115 . It is contemplated that alternate embodiments could employ other types of clasps or means of securing and loosening the drawstring 115 .
[0022] The CCF 110 can be manufactured using a number of different materials. In one embodiment, a breathable yet water-retaining material is used. Such a material has the dual benefits of allowing perspiration to escape while helping to retain cool water to enhance the cooling benefits of the ECS. In addition to holding water, the material can be infused with water-retaining crystals such as cross-linked polyacrylamide crystals or any of a number of other non-harmful cooling chemicals or materials. Another example of water-retaining/cooling materials that can be utilized is natural jute fiber. Such materials, when wetted, help to cool the wearer by utilizing the cooling effects of evaporation. As shown in FIG. 1 , the CCF 110 has square pockets 119 sewn into the fabric or core component material in order to contain and evenly distribute cooling agents throughout the body of the CCF 110 . In an alternate embodiment, the CCF 110 may contain warming agents instead of cooling agents. The ECS 100 shown in FIG. 1 contemplates the utilization of various component and materials in its manufacture, including those which facilitate warming and cooling, which are currently known in the art as well as those which become known.
[0023] The exemplary AWF 130 shown in FIG. 1 has an integrated weather-proof/water-resistant hat cover 134 . As shown in FIG. 1 , the hat cover 134 is shaped so as to cover a baseball-style cap. It is contemplated that alternative hat cover shapes would be utilized in order to cover alternative hat styles and shapes. The material utilized in manufacturing the hat cover can be any of a number of materials, depending on the properties desired in the hat cover 134 . For example, if water-resistance and breathability are desired a material such as that sold under the trademark Gortex® can be used. If more warmth is desired, a layer of insulation such as that sold under the trademark Thinsulate® can be included. Additionally, warming chemicals or agents can be incorporated in alternate embodiments for increased warmth.
[0024] The materials used to construct the CCF 110 , the AWF 130 , and the FP 150 can be selected based on the advantages and disadvantages they offer. Further, the materials can be colored as desired. For certain applications, camouflage colorings may be desired. For others, such as in very hot, sunny locations, all white colorings may be used. The ECS 100 is not limited to certain colors or fabric/material combinations.
[0025] The hat cover 134 has at least two additional subcomponents: the elastic or stretchable portion 135 at the front of the hat cover 134 and the adjustable attachment means or drawstring 136 , in the embodiment shown in FIG. 1 . Alternate embodiments are contemplated utilizing alternative means of attaching and adjusting the hat cover 134 to the cap 170 and the CCF 110 . In the embodiment in FIG. 1 , the stretchable portion 135 at the front of the hat cover 134 combined with the drawstring 136 allows the person 190 wearing the ECS 100 to tighten the AWF component separately from the other components. Furthermore, the wearer has the ability to remove the AWF completely if it is not needed.
[0026] The FP 150 shown in the embodiment in FIG. 1 has three features: the main structural material 151 , the upper attachment means 152 , and the vertical attachment means 153 . The main structural material 151 shown in this embodiment is an insect screen or netting. The main structural material 151 used to manufacture the FP 150 can be “see-through”, “rip-stop” nylon or other suitable material that can protect the person's 190 face from insects, sand, sun, blowing snow, etc., while still allowing the person 190 to see through the material. Other embodiments are contemplated in which the main structural material 151 is clear plastic, tinted plastic, etc.
[0027] The FP 150 has an upper attachment means 152 which provides a means for attaching the FP to the cap 170 . In the embodiment shown in FIG. 1 , a hook-and-loop material is used to attach the FP 150 to the underside of the bill of the baseball-style cap 170 ; this means of attaching requires that a complimentary hook-and-loop material be affixed to the underside of the bill of the cap 170 so that the upper attachment means 152 can attach thereto. Other embodiments utilizing alternative attachment means are contemplated. Similarly, the FP 150 has vertical attachment means 153 which also utilize hook-and-loop material in the embodiment shown in FIG. 1 to attach the sides of the FP 150 to the sides of the CCF 110 using the CCF's 110 vertical attachment means 113 . The FP's 150 vertical attachment means 153 are shown using dashed lines as the hook-and-loop material is on the rear-facing surface of the FP 150 . Further, only the left side of the FP is shown in FIG. 1 . However, there is another vertical attachment means 153 on the right side of the FP 150 that is not shown. Because the CCF's 110 vertical attachment means 113 are wider than those of the AWF 130 and the FP 150 , both the AWF 130 and the FP 150 can be attached to the CCF 110 at the same time.
[0028] FIG. 2 shows a close-up view of the ECS 200 . The CCF 210 component is displayed in detail without the AWF 130 or the FP 150 from FIG. 1 . A CCF 210 can be attached to a cap 270 by a myriad of means. Although not explicitly shown in FIG. 2 , the CCF 210 is attached to the cap 270 by means of two hook-and-loop tabs “Velcro-ed” to the inside of the sweat-band of the cap 270 . Other means of attaching the CCF 210 to the cap 270 are contemplated.
[0029] In addition to the attachment means described above, the CCF 210 can have a belt loop 211 . In the embodiment utilizing a baseball-style cap, the cap 270 has an adjustment band 271 . The adjustment band 271 can be threaded through the belt loop 211 to provide an additional means of attachment and minimize movement of the CCF 210 relative to the cap 270 .
[0030] As shown in the left side perspective view in FIG. 2 , the CCF 210 has a left horizontal attachment means 212 . A right horizontal attachment means is also contemplated, but not shown in FIG. 2 . The horizontal attachment means 212 shown in FIG. 2 is a hook-and-loop material, other attachment means are contemplated. The CCF's 210 horizontal attachment means 212 is placed so as to accept horizontal attachment means from the AWF. Furthermore, the CCF 210 has vertical attachment means 213 that are placed to accept vertical attachment means from both the AWF and the FP. Once again, both a left vertical attachment means 213 and a right vertical attachment means are contemplated, although only the left vertical attachment means 213 is visible in FIG. 2 .
[0031] The CCF 210 has a drawstring 215 and a push-button clasp 214 , as described under FIG. 1 , above. Furthermore, the description of the material used to manufacture the CCF 210 is the same as that given under FIG. 1 , above. FIG. 2 also shows the pockets 219 which, when filled with cooling chemicals or agents enhance the cooling characteristics of the CCF 210 . In another embodiment, the pockets 219 could be filled with warming chemicals or agents to enhance the warming characteristics of the CCF 210 in cold weather.
[0032] The cap 270 shown in FIG. 2 also has a FP storage tab 257 added to it in order to facilitate the storage of the FP when not in use. The storage tab 257 provides a means of securing the FP (shown in FIG. 7 as FP 750 ) out of the way when it is not in use. Storage is accomplished by folding the FP 750 over the top of the head and attaching the storage tab 755 on the FP 750 as shown in FIG. 7 to a corresponding FP storage tab 257 on the rear of the cap 270 , as shown in FIG. 2 . Given the exemplary hook-and-loop attachment means and using the baseball-style cap as an example, the FP 750 would be folded over the top of the cap and attached via the storage tab 755 to a corresponding hook-and-loop material FP storage tab 257 .
[0033] An embodiment of a CCF 310 is shown in FIG. 3 from a front view wherein the inside of the CCF 310 is shown in detail. The inside surface of the CCF 310 faces the back of the wearer's head and neck during use. The CCF 310 has a drawstring 315 and a push-button clasp 314 , as described under FIG. 1 , above. Furthermore, the description of the material used to manufacture the CCF 310 is the same as that given under FIG. 1 , above. FIG. 3 also shows the pockets 319 which, when filled with cooling chemicals or agents, enhance the cooling characteristics of the CCF 310 .
[0034] The eyelets briefly discussed above are shown in more detail in FIG. 3 . In the embodiment in FIG. 3 , three pairs of eyelets are shown. More or fewer pairs of eyelets could be utilized in alternate embodiments. The top pair of eyelets 316 and 366 can be utilized to tighten the CCF 310 closely to the face. The middle pair of eyelets 317 and 367 allows a slightly more relaxed fit, while the bottom pair of eyelets 318 and 368 provides the user with the ability to create a cooling “air-channel” against the back of the neck, as described under FIG. 1 , above.
[0035] Three vertical stays are embedded within the embodiment of the CCF 310 shown in FIG. 3 : the right stay 320 , the middle stay 321 , and the left stay 322 . The number of stays could be fewer or greater in alternate embodiments. The stays can be constructed of any suitable material that is lightweight, flexible, and semi-rigid. In one embodiment, plastic “zip-ties” are contemplated; in another, nylon, bendable stays are used. The stays keep the CCF 310 from bunching up around the back of the neck for the most effective cooling around the neck, lower head, and ears.
[0036] In the top center area of the CCF 310 is an elastic band or stretchable area 324 . The stretchable area 324 allows the CCF 310 to easily adjust to wearers with different size heads. Further, the stretchable area 324 provides for a comfortable and snug fit.
[0037] At the very top of the CCF 310 are two horizontal attachment tabs 325 and 326 . The tabs extend beyond the top of the CCF's 310 main body and are flexible so they can be folded over and attached inside the sweat-band of a hat. The attachment means are not visible in this embodiment; they reside on the outside surface of the tabs and so may be seen in FIG. 4 . In order to attach the CCF 310 to a standard baseball-style cap, the cap's sweat-band is unfolded from the inside rim of the hat. Then, corresponding hook-and-loop materials are attached to the inside of the sweat-band (using glue, stitches, or any other suitable means) such that the two horizontal attachment tabs 325 and 326 can be attached to the sweat-band. The sweat-band and tabs can then be folded together and the sweat-band returned to its original folded condition inside the rim of the hat. The attachment means (shown in FIG. 4 as attachment means 427 and 428 ) securely hold the tabs in place against the sweat-band, in turn securing the entire CCF 310 to the hat. Other embodiments are contemplated wherein the tabs utilize snaps, buttons, zippers, or any other means to attach the CCF 310 to the hat. In addition, the tabs themselves are not necessary and could be replaced by alternate means of attachment without departing from the spirit and scope of the invention.
[0038] An embodiment of a CCF 410 is shown in FIG. 4 from a rear view wherein the outside of the CCF 410 is shown in detail. The outside surface of the CCF 410 faces out and away from the back of the wearer's head and neck during use. The CCF 410 has a drawstring 415 and a push-button clasp 414 , as described under FIG. 1 , above. Furthermore, the description of the material used to manufacture the CCF 410 is the same as that given under FIG. 1 , above. FIG. 4 also shows the pockets 419 which, when filled with cooling chemicals or agents, enhance the cooling characteristics of the CCF 410 .
[0039] The eyelets, which include a top pair 416 and 466 , a middle pair 417 and 467 , and a bottom pair 418 and 468 in the CCF 410 , are as described under FIG. 3 , above. The two horizontal attachment tabs 425 and 426 are shown in FIG. 4 . The attachment means 427 and 428 are shown in this exemplary embodiment as hook-and-loop material. Other means of attaching the CCF 410 are contemplated. In order to attach the CCF 410 to a standard baseball-style cap, the cap's sweat-band is unfolded from the inside rim of the hat. Then, corresponding hook-and-loop materials are attached (using glue, stitches, or any other suitable means) to the sweat-band such that the two horizontal attachment tabs 425 and 426 can be folded into the sweat-band when it is returned to its original folded position inside the rim of the hat. The attachment means 427 and 428 securely hold the tabs in place against the sweat-band, in turn securing the entire CCF 410 to a hat. The belt loop 411 is shown in detail in FIG. 4 . It is placed such that the adjustable band on a standard baseball-style cap fits through the belt loop 411 and helps to secure the CCF 410 to the cap.
[0040] Both the left and the right horizontal attachment means 412 and 482 are shown in FIG. 4 . The horizontal attachment means 412 and 482 are located on the CCF 410 such that the AWF's corresponding horizontal attachment means 532 and 592 (as shown in FIG. 5 ) line-up with those on the CCF 410 when the AWF is placed onto the CCF 410 . In the embodiment shown in FIG. 4 , a hook-and-loop material is used as the attachment means, other means of attaching the AWF to the CCF 410 are contemplated. Similarly, both the left and the right vertical attachment means 413 and 483 are shown in FIG. 4 . The vertical attachment means 413 and 483 are located on the CCF 410 such that the AWF's corresponding vertical attachment means 533 and 593 (as shown in FIG. 5 ) line-up with those on the CCF 410 when the AWF is placed onto the CCF 410 . In the embodiment shown in FIG. 4 , a hook-and-loop material is used as the attachment means, other means of attaching the AWF to the CCF 410 are contemplated.
[0041] In addition to acting as a point of attachment for the AWF, the vertical attachment means 413 and 483 also receive the corresponding vertical attachment means on the FP and thereby help to hold the FP in place.
[0042] FIG. 5 shows an exemplary implementation of the AWF 530 . Note that the hat cover 134 from FIG. 1 is not utilized in this implementation of the AWF 530 . Instead, only that portion of the AWF 530 that covers the back of the wearer's head and neck is included. Both the left and the right horizontal attachment means 532 and 592 are shown as are both the left and the right vertical attachment means 533 and 593 . As described under FIG. 4 , above, the attachment means shown in the embodiment illustrated in FIG. 5 are the hook-and-loop materials. Other means of attachment are contemplated.
[0043] In the top center of the AWF 530 is an elastic band or stretchable area 537 . The stretchable area 537 allows the AWF 530 to easily adjust to wearers with different size heads. Further, the stretchable area 537 provides for a comfortable and snug fit.
[0044] Yet another exemplary implementation of the AWF 630 is illustrated in FIG. 6 . A left side view of the AWF 630 is shown. The AWF 630 has an integrated weather-proof/water-resistant hat cover 634 . As shown in FIG. 6 , the hat cover 634 is shaped so as to cover a baseball-style cap. It is contemplated that alternative hat cover shapes would be utilized in order to cover alternative hat styles and shapes. The material utilized in manufacturing the hat cover can be any of a number of materials, depending on the properties desired in the hat cover 634 . Similarly, any desired colored and/or patterned materials can be used.
[0045] The AWF 630 attaches to the CCF 110 via the left horizontal attachment means 632 and the left vertical attachment means 633 . Both attachment means are illustrated using dashed lines as they are on the inside, front-facing surface of the AWF 630 and so are not directly visible in the current view. The CCF 110 has a left horizontal attachment means 112 placed so as to accept the AWF's 630 left horizontal attachment means 632 . The AWF's 630 left vertical attachment means 633 attaches to the corresponding CCF's 110 left vertical attachment means 113 . Both the CCF 110 and the AWF 630 also have corresponding right vertical and horizontal attachment means (not shown) that are mirrors of the left attachment means.
[0046] The hat cover 634 has at least three additional subcomponents shown in the embodiment in FIG. 6 : the elastic or stretchable portion 635 at the front of the hat cover 634 , the adjustable attachment means or drawstring 636 , and the FP storage tab 656 . In the embodiment in FIG. 6 , the stretchable portion 635 at the front of the hat cover 634 combined with the drawstring 636 allows the person wearing an ECS to adjust and tighten the AWF component separately from the other components. Furthermore, the wearer has the ability to remove the AWF 630 completely if it is not needed. Alternate embodiments are contemplated utilizing alternative means of attaching and adjusting the hat cover 634 over the hat.
[0047] The FP storage tab 656 shown in the embodiment in FIG. 6 is a hook-and-loop material; alternate materials and means of storing the FP are contemplated. FIG. 6 does not show a FP. Nevertheless, the FP storage tab 656 is shown and would be used by the wearer to store the FP when it is not in use. The wearer would simply relocate the FP from its normal position in front of the wearer's face by swinging it back over the hat cover 634 and then fold the FP and secure it to the FP storage tab 656 via a similar hook-and-loop material on the FP, as shown in FIG. 7 as a storage tab 755 .
[0048] The FP 750 shown in the embodiment in FIG. 7 has four key features: the main structural material 751 , the upper attachment means 752 , the vertical attachment means 753 and 754 , and the storage tab 755 . The main structural material 751 shown in this embodiment is an insect screen or netting. The material used to manufacture the FP 750 can be “see-through”, “rip-stop” nylon or some other suitable material that can protect the wearer's face from insects, sand, sun, blowing snow, etc., while still allowing the wearer to see through the material. Other embodiments are contemplated in which the main structural material 751 is clear plastic, tinted plastic, etc.
[0049] The FP 750 has an upper attachment means 752 which provides a means for attaching the FP 750 to a hat. In the embodiment shown in FIG. 7 , a hook-and-loop material is used to attach the FP 750 to the underside of the bill of a baseball-style cap. A corresponding hook-and-loop material must also be affixed to the underside of the cap's bill with glue, stitches, or some other means. Other embodiments of the FP 750 utilizing alternative attachment means are contemplated. FIG. 7 illustrates the FP 750 from a rear view, showing the surface of the FP 750 that faces inward towards the wearer's face. The upper attachment means 752 is shown using dashed lines because it is on the outward facing surface of the FP 750 and would not normally be visible from the rear view. The same is true for the storage tab 755 : it is on the outward facing surface of the FP 750 , so would not normally be visible in the current view.
[0050] The storage tab 755 provides a means of securing the FP 750 out of the way when it is not in use. Storage is accomplished by folding the FP 750 over the top of the head and attaching the storage tab 755 to a corresponding attachment means on the rear of the hat. Given the exemplary hook-and-loop attachment means and using the baseball-style hat as an example, the FP 750 would be folded over the top of the hat and attached via the storage tab 755 to a corresponding hook-and-loop material previously affixed to the hat directly above the adjustment band 171 , on the back center of the hat, as shown in FIG. 2 as FP storage tab 257 .
[0051] The FP 750 has vertical attachment means 753 and 754 which also utilize hook-and-loop material in the embodiment shown in FIG. 7 to attach the sides of the FP 750 to the sides of the CCF 110 using the CCF's 110 vertical attachment means 113 . Both the left and right sides of the FP 750 are shown in FIG. 7 . However, in FIG. 1 , only one side of the CCF 110 is shown. Thus, only one vertical attachment means 113 is shown on the CCF 110 in FIG. 1 . Nevertheless, there is another vertical attachment means on the other side of the CCF 110 so that both the left and right vertical attachment means 753 and 754 can be attached to the left and right vertical attachment means of the CCF 110 in FIG. 1 . Because the CCF's 110 vertical attachment means 113 are wider than those of the AWF 130 and the FP 750 , both the AWF 130 and the FP 750 can be attached to the CCF 110 at the same time.
[0052] The above specification, examples and data provide a description of the structure and use of exemplary embodiments of the described articles of manufacture and methods. Many embodiments can be made without departing from the spirit and scope of the invention. | A system of head and neck garments and components that allows the wearer to control the environment around the wearer's head and neck is disclosed. The system requires that the wearer carry minimal additional gear while providing the wearer with the ability to cool, warm, waterproof, camouflage, and protect his or her head and neck areas against sun, wind, rain, snow, insects, blowing sand, etc. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to a process for the preparation of a water-soluble, partially-hydrolyzed, solid acrylamide polymer. Partially-hydrolyzed acrylamide polymers have found wide-spread commercial utility as coagulants for various suspensions. Recently, they are also employed as secondary recovering agents for mining petroleum resources.
An acrylamide polymer is generally obtained by polymerizing acrylamide alone or copolymerizing acrylamide and another monomer copolymerizable with acrylamide in an aqueous medium. A partially-hydrolyzed polymer may also be obtained by treating the thus-prepared acrylamide polymer with an alkaline substance. Such a polymer formed in water or subjected further to hydrolysis is in the form of an extremely-viscous hydrous gel containing a great deal of water. In the industry, such a hydrous gel is dehydrated into a solid polymer. As an industrially-applicable preparation process of a partially-hydrolyzed, solid acrylamide polymer, U.S. Pat. No. 4,146,690 teaches dividing a hydrous gel of a polymer, which has been obtained by polymerization of an aqueous solution of acrylamide, into grains, mixing an aqueous caustic alkali solution with the thus-formed grains and subsequently drying them by hot air. In this process, the hydrolysis reaction of the polymer is allowed to proceed only to the extent of about 20-30% of the intended percentage of hydrolysis during its mixing with the caustic alkali. The remaining part of the hydrolysis reaction is allowed to take place in the hot-air drying step. Namely, the added caustic alkali adheres substantially in its entirety on polymer grains but the hydrolysis reaction of the polymer grains does not take place to any significant extent while the polymer grains are mixed with the caustic alkali, because the reaction velocity of hydrolysis is slow at low temperatures. The hydrolysis is brought to completion in the subsequent hot-air drying step, owing to the action of the caustic alkali adhered on surfaces of the polymer grains.
However, polymers hydrolyzed in accordance with the above-described process tend to contain some components which will not be completely dissolved in water. Use of such polymers, which contain water-insoluble components, as coagulants or secondary petroleum-recovering agents may bring about some undesirable results. Accordingly, it is desirable to minimize such water-insoluble components to the extent possible.
An acrylamide polymer hydrolyzed in accordance with the above-described process is susceptible of forming an insoluble precipitate in a solution containing abundant calcium and sodium ions. U.S. Pat. No. 3,039,529 suggests that the formation of such a precipitate renders the polymer unsuitable for use in secondary oil recovery.
U.S. Pat. No. 3,039,529 has also proposed to employ a polymer having a degree of hydrolysis of 12-67%, and preferably 12-45% in order to avoid the formation of precipitate in a solution containing calcium and sodium ions at high concentrations. As a process for obtaining such a hydrolyzed polymer, it also discloses adding sodium hydroxide to an aqueous solution containing 0.934% of a polymer, carry out its hydrolysis for 5 hours at 90° C., and then pouring the liquid reaction mixture into the same volume of methanol so as to cause the resultant hydrolyzed polymer to precipitate. Use of such a dilute polymer solution is however uneconomical because a great deal of energy or a dehydrating agent such as methanol is indispensable for removing the water and obtaining the resultant polymer in a solid state.
The present inventors have conducted research with a view toward developing a process for preparation of a water-soluble, partially-hydrolyzed, solid polymer which contains less water-insoluble components and forms less precipitate in a solution containing calcium and sodium ions. As a result, it has been found that the contents of water-insoluble components and the formation of precipitate can both be reduced when the hydrolysis of an acrylamide polymer is effected by allowing the acrylamide polymer to contact a caustic alkali under certain specific conditions.
SUMMARY OF THE INVENTION
Namely, the essential features of this invention reside in a process for preparing a water-soluble, partially-hydrolyzed, solid acrylamide polymer, which process comprises polymerizing an aqueous acrylamide-containing solution in the presence of a polymerization initiator to obtain an acrylamide polymer in the form of a hydrous gel, dividing the hydrous gel into grains, bringing the grains into contact with an aqueous caustic alkali solution, maintaining the polymer at a temperature of from 50° to 150° C. while maintaining the water content of the granular polymer substantially at the same level so that the hydrolysis of the amido groups in the acrylamide polymer has been achieved to the 60% or higher of the desired percentage of hydrolysis, and then drying the thus-prepared polymer grains with hot air.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the term "an acrylamide polymer" embraces, besides a homopolymer of acrylamide, water-soluble copolymers of acrylamide and other copolymerizable monomers. As exemplary copolymerizable monomers, may be mentioned acrylic acid, sodium acrylate, 2-acrylamide propane-sulfonate, and their mixtures. The preferred proportion of acrylamide in such a copolymer is generally 50 mole % or higher. By polymerizing acrylamide singly or in combination with one or more copolymerizable monomers in an aqueous medium in a manner commonly known in the art, a high molecular weight, water-soluble, hydrous gel-like polymer is obtained.
Although not necessarily limited to any specific ranges, the concentration of the monomer or the monomers in the aqueous medium may generally range from 15 to 45 wt.% (wt.% means % by weight) and preferably from 20 to 35 wt.%. Excessively low or high concentrations are not preferred because excessively low concentrations not only result in gel-like polymers having high tackiness but also render the drying of the gel-like polymers cumbersome whereas extremely high concentrations lead to extremely high temperatures in the polymerization systems, thereby causing thermal degradation of the resultant polymers.
As the polymerization initiator, a so-called radical polymerization initiator may be used. As illustrative radical polymerization initiators, may be mentioned azo compounds such as azobisisobutyronitrile and azobis(2-amidinopropane) hydrochloride, peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide. The peroxide may be used singly as well as redox polymerization initiators in combination with reducing agents such as sodium sulfite, ferrous sulfate and ferrous chloride. Two or more of the abovedescribed polymerization initiators may also be used in combination. The polymerization initiator may be used, generally, at 100-10,000 ppm and preferably at 200-5,000 ppm based on the monomer.
The polymerization is usually carried out by, after bubbling the aqueous solution of the monomer or monomers with N 2 gas, incorporating a predetermined amount of a catalyst and maintaining the polymerization system at temperatures in the range of -10° C.-+100° C. The resulting polymer is in the form of a hydrous gel. Where the concentration of the monomer or the monomers in the aqueous monomer solution ranges from 15 wt.% to 45 wt.%, the water content of the resultant polymer ranges from 85 wt.% to 55 wt.%.
The thus-obtained polymer in the hydrous gel form is then divided into grains. This granulation may be carried out, for example, by extruding the polymer through a perforated plate by means of a screw and then cutting it by a cutter. The thus-obtained grains may be of any shape such as spherical, cylindrical, cubic or the like. Their average grain diameters may generally be 2-20 mm and preferably 2-10 mm. Too small a grain diameter leads to excessively small diameters of the final solid products, whereas use of too large a grain diameter tends to induce uneven hydrolysis when the grains are brought into contact with an aqueous caustic alkali solution.
The thus-granulated polymer is thereafter brought into contact and treated with an aqueous caustic alkali solution. This is usually carried out by spraying the aqueous caustic alkali solution over polymer grains while mixing the polymer grains. Caustic soda or caustic potash may be employed as the caustic alkali and it is usually employed as an aqueous 20-47 wt.% solution. The amount of the caustic alkali to be used is determined by the desired percentage of hydrolysis. It may be the chemical equivalent to or somewhat in excess of the amount of amido groups to be hydrolyzed. The desired percentage of hydrolysis of the acrylamido groups in the polymer may vary depending on the end use of the polymer, and it may generally range from 5 to 50 mole % of the amido groups present in the starting acrylamide polymer.
It is essential in the present invention to achieve at least 60% and preferably 70% or more of a desired percentage of hydrolysis prior to the drying of the granular polymer by conducting the hydrolysis reaction of the polymer under specific conditions. It is preferable not to stop the hydrolysis from proceeding to a satisfactory extent prior to drying the granular polymer which would allow the hydrolysis to take place more intensively in the subsequent hot-air drying step, since this will result in more water-insoluble components in the resultant polymer.
After adding caustic alkali solution, the polymer may be maintained at temperatures of 50°-150° C. and preferably 65°-100° C. If the temperature should be too low, the hydrolysis reaction will not proceed smoothly. On the contrary, excessively high temperatures will induce thermal degradation of the resultant polymer. Therefore, neither too low temperatures nor too high temperatures are preferred. In addition, it is necessary to maintain the water content of the polymer at a substantially constant level during hydrolysis. The water content of polymer means percent of water per sum of water and polymer. The weight of the polymer changes after hydrolysis since carboxamide groups of the polymer are converted to carboxylate groups by the hydrolysis. So the water content differs a little after hydrolysis, if there is no addition nor loss of water from the reaction system. In the present invention, it is recommended that the drop of the water content (%) of the polymer after hydrolysis is kept within 10% (on the wet weight basis), preferably within 3%.
If the water content of the polymer should drop to any significant extent in the course of the first hydrolysis reaction, it would be impossible to bring about the effects of this invention. Thus, it is important to allow the hydrolysis to proceed to an extent of 60% or higher and preferably 70% or higher of the desired percentage of hydrolysis while maintaining the reaction system at the above-described temperatures without allowing the humidity of the reaction system to drop. The time required for hydrolysis varies in accordance with the temperature of the treatment and is usually 1 minute or longer and preferably 3 minutes or longer. It is unfeasible to conduct the hydrolysis reaction to any sufficient extent if the hydrolysis time is too short.
The means of carrying out the hydrolysis under above-mentioned conditions are, for example, as follows. The polymer grains, to which the caustic alkali has been added in advance, are charged into a closed container and then heated to a desired temperature by blowing steam into the container; or the polymer grains, to which the caustic alkali has been added in advance, are charged for example into a rotary drum internally provided with steam pipes equipped with a number of spray nozzles and steam is then blown into the rotary drum while rotating the drum. Alternatively, the polymer grains with caustic alkali are placed on a perforated plate and steam is then passed through the polymer grains. It is also possible to add an aqueous caustic alkali solution to the polymer grains while mixing the polymer grains and supplying steam to the polymer grains. It may be feasible to use a gas, for example air, heated and humidified to a relative humidity of 80% or higher, in place of steam. It is preferred to make or line the interior of a reactor, mixer and the like equipments to be employed for the hydrolysis treatment, with which the resultant polymer of a hydrous gel form is brought into contact, with a synthetic resin. Preferred synthetic resins include polyolefins, polyesters, fluoroplastics, etc.
The granular polymer, on which the hydrolysis reaction has been allowed to proceed to a satisfactory extent in the above treatment, is thereafter dried by hot air in accordance with a method routinely employed in the art, normally, at temperatures in the range of 40°-130° C. and preferably 60°-110° C. until the water content of the granular polymer is lowered to 15 wt.% or less and preferably 10 wt.% or less. For the above drying processing, a band drier, rotary drier or the like is generally used. The thus-dried polymer is, subsequent to its comminution if necessary, classified into a final product. Grains having diameters in the range of 0.2-5 mm are generally used as the final product.
The partially-hydrolyzed acrylamide polymer obtained in accordance with the process of this invention features extremely little water-insoluble components present therein. Furthermore, it hardly forms a precipitate even when dissolved in a solution containing calcium ions at a high concentration. It is thus extremely useful as a coagulant or a secondary oil-recovering agent.
The invention will next be described in further detail in the following Examples. It should however be borne in mind that the present invention is not be limited to the following Examples.
EXAMPLE 1
Ten kilograms of a 25 wt.% aqueous solution of acrylamide were charged into a 15-liter polymerization reactor, followed by bubbling with nitrogen gas. Thereafter, 2,2-azobis-(2-amidinopropane) hydrochloride and sodium bisulfite were added respectively in such amounts that their concentrations became 1,000 ppm and 100 ppm of the monomer. The polymerization was initiated at 20° C. and lasted for 5 hours.
The resultant gel-like polymer (water content: 75 wt.%), obtained in the above polymerization, was granulated into grains each of about 3 mm in diameter by means of a meat grinder-like extrusion granulator and then passed into a screw conveyor equipped with a double-helical ribbon screw. A 47% aqueous caustic soda solution was sprayed over the grains in the amount of 90 g per kg of the grains (i.e., in an amount sufficient to hydrolyze 30 mole % of the amido groups present in the starting polymer) while mixing the grains.
Thereafter, steam at 135° C. was blown, at a rate of 3.5 kg/cm 2 for each of the time periods given in Table 1, onto the grains which were placed on a 100-mesh sieve and their hydrolysis reaction was allowed to proceed while maintaining the temperatures of the grains at 70° C. Then, the thus-treated grains were dried for 60 minutes by hot air of 100° C. to a water content of 12 wt.% or lower.
The thus-prepared granular polymers were dissolved in water and the proportions of insoluble components were measured. Results are shown in Table 1. Incidentally, the polymer identified as No. 4 is a polymer obtained in accordance with the prior art process, namely, by spraying an aqueous solution of caustic soda over grains of a hydrous polymer gel and then immediately drying them with hot air.
TABLE 1__________________________________________________________________________ Contents Ca.sup.2+ - Time period of water- precipi- Percentage Viscosity maintained Percentage hydroly- insoluble tation hydrolysis of polymer at 70° C. sis after maintain- components test** of polymer product***No. (min) ed at 70° C. (%) (wt. %)* (ppm) (%) (cps)__________________________________________________________________________1 1 16.8 0.3 2,000 28 2002 2 21.0 0.1 10,000< 30 2103 15 24.0 trace 10,000< 30 2104 none 7.3 1.0 500 29 190 (control)__________________________________________________________________________ Note: *Content of waterinsoluble components: Indicates the percentage of insoluble components upon dissolving each 5 g of the polymers at room temperature in 5,000 ml of water, and stirring for 120 **Ca.sup.2+ precipitation test: Indicates the Ca.sup.2+ concentration a the precipitation point when an aqueous solution containing calcium chloride in the concentration of 4% as measured in terms of Ca.sup.2+ ions was gradually dropped into each aqueous 0.1 wt. % polymer solution with stirring. ***Viscosity: Each of the polymers was dissolved in an aqueous 4% NaCl solution to give the polymer concentration of 0.5% and its viscosity at 25° C. was measured by a ModelB viscometer (No. 2 rotor; 60 r.p.m.).
EXAMPLES 2
Ten kilograms of a 25 wt.% aqueous solution of acrylamide were charged into a 15-liter polymerization reactor, followed by bubbling with nitrogen gas. Thereafter, 2,2-azobis(2-amidinopropane)hydrochloride and acid sodium sulfite were added in such amounts that their concentrations became 1,000 ppm and 100 ppm respectively. The polymerization was initiated at 20° C. and allowed to proceed for 5 hours.
The resultant gel-like polymer taken out of the polymerization reactor was extruded as grains of 3 mm in diameter from a meat grinder-like extrusion granulator onto a screw conveyor equipped with a double helical ribbon screw.
Ninety grams of a 47% aqueous solution of caustic soda (which contained caustic soda in an amount sufficient to hydrolyze 30% of the amido groups in the polymer) at 25° C. were sprayed over 1 kg of the above-obtained grains (water content: about 75 wt.%; grain temperature: 20° C.) while mixing the grains. The thus-sprayed grains were stirred for 3 minutes into a uniform mixture.
The polymer grains, which had been sprayed with the aqueous caustic soda solution, (water content: about 75 wt.%; grain temperature: 22° C.) were then placed in a polypropylene-made rotary drum equipped with steam pipes having spray nozzles and four baffle plates and the rotary drum was rotated at 40 r.p.m. While the drum was rotated, steam at 135° C. was blown into the drum through a steam pipe for a predetermined time period so as to maintain the granular polymer at 80° C., thereby hydrolyzing the same granular polymer. The water content of the thus-obtained grains was 74.5 wt.% and this water content was not lowered to any substantial extent in the course of the hydrolysis reaction.
Thereafter, hot air at 100° C. was used for 60 minutes to dry the grains until the water content of the granular polymer had been reduced to 12 wt.% or less.
Similar to Example 1, the thus-obtained hydrolyzed polymer was subjected to various measurements or tests.
Results are summarized in Table 2.
TABLE 2______________________________________Time period Content ofmaintained Percentage hydrolysis water-insolubleat 80° C. after maintained at componentsNo. (min.) 80° C. (%) (wt. %)______________________________________1 2 24 trace2 10 28 trace______________________________________Ca.sup.2+ -precipitation Percentage hydrolysis Viscosity oftest of polymer product polymer productNo. (ppm) (%) (cps)______________________________________1 10,000< 30 2102 10,000< 30 220______________________________________ | A partially-hydrolyzed, solid acrylamide polymer is prepared by bringing a hydrous gel of a water-soluble acrylamide polymer into contact with an aqueous caustic alkali solution, maintaining the polymer at an elevated temperature and under highly humid conditions to hydrolyze certain amido groups of the water-soluble acrylamide polymer and then drying the thus partially-hydrolyzed acrylamide polymer. The resultant polymer contains less water-insoluble components and hardly forms precipitate even in salt water containing calcium ions. It can be suitably used for coagulation of suspension and in secondary oil recovery. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0000]
This is a divisional application which claims the benefit of pending U.S. patent application Ser. No. 12/919,360, filed Sep. 15, 2010, which is a National Stage entry of International Application No. PCT/EP2009/001211, filed Feb. 19, 2009, and claims priority of Italian Patent Application No. MI 2008 A 000316, filed Feb. 27, 2008. The disclosures of the prior applications are hereby incorporated herein in their entirety by reference.
[0002] The present invention relates to the use of extracts of hypericum ( Hypericum perforatum L.) flowering stems and the components thereof for the preparation of pharmaceutical preparations and/or food supplements for the treatment of various forms of neuropathic pain (caused by chemotherapy drugs, mononeuropathy or osteoarthritis).
BACKGROUND TO THE INVENTION
[0003] Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.
[0004] Within this definition a particular type of pain associated with neurological abnormalities, called neuropathic pain, is becoming increasingly important due to its significant, growing worldwide prevalence. Neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”, which may take the form of dysaesthesia, allodynia, hyperpathy, stinging or stabbing pain.
[0005] Neuropathic pain is distinguished from other types of commonly reported (nociceptive) pain, including headache, backache, and other types of musculoskeletal pain, and comprises a heterogeneous group of conditions which cannot be explained by a single etiology or a particular anatomical lesion.
[0006] These disorders of the structures of the central or peripheral nervous system include various neuropathies (diabetic neuropathy, post-herpetic neuropathy, inflammatory neuropathies, neuropathy caused by alcohol abuse and neuropathy associated with HIV/AIDS infection), and can derive from various toxins (such as neurotoxins), acute trauma (including surgical traumas), chronic trauma (such as repetitive stress syndrome), mononeuropathies, such as carpal tunnel syndrome (the most common type of mononeuropathy, which affects 2.8% to 4.6% of the adult population), and disorders of the central nervous system (such as stroke, multiple sclerosis, cerebral ischaemia, Parkinson's disease, spinal cord lesions and head injuries).
[0007] The disorder is not easy to diagnose, because although the nerve produces continual painful discharges, it is often anatomically intact.
[0008] Neuropathic pain covers a variety of pathological states and presents with a variety of symptoms, which have the following common denominators:
pain is perceived in the absence of a permanent, identifiable tissue lesion or process; unpleasant, abnormal or unusual sensations (dysaesthesia) are present, frequently described as stinging or electric shocks; brief episodes of paroxystic stabbing or piercing pain are present; the pain appears some time after the lesion that triggered it the pain is perceived in a region with a sensory deficit; even mild stimuli are painful (allodynia); marked summation and persistent activity occur after the application of repeated stimuli.
[0016] It is estimated that neuropathic pain affects up to 3% of the population, and that some 1 to 5% of European adults suffer from chronic pain.
[0017] According to the literature, in the USA the problem of neuropathic pain is potentially onerous for the national insurance systems, with a prevalence of 1.5%.
80% of patients with tumours at an advanced stage present neuropathic symptoms.
[0019] Chronic neuropathic pain is a major problem in neurology because it is frequent and often disabling, due to its unpleasant, chronic nature.
[0020] It is also a type of pain which does not respond well to the most common analgesics, such as acetylsalicylic acid, paracetamol or the most common non-steroidal anti-inflammatory drugs.
[0021] The aim of pharmacological treatments should be to prevent pain, but in practice, the most that can be achieved is to reduce the pain to a bearable level.
[0022] At present, no class of drugs has proved universally effective for patients with neuropathic pain.
[0023] “Off-label” drugs belonging to the following categories are generally used, but cause serious side effects in the long term:
antidepressants anticonvulsants (gabapentin) opioids (methadone, oxycodone) tramadol lidocaine cytokine-inhibiting anti-inflammatories.
[0030] When these drugs are effective, they reduce pain by 25-40% in 40-60% of patients.
[0031] Moreover, numerous adverse effects are caused by continuous use of these drugs.
[0032] Neuropathic pain therefore represents a major clinical challenge due to its severity, chronic nature, resistance to the usual treatments and serious effect on the quality of the life.
[0033] The main research into this disorder uses experimental metabolic, pharmacological or trauma models in rodents, which reproduce the characteristics of human pain symptoms (Ref 1-7).
[0034] Hypericum , also known as St. John's Wort, consists of the flowering stems of Hypericum perforatum . It contains a large number of different classes of substances: naphthodianthrone derivatives such as hypericin, pseudohypericin and isohypericin, and phloroglucinol derivatives such as hyperforin. It also contains flavonoids such as hyperoside, rutin, I3,II8-biapigenin, quercetin, quercitrin and isoquercitrin, procyanidins, essential oil and xanthones.
[0035] It is widely used in modern phytotherapy to treat some forms of mild or moderate depression and psychovegetative problems, with effective results at the dose of 500-1050 mg of extract/day divided into 2-3 doses, for 2-4 weeks, and fewer side effects than treatment with synthetic antidepressants.
[0036] Hypericum perforatum extracts have been tested in many experimental pharmacological and clinical trials, which fully support its use for depression, but many questions about its characteristics still remain unanswered. A number of action mechanisms have been suggested to explain its antidepressant effects: 1) non-selective serotonin, noradrenaline and dopamine reuptake inhibition; 2) increased density of the serotoninergic, dopaminergic and GABA receptors; 3) increased affinity for the GABA receptors; 4) inhibition of the enzyme monoamine oxidase (MAO). The identity of the active components is still in doubt, and its pharmacological activity seems to be complex and determined by the concomitant effects of a number of active substances. Hypericin has been identified as “the” active ingredient, but a new component, hyperforin, which was recently identified, seems to play an important part in the efficacy of the plant, while flavonoids, in particular rutin, have been identified as compounds which can influence its activity (Ref. 8-15).
[0037] A clinical trial (16) published in 2000 describes the inefficacy of a hypericum extract in the treatment of neuropathies.
[0038] Other studies describe the analgesic activity of hypericum , but they were conducted on different species from Hypericum perforatum , the extracts were not chemically characterised, the administration route was often not oral, and above all, they were evaluated on non-neuropathic pain models (hot plate test, writhing test, Ref. 16-22).
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 shows a flow chart of a method of preparing total freeze-dried extracts: and
[0040] FIG. 2 shows a flow chart of a method of preparing freeze-dried extracts of a hydrophilic fraction of hypericum.
DESCRIPTION OF THE INVENTION
[0041] Freeze-dried extracts of hypericum ( Hypericum perforatum ) flowering stems and one of its components, hypericin, have proved effective in reducing the symptoms of neuropathic pain in various experimental models, following oral administration.
[0042] The studies were conducted on rodents, which have always constituted a good animal model to reproduce the characteristics of human pain symptoms and predict possible remedies.
[0043] The freeze-dried extracts can derive from freeze-drying of either the whole plant material extracted with water-ethanol solvent, or of the most hydrophilic component of the plant.
[0044] The active closes of freeze-dried hypericum extracts range from 10 mg/kg to 100 mg/kg.
[0045] The freeze-dried extracts preferably derive from extraction of the whole plant with water-alcohol solvents (0-100% ethanol, methanol, isopropanol, etc.) or water-acetone solvents (0-100%) and separation and freeze-drying of a more hydrophilic component from the plant.
[0046] Freeze-dried hypericum extracts preferably have a content of naphthodianthrone derivatives (hypericin+pseudohypericin) amounting to not less than 0.25%, evaluated by the HPLC method (minimum 0.025 mg per kg of body weight).
[0047] One of the naphthodianthrone derivatives, hypericin, has proved active at a dose corresponding to its concentration in freeze-dried extracts.
[0048] The phloroglucinol derivatives isolated (hyperforin and adihyperforin) have proved unable to reduce neuropathic pain.
[0049] Up to the dose of 3000 mg/kg per os the freeze-dried extract does not change the animal's behaviour, as demonstrated by the fact that the number of falls from the rotating rod consecutively declines as the sessions are repeated, demonstrating that the animals' motor coordination is wholly comparable to that of the controls (Ref. 29 Rota Rod test).
[0050] When analyzed in terms of numerous parameters (behaviour, movement, muscle tone, autonomic signs), the extracts did not cause any alteration. The scores of the treated animals did not differ from those of the controls (Ref. 28 Irwin test).
[0051] The invention is described in greater detail in the Examples and Preparations below.
[0052] Preparation 1. Total Freeze-Dried Extract
[0053] FIG. 1 shows the flow chart of the preparation method. The freeze-dried hypericum ( Hypericum perforatum ) flowering stem extract is prepared from hypericum flowering stems. After drying and selection of the tips, extraction is performed with a water-ethanol solution containing, 50-80% alcohol, with a plant:solvent ratio of 1:13.
[0054] The solution is concentrated under reduced pressure to remove the ethanol, and dried by a freeze-drying process in suitable freeze-dryers.
[0055] Preparation 2. Freeze-Dried Extract of the Hydrophilic Fraction
[0056] FIG. 2 shows the flow chart of the preparation method.
[0057] The freeze-dried extract of the hydrophilic fraction of hypericum , containing polar water-soluble substances, was prepared by a process of physical separation of the non-hydrophilic substances, and centrifugation with a decanter. The two fractions were then freeze-dried separately.
[0058] The freeze-dried extract was chemically characterised by HPLC analysis, which showed a total hypericin concentration (hypericin+pseudohypericin) of 0.27 to 0.37%.
Example 1
Oxaliplatin-Induced Neuropathy
[0059] A reduction in the pain threshold was induced by administering oxaliplatin 2.4 mg/kg for 5 consecutive days for a total of 3 weeks. By the end of the treatment period, the pain perception threshold of the rats was statistically lower than that of the controls (Ref. 23).
[0060] The total freeze-dried extract at the dose of 30 and 60 mg/kg of body weight proved to be active to a statistically significant extent.
[0000]
TABLE 1a
DOSE-RESPONSE CURVE OF HYPERICUM EXTRACT ON OXALIPLATIN-
INDUCED HYPERALGESIA IN THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
TREATMENT
3rd week +
3rd week +
3rd week +
i.p.
MG/KG P.O.
Pre-test
15 min.
30 min
45 min
SALINE
CMC
57.4 ± 3.5
61.8 ± 5.4
67.4 ± 6.3
62.3 ± 5.4
OXALIPLATIN
CMC
22.6 ± 4.6
25.1 ± 6.1
26.9 ± 5.4
24.3 ± 6.6
OXALIPLATIN
HYPERICUM
21.7 ± 1.2
58.1 ± 3.5*
67.8 ± 2.0*
29.1 ± 2.0
EXTRACT
30 mg/kg
OXALIPLATIN
HYPERICUM
24.5 ± 1.3
48.2 ± 4.6*
25.7 ± 2.4
21.5 ± 0.0
EXTRACT
60 mg/kg
Oxaliplatin 2.4 mg/kg−1 for 5 consecutive days a week (15 i.p. injections - cumulative dose 36 mg/kg)
{circumflex over ( )}P < 0.05
*p > 0.01
[0061] The freeze-dried extract of the hydrophilic fraction at the dose of 30 mg/lag of body weight proved active to a statistically significant extent in the oxaliplatin-induced neuropathy pain test.
[0000]
TABLE 1 b
DOSE-RESPONSE CURVE OF HYDROPHILIC FRACTION
OF HYPERICUM EXTRACT ON OXALIPLATIN-INDUCED
HYPERALGESIA IN THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
TREATMENT
3rd week +
3rd week +
3rd week +
i.p.
MG/KG P.O.
PRE-TEST
15 min.
30 min
45 min
SALINE
CMC
57.4 ± 3.5
61.8 ± 5.4
67.4 ± 6.3
62.3 ± 5.4
OXALIPLATIN
CMC
22.6 ± 4.6
25.1 ± 6.1
26.9 ± 5.4
24.3 ± 6.6
OXALIPLATIN
HYDROPHILIC
21.0 ± 2.0
42.0 ± 1.9*
63.0 ± 1.9*
14.5 ± 1.0
HYPERICUM
EXTRACT
30 mg/kg
Oxaliplatin 2.4 mg/kg−1 for 5 consecutive days a week (15 i.p. injections - cumulative dose 36 mg/kg)
{circumflex over ( )} P < 0.05
*p > 0.01
Example 2
Mononeuropathy Induced by Ligature of the Sciatic Nerve
[0062] Neuropathic pain is characterised by the development of an altered perception of pain, which is manifested as continuous spontaneous pain and hyperalgesia. In this model, the rats were anaesthetised with chloral hydrate 400 mg/kg i.p. or sodium pentobarbital 40 mg/kg i.p. The sciatic nerve was then exposed at thigh level by retracting the femoral biceps. Proximally to the trifurcation of the sciatic nerve, approx. 7 mm of nerve was released from the membranes and 4 loose ligatures were tied round the nerve, approx. 1 mm apart. In another group of animals an identical incision was made, but without the nerve ligature (sham operation). Neuropathy developed in 14 days. The tests with the potentially analgesic substances were performed on the 14th and 21st days after the operation using the paw pressure test (ref. 24).
[0063] The total freeze-dried extract at the dose of 10, 30, 60 and 100 mg/kg of body weight proved to be active to a statistically significant extent.
[0000]
TABLE 2a
EFFECT OF HYPERICUM EXTRACT IN A RIGHT-SIDE MONONEUROPATHY
MODEL IN RATS, EVALUATED WITH THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
Before
After treatment
i.p.
PAW
treatment
15 min
30 min
45 min
CMC
L
60.5 ± 3.8
61.8 ± 3.7
64.6 ± 3.3
59.8 ± 3.2
CMC
R
22.8 ± 2.2
21.6 ± 3.5
23.0 ± 2.6
21.9 ± 3.7
HYPERICUM
L
56.2 ± 6.6
56.2 ± 7.2
58.7 ± 3.9
51.2 ± 4.3
EXTRACT
R
20.9 ± 4.0
22.5 ± 3.2
33.7 ± 4.7 {circumflex over ( )}
18.7 ± 2.4
10 mg/kg
HYPERICUM
L
63.3 ± 5.7
68.8 ± 4.4
73.3 ± 6.7
51.7 ± 7.5
EXTRACT
R
20.3 ± 4.4
59.8 ± 3.1 *
65.5 ± 1.7 *
31.3 ± 1.7
30 mg/kg
HYPERICUM
L
62.6 ± 3.0
68.5 ± 4.1
77.6 ± 4.3
60.7 ± 2.2
EXTRACT
R
21.9 ± 2.4
37.0 ± 2.8 {circumflex over ( )}
41.8 ± 4.4 *
22.7 ± 2.4
60 mg/kg
HYPERICUM
L
62.8 ± 1.7
72.2 ± 2.4
78.6 ± 2.0
62.5 ± 3.8
EXTRACT
R
21.3 ± 2.7
27.5 ± 4.3
31.5 ± 4.3 *
20.5 ± 2.9
100 mg/kg
{circumflex over ( )} P < 0.05
* p > 0.01
[0064] The freeze-dried extract of the hydrophilic fraction at the doses of 10, 30, 60 and 100 mg/kg of body weight proved active to a statistically significant extent, as shown in Table 2h below.
[0000]
TABLE 2 b
EFFECT OF HYDROPHILIC FRACTION OF HYPERICUM
EXTRACT IN A RIGHT-SIDE MONONEUROPATHY MODEL IN
RATS, EVALUATED WITH THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
BEFORE
AFTER TREATMENT
MG/KG P.O.
PAW
TREATMENT
15 min
30 min
45 min
CMC
L
60.5 ± 3.8
61.8 ± 3.7
64.6 ± 3.3
59.8 ± 3.2
CMC
R
22.8 ± 2.2
21.6 ± 3.5
23.0 ± 2.6
21.9 ± 3.7
HYDROPHILIC
L
60.9 ± 4.7
62.5 ± 5.8
61.3 ± 6.0
58.2 ± 3.0
HYPERICUM
R
20.3 ± 2.9
33.5 ± 3.3
41.6 ± 3.5 *
19.8 ± 6.0
EXTRACT
10 mg/kg
HYDROPHILIC
L
59.4 ± 4.6
67.5 ± 4.8
63.6 ± 2.4
58.7 ± 3.1
HYPERICUM
R
22.3 ± 2.4
55.1 ± 3.2 *
62.0 ± 3.5 *
26.5 ± 3.3
EXTRACT
30 mg/kg
HYDROPHILIC
L
60.4 ± 3.6
65.8 ± 2.0
71.2 ± 3.7
57.7 ± 4.8
HYPERICUM
R
20.2 ± 2.3
52.4 ± 3.7 *
59.7 ± 3.0 *
24.5 ± 3.2
EXTRACT
60 mg/kg
HYDROPHILIC
L
63.7 ± 3.5
71.2 ± 4.3
73.0 ± 2.9
61.2 ± 3.1
HYPERICUM
R
23.5 ± 3.9
30.2 ± 3.4
35.8 ± 2.5 *
20.3 ± 3.3
EXTRACT
100 mg/kg
{circumflex over ( )} P < 0.05
* p > 0.01
Example 3
Paclitaxel-Induced Neuropathy
[0065] The total freeze-dried extract at the doses of 30 and 100 mg/kg of body weight and the extract of the hydrophilic fraction at the dose of 30 mg/kg proved active to a statistically significant extent in the paclitaxel-induced neuropathic pain test (Ref 25)
[0000]
TABLE 3
EFFECT OF HYPERICUM EXTRACT (30 and 100
mg/kg −1 p.o.) AND THE HYDROPHILIC FRACTION ON
PACLITAXEL-INDUCED HYPERALGESIA IN THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
TREATMENT
Before treatment
i.p.
p.o.
Pre-test
15 min
30 min
45 min
SALINE
SALINE
57.2 ± 3.9
62.6 ± 4.4
58.3 ± 4.7
56.9 ± 3.9
PACLITAXEL
SALINE
43.7 ± 4.2
39.6 ± 3.8
41.9 ± 4.3
42.5 ± 4.9
SALINE
HYPERICUM
62.6 ± 3.3
59.8 ± 4.4
57.6 ± 4.7
60.1 ± 4.6
EXTRACT
30 mg/kg
BATCH 7I0525
PACLITAXEL
HYPERICUM
40.5 ± 3.8
50.3 ± 3.4 *
48.0 ± 4.0
36.6 ± 4.2
EXTRACT
30 mg/kg
BATCH 7I0525
PACLITAXEL
HYPERICUM
39.6 ± 3.3
51.6 ± 3.1 *
46.3 ± 3.9
39.5 ± 4.0
EXTRACT
100 mg/kg
BATCH 7I0525
PACLITAXEL
HYDROPHILIC
38.3 ± 3.9
49.2 ± 3.8 *
44.0 ± 3.5
33.8 ± 3.7
FRACTION
30 mg/kg
BATCH 7I0660
Treatment: Paclitaxel 0.5 mg/kg −1 was injected i.p. for four days (days 1, 3, 5 and 8). The cumulative dose of Paclitaxel was 2.0 mg/kg −1 . The test was performed 14-15 days after the last injection of paclitaxel. Vehicle: Saline: ethylene oxide 9:1 8 rats per group (two experiments).
{circumflex over ( )} P < 0.05; versus rats treated with paclitaxel.
Example 4
Vincristine-Induced Hyperalgesia
[0066] A reduction in the pain threshold was obtained in the rat by i.v. administration of vincristine (150 gamma/kg i.v. every 2 days for 5 days until the cumulative dose of 750 gamma/kg was reached); the test (paw-pressure) was conducted 4 days after the last injection (Ref 26). Alternatively, the vincristine was applied (brushed) directly onto the sciatic nerve. The total freeze-dried extract at the doses of 30 and 100 mg/kg of body weight and the freeze-dried extract of the hydrophilic fraction at the dose of 30 mg/kg proved active to a statistically significant extent.
[0000]
TABLE 4
EFFECT OF HYPERICUM EXTRACT (30 and 100 mg kg−1 p.o.)
AND THE HYDROPHILIC FRACTION ON VINCRISTINE-INDUCED
HYPERALGESIA IN THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
TREATMENT
TREATMENT
Before treatment
mg kg−1 i.v.
mg kg−1 p.o.
Pre-test
15 min
30 min
45 min
60 min
SALINE
SALINE
61.6 ± 3.3
57.2 ± 4.5
62.4 ± 4.0
58.3 ± 4.1
61.6 ± 5.3
VINCRISTINE
SALINE
35.2 ± 3.4
33.8 ± 4.5
35.1 ± 3.6
36.2 ± 3.7
34.9 ± 2.8
SALINE
HYPERICUM
56.3 ± 3.3
63.4 ± 4.0
61.6 ± 3.8
57.3 ± 4.4
58.7 ± 3.3
EXTRACT
30 mg/kg
BATCH
7I0525
VINCRISTINE
HYPERICUM
34.9 ± 3.1
52.6 ± 4.2*
51.9 ± 4.5*
38.3 ± 5.0
34.9 ± 5.2
EXTRACT
30 mg/kg
BATCH
7I0525
VINCRISTINE
HYPERICUM
33.90 ± 3.5
48.2 ± 4.1*
47.5 ± 4.7*
35.7 ± 4.1
EXTRACT
100 mg/kg
BATCH
7I0525
VINCRISTINE
HYPERICUM
31.5 ± 3.2
50.9 ± 3.7*
53.4 ± 4.2*
36.5 ± 4.9
31.3 ± 3.8
EXTRACT
30 mg/kg
BATCH
7I0660
Treatment with vincristine: five i.v. injections of 150 μg/kg −1 performed every 2 days up to a cumulative dose of 750 μg/kg −1 i.v.
The test was performed 4 days after the last injection of vincristine. 7-8 rats per group (two experiments).
{circumflex over ( )}P < 0.05
*P < 0.01 versus rats treated with vincristine
14 rats per group (two experiments).
*P > 0.05 versus rats treated with vincristine.
Example 5
Hypericin in Oxaliplatin-Induced Neuropathy
[0067] Using the same method as in Example 1, the following results were obtained by administering hypericin at the doses indicated in Table 5.
[0000]
TABLE 5
EFFECT OF HYPERICIN (single administration) ON OXALIPLATIN-
INDUCED HYPERALGESIA IN THE RAT PAW PRESSURE TEST
Pressure on rats' paws (g)
Treatment period (weeks of oxaliplatin)
Pre-test
TREATMENT
TREATMENT
before all
3rd week
3rd week +
3rd week +
3rd week +
3rd week +
i.p.
p.o.
treatments
Pre-test
15 min
30 min
45 min
60 min
SALINE
SALINE
60.1 ± 2.2
66.2 ± 4.5
65.0 ± 4.3
63.9 ± 3.8
66.5 ± 4.4
68.1 ± 4.1
OXALIPLATIN
SALINE
58.4 ± 4.6
30.5 ± 4.7
28.4 ± 4.1
25.8 ± 3.6
27.1 ± 4.1
29.1 ± 2.8
OXALIPLATIN
HYPERICIN
63.2 ± 3.5
32.4 ± 2.0
44.1 ± 2.8*
55.0 ± 2.2*
53.3 ± 2.6*
31.3 ± 3.0
0.11 mg/kg +
CMC
OXALIPLATIN
HYPERICIN
60.6 ± 3.8
31.7 ± 2.5
56.3 ± 2.6*
58.5 ± 2.7*
52.5 ± 1.2*
33.0 ± 2.8
0.11 mg/kg +
HYPERISIDE
3.118 mg/kg
Treatment: Oxaliplatin 2.4 mg kg −1 for 5 consecutive days a week (15 i.p. injections - cumulative dose 36 mg/kg)
8 rats per group (two experiments).
*P < 0.01
Example 6
Hypericin in Neuropathy Induced by Ligature of the Sciatic Nerve
[0068] Using the same method as in Example 2, the following results were obtained by administering hypericin at the doses indicated in Table 6.
[0000]
TABLE 6
EFFECT OF HYPERICIN IN A RIGHT-SIDE MONONEUROPATHY MODEL
IN THE RAT, EVALUATED WITH THE RAT PAW PRESSURE TEST
Paw
Treatment
Before
After treatment
MG/KG. P.O.
PAW
treatment
15 min
30 min
4 min
60 min
CMC
L
60.8 ± 2.9
57.8 ± 3.3
57.4 ± 3.8
59.2 ± 4.9
55.9 ± 3.8
CMC
R
23.2 ± 2.2
24.7 ± 3.5
22.9 ± 2.8
23.6 ± 3.7
20.7 ± 3.5
HYPERICIN
L
21.6 ± 2.7
23.8 ± 3.3
22.7 ± 2.1
24.8 ± 3.9
21.5 ± 3.0
0.11 mg/kg
HYPERICIN
R
24.3 ± 4.6
28.1 ± 1.2
43.7 ± 2.0*
41.6 ± 2.7*
25.9 ± 2.2
0.11 mg/kg
The doses of hypericin, hyperoside and amentoflavone corresponded to 30 mg/kg p.o. of hydrophilic fraction of hypericum extract - batch 070305/I)
{circumflex over ( )}P < 0.05;
*P < 0.01.
Each value represents the mean of 8 rats.
Example 7
Effect of Freeze-Dried Hypericum Extract and Hypericin in Pain Caused by Monosodium Iodoacetate-Induced Osteoarthritis
[0069] The reduction in the pain threshold was induced by a single administration of monoiodoacetate (MIA) into the paw joint of the rat (Ref. 27).
[0000]
TABLE 7
EFFECT OF HYPERICIN AND HYPERICUM EXTRACT
ON PAIN INDUCED BY OSTEOARTHRITIS OF THE KNEE,
EVALUATED IN THE RAT PAW PRESSURE TEST
TREAT-
TREATMENT
After treatment
MENT
mg kg−1 p.o.
Pre-test
15 min
30 min
45 min
60 min
SALINE
CMC
63.9 ± 3.3
64.6 ± 2.5
60.5 ± 3.8
62.6 ± 3.7
64.6 ± 4.0
MIA
CMC
22.6 ± 2.9
20.3 ± 4.1
24.9 ± 2.7
23.2 ± 3.5
24.0 ± 2.7
MIA
HYPERICIN
23.4 ± 3.3
45.9 ± 2.7*
49.7 ± 3.8*
42.8 ± 3.9*
31.7 ± 3.5
0.11 mg/kg
MIA
HYPERICUM
21.1 ± 2.1
39.7 ± 3.1*
42.7 ± 2.1*
38.4 ± 3.3*
22.1 ± 3.0
EXTRACT
60 mg/kg
BATCH
7I0525
Treatment: Monosodium iodoacetate (MIA) 2 mg in a volume of 25 μl was injected into the antechamber of the left knee of non-anaesthetised rats.
Each value represents the mean of 2 experiments (11 rats).
{circumflex over ( )}P < 0.05;
*P < 0.01 by comparison with rats treated with MIA/CMC.
Fernihough J. et al. Pain 112: 83-93 (2004).
REFERENCES
[0000]
1. Nanna B et al “An evidence-based algorithm for the treatment of neuropathic pain” Medscape General Medicine 2007; 9(2):36.
2. Bridges D, Thompson S W, Rice A S. Mechanisms of neuropathic pain. Br J Anaesth. 2001; 87(1):12-26. Review.
3. Andrés J. D.; Garcia-Ribas G. Neuropathic Pain Treatment: The Challenge Pain Practice: 2003, 3, (1): 1-7.
4. Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, Kidd B, Bevan S, Winter J. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain. 2004 November; 112(1-2):83-93.
5. Jackson K C 2nd. Pharmacotherapy for neuropathic pain. Pain Pract. 2006 March; 6(1):27-33.
6. Dworkin R H, Backonja M, Rowbotham M C, Allen R R, Argoff C R, Bennett G J, Bushnell M C, Farrar J T, Galer B S, Haythornthwaite J A, Hewitt D J, Loeser J D, Max M B, Saltarelli M, Schmader K E, Stein C, Thompson D, Turk D C, Wallace M S, Watkins L R, Weinstein S M. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003; 60(11):1524-34.
7. Taylor R S. Epidemiology of refractory neuropathic pain. Pain Pract. 2006 March; 6(1):22-6.
8. Butterweck V. Mechanism of action of St John's Wort in depression: what is known? CNS Drugs. 2003; 17(8):539-62.
9. Rodríguez-Landa J F, Contreras C M. A review of clinical and experimental observations about antidepressant actions and side effects produced by Hypericum perforatum extracts. Phytomedicine. 2003 November; 10(8):688-99.
10. Mennini T, Gobbi M. The antidepressant mechanism of Hypericum perforatum . Life Sci. 2004 Jul. 16; 75(9):1021-7.
11. No authors listed] Monograph. Hypericum perforatum . Altern Med Rev. 2004 September; 9(3):318-25.
12. Di Carlo G, Borrelli F, Ernst E, Izzo A A. St John's Wort: Prozac from the plant kingdom. Trends Pharmacol Sci. 2001 June; 22(6):292-7.
13. Müller W E. Current St John's Wort research from mode of action to clinical efficacy. Pharmacol Res. 2003 February; 47(2):101-9.
14. Nöldner M, Schötz K. Rutin is essential for the antidepressant activity of Hypericum perforatum extracts in the forced swimming test. Planta Med. 2002 July; 68(7):577-80.
15, Butterweck V, Christoffel V, Nahrstedt A, Petereit F, Spengler B, Winterhoff H. Step by step removal of hyperforin and hypericin: activity profile of different Hypericum preparations in behavioral models. Life Sci. 2003 Jun. 20; 73(5):627-39.
16. Sindrup S H, Madsen C, Bach F W, Gram L F, Jensen T S. St. John's Wort has no effect on pain in polyneuropathy. Pain. 2001 April; 91(3):361-5.
17. Sánchez-Mateo C C, Bonkanka C X, Hernández-Perez M. Rabanal R M. Evaluation of the analgesic and topical anti-inflammatory effects of Hypericum reflexum L. fil. J. Ethnopharmacol. 2006; 11:107(1):1-6.
18. Trovato A, Raneri E, Kouladis M, Tzakou O, Taviano M F, Galati E M. Anti-inflammatory and analgesic activity of Hypericum empetrifolium Willd. (Guttiferae). Farmaco. 2001; 56(5-7):455-7.
19. Viana A F, Heckler A P, Fenner R. Rates S M. Antinociceptive activity of Hypericum caprifoliatum and Hypericum polyanthemum (Guttiferae). Braz J Med Biol Res. 2003:36(5):631-4.
20. Rabanal R M, Bonkanka C X, Hernandez-Perez M, Sanchez-Mateo C C. Analgesic and topical anti-inflammatory activity of Hypericum canariense L. and Hypericum glandulosum Ait. J. Ethnopharmacol. 2005 Jan. 15; 96(3):591-6.
21. Bukhari I A, Dar A, Khan R A. Antinociceptive activity of methanolic extracts of St. John's Wort ( Hypericum perforatum ) preparation. Pak J Pharm Sci. 2004; 17(2):13-9.
22. Abdel-Salam O M Anti-inflammatory, antinociceptive, and gastric effects of Hypericum perforatum in rats. Scientific World Journal. 2005 Aug. 8; 5: 586-95.
23. Cavaletti U, Tredici G, Petruccioli M G, Donde F, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne G G. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J. Cancer. 2001; 37(18):2457-63.
24. Bennett G J, Xie Y K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988; 33(1):87-107.
25. Polomano R C, Mannes A J, Clark U S, Bennett G J. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain. 2001 December; 94(3):293-304.
26. Aley K O, Reichling D B, Levine J D. Vincristine hyperalgesia in the rat: a model of painful vincristine neuropathy in humans. Neuroscience. 1996 July; 73(1):259-65.
27. Fernihough J, Gentry C, Malcangio M, Fox A, Rediske J, Pellas T, Kidd B, Bevan S, Winter J. Pain related behaviour in two models of osteoarthritis in the rat knee. Pain. 2004 November; 112(1-2):83-93.
28. Irwin S. Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia. 1968 Sep. 20; 13(3):222-57.
29. Vaught J L, Pelley K, Costa L G, Setler P, Enna S J. A comparison of the antinociceptive responses to the GABA-receptor agonists THIP and baclofen. Neuropharmacology. 1985 March; 24(3):211-6. | Disclosed is the use of hypericum ( Hypericum perforatum L.) tip extracts containing hypericin, of hypericin, to prepare medicinal products and/or food supplements for the treatment of neuropathic pain. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to European patent application No. 15182057.8, filed Aug. 21, 2015, which is incorporated herein by reference in its entirety as though fully set forth herein.
TECHNICAL FIELD
[0002] The present invention relates to a protective cover for the protection against contamination from body and/or irrigation fluid during the treatment of wounds or ulcers. It further relates to a device equipped with such a protective cover for irrigating wounds or ulcers.
BACKGROUND
[0003] Irrigation is a commonly used method for cleaning open, contaminated and chronic wounds. During irrigation, sterile irrigation fluids act upon wounds to remove lifeless tissue, bacterial inoculum, blood clots, loose dirt and foreign bodies in the vicinity and in the depths of the wound. The critical parameters of any wound irrigation method are the application of an adapted volume of sterile irrigation fluid to the wound and the use of sufficient pressure that must be applied in a precise pattern of distribution for effectively removing the contaminants.
[0004] In this context, a disposable nozzle is known from EP 2 251 142 A1 for insertion into a handpiece, where said nozzle produces a highly focused high-pressure micro water jet for the treatment of wounds. Such a high-pressure micro water jet can be used in particular for cleaning, washing and debriding necrotic, wet, or otherwise poorly healing wounds (e.g. caused by diseases such as ulcers, gangrene, bedsores, abscesses or fistulas). The kinetic impact force of the fluid under pressure is there utilized in order to clean the wound and to debride it. In particular debridement, i.e. the restoration of the wound bed by removing necrotic and fibrinous layers, requires the use of an irrigation fluid jet that is operated with high pressure.
[0005] However, the high pressure of the fluid jet does not only lead to the removal of the layer or of the particles from the wound, but inevitably also to an aerosol (fluid mist) around the wound composed of droplets of body fluid and irrigation fluid floating in the air. However, aerosols can also be produced in other ways, for example, during wound treatment by way of plasma or ultrasound. In the event that no protective measures are taken, such aerosols can freely escape into the environment and thus pose a significant hazard to patients and/or the respective health care professional.
[0006] The high hazard potential of such aerosols is due to the fact that wounds almost always are colonized by pathogens (such as bacteria, viruses or fungi), whereby also the aerosols being produced during their treatment represent a potentially infectious medium because they are laden with pathogens. Consequently, dangerous cross-infection could in the absence of additional protection measures occur between the patients and the individuals present in the treatment room or the individuals later entering the treatment room or the individuals later using the treatment equipment. In addition, free distribution of the aerosol during wound treatment would lead to contamination in the treatment room, in particular of the treatment table and the surrounding floor surfaces. This in turn results in an increased risk of slipping and thereby the risk of injury to individuals in the treatment room. A further problem is the obstruction of the view onto the treatment area when the freely spreading aerosol e.g. collects on the protective glasses of the attending person.
[0007] In view of the aforesaid drawbacks, numerous methods and devices are known from prior art to mitigate or even to entirely prevent contamination of the environment by aerosols produced during wound irrigation.
[0008] The most common and easiest way is to place the body part of the patient to be treated under a transparent disposable protective foil which can be suspended with the aid of a respective stand device and spanned in a tent-like manner. The respective health care professional dons a protective coat, protective gloves, a protective mask and protective glasses before he reaches either under the protective foil or in respective hand openings provided in the protective foil for performing wound treatment. The treatment fluid draining during the treatment can be collected by way of compresses and/or a good absorbent wound pad.
[0009] Such protective foils, however, offer only inadequate protection for the health care professionals and patients from body and irrigation fluids laden with bacteria, viruses, fungi, parasites and/or other pathogens spraying back. Firstly, such pathogens can naturally enter the environment through the two hand openings. Secondly, it is disadvantageous that the gloved hand still needs to reach into the treatment chamber located under the protective foil and contaminated with aerosol. The pathogens can therefore after termination of the treatment enter the environment via gloves and protective clothing, e.g., at control buttons of treatment devices. Also disadvantageous is that the visibility and the splash protection effect are inversely proportional to each other. The more hermetically the wound is covered by the protective foil, the more obstructed the vision of the attending person onto the wound area and vice versa.
[0010] Though protective foils with extensions designed as gloves for an attending person to slip into are known, such integrated solutions are disadvantageous, however, in that forcing the hands into or out from then glove extensions proves to be very difficult. In addition, the drawback remains that the attending person must reach into the aerosol-contaminated treatment chamber. Also pathogens (such as e.g. bacteria) can continue to enter the environment through the glove extensions.
[0011] Furthermore, suction/irrigation tips are known from prior art which have a generally funnel-shaped splash shield at the front (distal) end in order to prevent irrigation fluid from splashing rearward (cf. for example, U.S. Pat. No. 5,460,604 A). A drawback of such devices is that the motion performed during wound treatment by the suction/irrigation tip must also be carried out by the splash shield that bears snugly on the patient's skin. This motion can by the patient be perceived as being painful. Once the splash shield is lifted from the skin to eliminate this pain, however, the tightness of the treatment chamber formed under the splash shield is also reduced. Dangerous, highly contagious fluid droplets can thereby escape into the environment despite the splash shield.
[0012] In addition, systems are known in which a fluid jet device is combined with a suction device for the extraction of the tissue cells separated or dissolved and/or the irrigation fluid. Such systems, however, are very complex in design since not only fluid supply but also additional extraction (possibly with recirculation of the irrigation fluid) must be present.
BRIEF SUMMARY
[0013] The object of the present invention is therefore to provide a protective cover which in a simple manner provides reliable protection against contamination without impairing the effectiveness of wound treatment.
[0014] This object is satisfied by a protective cover having the features of claim 1 .
[0015] The protective cover according to the invention for protection against contamination from body and/or irrigation fluid in the treatment of wounds or ulcers has a first opening to be placed on a body part of a patient and a second opening adapted for the insertion of a handpiece for wound or ulcer treatment. Furthermore, the protective cover of the invention comprises a fluid-tight and flexible hollow body which in the interior defines a treatment chamber having a shape that adapts to the motion of the handpiece, where the hollow body is provided with at least one stiffening element for keeping the first opening in an open state during treatment.
[0016] Due to the flexible design of the hollow body, the latter is arbitrarily bendable and adaptable in length. Consequently, the shape of the treatment chamber formed in the interior of the hollow body, i.e. the chamber that connects directly above the wound to be treated and receives the aerosol produced during wound treatment, can be adapted to any motion of the handpiece emitting the irrigation fluid jet. The handpiece can in particular by the doctor or wound specialist be positioned at any distance and any angle to the wound to be treated, without fluid-tightness of the protective cover thereby being impaired. Due to the stiffening element additionally provided in the hollow body, however, the first opening of the protective cover to be placed on the body part of the patient always remains in an unfolded i.e. expanded during every motion of the hand piece. The first opening can therefore with its edge be placed flush on the skin of the patient in order to hermetically enclose the wound to be treated.
[0017] The stiffening element can in particular extend over only a part of the length of the protective cover, so that the first opening is formed not directly on the underside of the protective cover, but offset therefrom upwardly. An additional unstiffened material portion (e.g. nonwoven) is therefore present below the first opening and can be stuck under the body part (e.g. the limb) of the patient to close the first opening in a tight manner.
[0018] Only the handpiece of the wound cleaning device must for treating wounds advantageously additionally be inserted through the second opening of the protective cover, where the hand of the doctor or other wound specialist guiding the handpiece, however, remains outside the treatment chamber. Potentially infectious contact with the aerosol is thereby avoided.
[0019] One advantageous embodiment of the invention provides that at least one inner layer of the hollow body facing the treatment chamber is made of absorbent material, in particular of porous absorbent material for receiving fluid from the aerosol produced during the treatment in the treatment chamber.
[0020] The fluid contained in the aerosol is received by the absorbent inner layer and retained therein, so that only relatively little or no fluid can penetrate to the outer layer and the other surfaces of the protective cover, with the advantageous result that pathogens (such as bacteria, viruses and fungi) possibly contained in this fluid are reliably prevented from escaping. The thickness and absorbency of the absorbent layer is dimensioned such that the total fluid volume in the aerosol that is emitted during normal wound treatment duration is reliably absorbed by the absorbent layer without the structural integrity of the absorbent layer there being lost.
[0021] It is in a further advantageous embodiment provided that at least one outer layer of the hollow body facing the environment is made of fluid-tight material, in particular fluid-tight plastic, for preventing the contaminated fluid from escaping into the environment.
[0022] The fluid possibly escaping through the absorbent inner layer can thereby be reliably retained by the fluid-tight outer layer (e.g. made of polyethylene foil) and prevented from uncontrollably escaping into the environment. It is understood that the hollow body can also be formed having a single layer from material which combines both above requirements (namely absorbency and fluid-tightness), whereby in particular textile barrier materials would there need to be mentioned, for example, microfiber fabric.
[0023] According to a particularly advantageous embodiment of the invention, the hollow body is formed having a funnel shape, where its larger opening forms the first opening and its smaller opening is covered with a transparent plate for visually monitoring the treatment area.
[0024] The diameter of the funnel-shaped hollow body increases toward the patient, where the hollow body in the first opening surrounding the wound or ulcer reaches its maximum diameter to thereby reliably seal the entire treatment area. Inserted in the opposite opening of the hollow body facing away from the patient is a transparent plate functioning as a window through which the attending person has a clear view onto the treatment area.
[0025] According to a further embodiment of the invention, the stiffening element extends around the longitudinal axis of the funnel-shaped hollow body in a helical or circular shape over at least part of the length of its shell.
[0026] The helical or circular shape of the stiffening element in particular causes reinforcement in the radial direction in order to keep the two openings of the funnel-shaped hollow body stable in an open state, which is the unfolded or expanded state of the hollow body, so that the lower opening, being larger in diameter, can serve to enclose the treatment area and the upper opening, being smaller in diameter, to see the treatment area. The length of the helically shaped stiffening element is preferably dimensioned such that a projection length of hollow body material with no stiffening remains in the lower region of the hollow body facing the patient, which is loosely placed onto the patient's skin and, if necessary, can also be glued on in order to seal the treatment area in a fluid-tight manner.
[0027] Furthermore, it is in an advantageous embodiment of the invention provided that the stiffening element is composed of elastically resilient material, in particular of elastically resilient plastic, the elasticity of which during the treatment allows the compression and expansion of the funnel-shaped hollow body in the direction of its longitudinal axis.
[0028] Unlike a rigid spray shield, the protective cover according to the invention makes it possible to vary the distance of the handpiece, emitting the fluid jet, to the treatment area, depending on the wound situation given. The stiffening element there behaves like a low stiff compression spring which is flexible in all directions and compressible or expandable along its length.
[0029] According to a particularly advantageous development of the invention, the funnel-shaped hollow body is formed from a web of material that is composed of one or more layers, the ends of which are connected to each other by a seam, where the seam extends in particular along a surface line of the funnel-shaped hollow body.
[0030] Fabrication of the hollow body from a single funnel-shaped rolled-up web of material requires only the application of a longitudinal seam for connecting together the two abutting or overlapping ends of the web of material. This can in terms of manufacturing technology be realized in a simple manner and therefore at particularly low costs.
[0031] In a further embodiment of this advantageous development, the stiffening element is integrated into the web of material of the funnel-shaped hollow body, in particular glued into and/or welded into and/or sewn into the web of material.
[0032] Sewing it in using a sewing machine is in this case particularly advantageous because also dissimilar materials can there be permanently connected to each other. The stiffening element can there be made of material suitable for the respective application, for example, of plastic, in particular plastic fiber and/or made of a fabric material and/or foil material, where each of these materials can easily be sewn to the web of material of the hollow body.
[0033] The stiffening element can be disposed between an inner and an outer layer of the web of material of the funnel-shaped hollow body, whereby reliable and stationary positioning of the stiffening element protected against external influences is obtained.
[0034] An embodiment of the invention is illustrated in the figure and shall be described in more detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 shows an overall perspective view of a preferred embodiment of a protective cover according to the invention;
[0036] FIG. 2 shows a side view of the protective cover of FIG. 1 ;
[0037] FIG. 3 shows a top view of the protective cover of FIG. 1 ;
[0038] FIG. 4 shows an enlarged top view of the protective cover in the region “X” of FIG. 3 ; and
[0039] FIG. 5 shows an enlarged top view of the protective cover in the region “Y” of FIG. 4 .
DETAILED DESCRIPTION
[0040] Protective cover 1 according to the invention illustrated in FIGS. 1, 2 and 3 respectively in an overall view in its non-deformed initial state has a shape resembling a jellyfish. The core component of protective cover 1 is there formed by an axially symmetric funnel-shaped hollow body 4 which along its longitudinal axis A comprises two openings 2 , 7 which are in turn arranged axially and diametrically opposite to one another, where these openings 2 , 7 are of different size.
[0041] Larger opening 2 , in FIGS. 1 and 2 respectively facing downwardly, is in the later use placed on a body part of a patient, generally a limb, where the edges of opening 2 define a treatment area in which a wound to be treated with an irrigation fluid jet or other skin disorders of the patient (e.g. an ulcer) is located.
[0042] Hollow body 4 encloses a frustoconical interior which in later use acts as a treatment chamber 5 into which the head end (not shown) of a handpiece is introduced, from which in turn an irrigation fluid jet is emitted for treating wounds (wound irrigation and optionally wound debridement). The handpiece is for this purpose outside of treatment chamber 5 via a hose connected to an irrigation fluid reservoir for supplying pressurized irrigation fluid (e.g. sterile water or a saline solution).
[0043] The handpiece, however, can also be any part of a wound treatment device that is for local wound treatment movable by hand. For example, plasma or ultrasonic waves can also be emitted from the handpiece for wound treatment instead of the irrigation fluid jet. It is only crucial that aerosol harmful to health forms during the treatment of wounds using the handpiece and requires shielding.
[0044] In order to, firstly, seal treatment chamber 5 in a fluid-tight manner toward the top and, secondly, to enable the attending person a clear view onto the treatment area bordered by the oppositely disposed lower opening 2 , the smaller opening 7 of the funnel-like hollow body 4 in FIGS. 1 and 2 respectively facing upwardly is covered with a circular rigid plate 8 made of transparent material, e.g. made of transparent plastic such as polymethylmethacrylate (PMMA). Plate 8 —as clearly visible in the enlarged top view of FIG. 4 —is by way of a circular circumferential seam 10 , which, for example, can be mechanically produced by a sewing machine, connected to the upper opening edge of hollow body 4 . However, it would alternatively also be conceivable to place plate 8 only loosely onto smaller opening 7 . In such a case, plate 8 could as a disposable item after each treatment of wounds be disposed of separately from hollow body 4 .
[0045] As is apparent from FIG. 2 , plate 8 has a bowl-like curved shaped that is convex outwardly, where the curvature of the plate can cause a magnifying glass effect in order to be able to see the wound to be treated more closely. In addition, it can with such a plate curvature be prevented that fluid droplets obstructing the view can accumulate.
[0046] As is evident in particular in the enlarged views of FIGS. 4 and 5 , transparent plate 8 comprises an opening in the form of a cross recess 3 disposed eccentrically, i.e. laterally offset from center M of plate 8 which is in alignment with the longitudinal axis A of hollow body 4 . This cross recess 3 is used for insertion of a handpiece for treating wounds (e.g. a handpiece emitting an irrigation fluid jet, plasma, or ultrasonic waves) and is in the plan view of FIG. 4 illustrated with an arrangement located vertically below the plate center M. In later use, however, protective cover 1 can be turned such that cross recess 3 assumes a position that is pleasant for the attending person when inserting and handling the handpiece. A right hander will therefore generally twist protective cover 1 about its longitudinal axis A such that cross recess 3 is from his perspective located to the right of longitudinal axis A and plate center M.
[0047] The recess widths of cross recess 3 are preferably approximately 0.5 mm. The head end of the handpiece is inserted at the intersection of the two recesses, whereby cross recess 3 initially expands elastically. Once the head end has been introduced into treatment chamber 5 , cross recess 3 again bears against the outer perimeter of the handpiece in a fluid-tight manner such that no contaminated fluid can escape between cross recess 3 and the handpiece.
[0048] The attending person must advance the handpiece only to such a degree through cross recess 3 of plate 8 that the nozzle arranged at the head end of the handpiece is positioned within treatment chamber 5 (below plate 8 ). However, the remaining part of the handpiece remains outside treatment chamber 5 (above plate 8 ) in order to be moved, for example, by way of a handle used by the hand of the attending person for the purpose of performing wound treatment. Since directing the irrigation fluid jet is thereby effected by a part of the handpiece disposed above plate 8 and as a free view to the fluid jet generated below plate 8 and the wound is at the same time given, the attending person must no longer with his hands enter the aerosol-contaminated treatment chamber 5 . This risk of infection is thereby significantly reduced. This advantageous effect is also obtainable when the opening (cross recess 3 ) is for insertion of the hand piece not—as shown in FIG. 3 —formed in plate 8 , but instead in hollow body 4 . In such a case, plate 8 would serve as a pure viewing window.
[0049] In addition to the embodiment shown, however, it is also conceivable to provide hand openings laterally in hollow body 4 through which a gloved hand can in case of need reach into treatment chamber 5 in order to, for example, collect treatment fluid draining during wound treatment by use of compresses or swabs. These hand openings can additionally be fitted integrated gloves. It is there important that irrigation fluid can escape from treatment chamber 5 neither in the region of the hand openings nor in the region of the gloves that are possibly integrated there. In addition, straps can be formed at the side on hollow body 4 for raising protective cover 1 as a whole or possibly suspend it in the unused state.
[0050] A large potential hazard emanates from the aerosols that are produced during wound treatment due to the high impact pressure of the irrigation fluid jet. Due to the bacterial, viral, fungal or parasitic content of most wounds, these aerosols are in fact usually highly contagious. In addition, the resulting aerosol affects the unobstructed view onto the treatment area, thereby making it difficult for the attending person to precisely recognize the wound treatment progress.
[0051] It is consequently to be required of the material of hollow body 4 that, firstly, it exhibits sufficient absorbency to absorb and retain the fluid droplets produced during wound treatment in treatment chamber 5 . It is there sufficient to merely provide the inner layer of hollow body 4 facing treatment chamber 5 with absorbent material. Paper, textile or nonwoven fabric can be used as absorbent material. These materials have the advantageous property that saturation of the absorption capacity is not reached even after long duration of treatment and that therefore the adsorption by surface wetting can act throughout the entire treatment period. This adsorption acts as a driving force which binds the fluid-bound pathogens (such as bacteria) to the fibers of the paper, textile or nonwoven. The small droplets laden with pathogens are there quickly and successfully absorbed and retained by the paper, fabric or non-woven. With an increasing amount of fluid bound in the paper, fabric or nonwoven, the fluid-soaked surface enlarges and the adsorption effect can even be accelerated.
[0052] Fluid-tightness in addition to absorbency is secondly required of the material of hollow body 4 to reliably prevent the body and irrigation fluid droplets that are during the wound treatment flung into treatment chamber 5 and mixed with highly contagious ichor, from escaping into the environment and to thereby avoid contamination of the environment. It is for this purpose sufficient to have at least one outer layer, i.e. a layer facing away from treatment chamber 5 , of hollow body 4 be made of fluid-tight material, e.g. fluid-tight plastic foil.
[0053] A preferred multi-layer material for hollow body 4 that satisfies the above-described properties in terms of absorbency and fluid-tightness has a polyethylene foil as an outer layer and one or two layers of cellulose as an inner layer.
[0054] When using the aforementioned material, however, the fundamental problem exists that it has no or only low inherent stability. Like a disposable protective foil commonly used for patient coverage, such material would collapse upon itself if no additional stiffening measures were taken. It must in particular be ensured that lower opening 2 on the patient body for enclosing the wound is at all times kept in an unfolded or expanded state. Only in this manner can it be ensured that the hollow body material can not enter the patient's wound or in the field of view of the attending person.
[0055] In order to obtain—as shown in FIGS. 1 and 2 —stable installation of protective cover 1 with a lower opening 2 permanently held in the unfolded or open position, stiffening element 6 is provided counteracting deformation of hollow body 4 in the radial and axial directions, which is in accordance with the overall views shown in FIGS. 1 and 2 formed as a plastic wire (having a diameter of, for. example, 2 mm) extending helically with two and a half turns about the longitudinal axis.
[0056] The helical stiffening element 6 is integrated into the material of hollow body 4 , where this integration can be effected e.g. by stiffening element 6 being sewn in. This integration can be effected in a fixed or detachable manner. In the latter case, stiffening element 6 can e.g. only be inserted or clicked into the material of hollow body 4 . Dissimilar materials can be connected together easily by sewing, for which reasons stiffening element 6 can instead of plastic also be made of any other desired material having a reinforcement effect, e.g. metal. Stiffening element 6 must also not necessarily be given in wire form, but can also be of any other form that is integrated in hollow body 4 , e.g. foil form. With a multi-layered hollow body 4 , stiffening element 6 is preferably arranged between the layers. Such an embedded arrangement has the advantage that stiffening element 6 is protected against external influences, such as aerosol produced during wound treatment, and that particularly stable positioning of stiffening element 6 in hollow body 4 is additionally obtained.
[0057] In the plan view of FIG. 3 , stiffening element 6 extends helically around center M of plate 8 which is arranged in extension of longitudinal axis A. Upper end point 6 o —as seen in the longitudinal direction—of stiffening element 6 and lower end point 6 u —as seen in the longitudinal direction—of stiffening element 6 are in relation to center point M of plate 8 arranged diametrically opposite to one another, wherein cross recess 3 for the insertion of the handpiece emitting the fluid jet is located on the line connecting these two end points 6 o, 6 u.
[0058] Despite the provision of stiffening element 6 , flexibility of hollow body 4 is nevertheless maintained and allows adapting the shape of treatment chamber 5 defined in the interior of hollow body 4 to any arbitrary motion of the handpiece. Stiffening element 6 has deformation properties similar to a low compression spring with a high pitch. Accordingly, hollow body 4 with integrated stiffening element 6 can continue to be bent freely to all sides and also be compressed and expended in the longitudinal direction. These deformation properties allow positioning the handpiece during wound treatment at any angle and/or at any distance to the wound to be treated.
[0059] The attending person will for this during wound treatment exert a deforming force upon hollow body 4 via a free hand and/or directly via the handpiece inserted in cross recess 3 in order to adapt the shape of hollow body 4 and treatment chamber 5 defined by it to a new position of the handpiece. Irrespective of this, however, fluid-tightness of treatment chamber 5 is maintained at all times. Treatment chamber 5 is namely—irrespective of the shape just adopted—always closed in a fluid-tight manner toward the top by plate 8 and toward all sides by the shell of hollow body 4 .
[0060] The reinforcement effect in the radial and the axial direction of hollow body 4 achieved by integrated stiffening element 6 , however, advantageously leads to hollow body 4 at all times having a stable open lower opening 2 regardless of its current shape adapted to the motion of the handpiece. Stiffening element 6 therefore opens i.e. expands the treatment chamber 5 . It is during use sufficient to hold protective cover 1 with a free hand, e.g. at the edge of plate 8 . However, manually holding protective cover 1 can also be dispensed with entirely, as the latter is already fixed by the handpiece that has been pushed into cross recess 3 . Both hands of the doctor or other wound specialist are therefore advantageously available for wound treatment.
[0061] Due to the compressibility of hollow body 4 given in the direction of longitudinal axis A, it is with slight manual pressure possible to place protective cover 1 in a flush manner on any body part of a patient. The shape of the lower side of protective cover 1 is thereby optimally adapted to the shape of the respective body part, thereby reducing the risk of leakage between the patient body and protective cover 1 to a minimum. In addition, protective cover 1 can due to the compressibility of hollow body 4 be squeezed together for shipping and storage purposes almost flat to possibly be inserted into a respective wrapper.
[0062] Hollow body 4 is in terms of manufacturing technology configured in a particularly simple and therefore cost-effective manner as it consists only of a single web of material. In order to form hollow body 4 , an arcuate web of material is rolled up such that the two opposite ends of the web of material come to rest on one another overlapping each other and are then sewn with a thread. Such an overlap seam 9 is basically more durable than an edge-to-edge configuration and also tends to be easier to manufacture. Overlap seam 9 is in the final protective cover 1 located on the inner side toward treatment chamber 5 in order not to affect tightness and the overall visual impression of hollow body 4 . In the non-deformed initial state of protective cover 1 according to FIG. 1 , overlap seam 9 extends along a surface line of funnel-shaped hollow body 4 .
[0063] Helical stiffening element 6 —as seen in the direction of longitudinal axis A—does not extend over the entire length of hollow body 4 . Though stiffening element 6 starts almost flush at the upper edge of hollow body 4 covered by plate 8 , it terminates at a significant distance to the lower edge of hollow body 4 . The length of stiffening element 6 measured in the direction of longitudinal axis A assumes a value relative to the overall length of hollow body 4 of approx. ½ to ¾, preferably approx. ⅔. Accordingly, there is a lower longitudinal section of hollow body 4 only made of a non-reinforced web of material (without integrated stiffening element 6 ). This lower longitudinal section can in later use be fitted loosely on the patient's body and optionally also be glued on to create a tight closure downwardly between the patient's body and protective cover 1 .
[0064] Protective cover 1 according to the invention can be advantageously employed in any device for irrigating wounds or ulcers. It can in particular be part of a device for debriding necrotic body tissue by way of a micro water jet. In such a device, a hand-operated lance is used as a hand device, where this lance is inserted into cross recess 3 of protective cover 1 so far that the nozzle disposed on the free end of the lance for generating the micro water jet is located within treatment chamber 5 . Use of protective cover 1 according to the invention achieves high safety from contamination of the environment with body and/or irrigation fluid during the wound debridement, however, without the freedom of movement of the handpiece and the vision of the attending person onto the wound to be debrided and the micro-water jet being obstructed | A protective cover for the protection against contamination from body and/or irrigation fluid during treatment of wounds/ulcers includes a first opening to be placed on a patient and a second opening for inserting a handpiece. The protective cover includes a fluid-tight and flexible hollow body that defines a treatment chamber having a shape that adapts to motion of a handpiece. The hollow body may include a stiffening element for keeping the first opening in an open state during treatment. Additionally, a device for the irrigation of wounds or ulcers, such as for debriding dead body tissue by way of a micro water jet, may include a hand-operated lance with a nozzle for producing an irrigation fluid jet, such as a micro water jet. The lance may be inserted through the second opening of the protective cover so that the nozzle is located within the treatment chamber of the protective cover. | 0 |
BACKGROUND
1. Field of the Invention
This invention generally relates to artificial eyes, and more particularly to an artificial eye ball for use in a toy.
2. Description of Related Art
As manufacturing technology develops, requirements for toys and novelties to feature enhanced and innovative function increase. One example is the authenticity of behavior exhibited by human or animal figures, and specifically, the eyes of such a toy.
In many artificial eyes, expansion and contraction of a pupil are achieved by mechanical transmission driven by electrical motors. However, such mechanical structures controlling expansion and contraction of a pupil are complicated, and the effects tend to be far from lifelike. Furthermore, such controllers and electrical motors are easily damaged and have short lifetimes.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-section of an eye as disclosed, showing driving components not electrically powered, and in which an elastic body is not depressed by a coil rod.
FIG. 2 is another cross-section of the disclosed eye, showing driving components being electrically powered, and an elastic body depressed by the coil rod.
FIG. 3 is a toy system with the disclosed eye.
DETAILED DESCRIPTION OF THE EMBODIMENTS
An embodiment of the disclosure is now described in detail and with reference to the drawings.
FIG. 1 and FIG. 2 show an eye 100 as disclosed, comprising a spherical shell 11 , a transparent body 13 , a movable plate 22 , an elastic body 23 , and an electromagnetically driven assembly 30 . The transparent body 13 acts as an intraocular lens, and the elastic body 23 mimics a pupil. Here, the spherical shell 11 and the transparent body 13 are manufactured integrally of transparent material with plasticity, such as silica gel, rubber or a combination. It is understandable that the transparent body 13 and the spherical shell 11 can be manufactured as two individual components rather than a whole body, and that spherical shell 11 can be glass, and the transparent body 13 can be of plastic material. Materials and manufacture of the spherical shell 11 and the transparent body 13 do not result in any limitation to the disclosure.
In a first embodiment of the disclosure, the elastic body 23 is a plastic ball. In another embodiment of the disclosure, the elastic body 23 is rubber. It is also understood that the elastic body 23 can have different colors, depending on design.
The movable plate 23 is provided opposite to the transparent body 13 . The transparent body 13 comprises a back plate 132 opposite the movable plate 22 . A recessed portion 134 defined in the center of the back plate 132 can be a hemisphere. The depth of the recessed portion 134 can be less than the diameter of the elastic body 23 . The elastic body 23 is partially received in the recessed portion 134 .
The movable plate 22 comprises a first surface 221 , a second surface 222 located apart from the transparent body 13 , and two sides 223 perpendicular to the first surface 221 and the second surface 222 . A coil rod 26 extends from the center of the second surface 222 , and it is perpendicular to the second surface 222 . At least one first hook 224 is provided on each of the sides 223 , and at least one second hook 116 is provided on the spherical shell 11 which is opposite to the first hook 224 .
The eye 100 further comprises at least one resilient component 40 , in this embodiment, a spring. One end of the resilient component 40 is connected to the first hook 224 , and another end is connected to the second hook 116 to suspend the movable plate 22 in the spherical shell 11 . In varied application, the resilient component can be a rubber band or any other resilient material.
The electromagnetic driving assembly 30 drives the movable plate 22 to approach or leave the elastic body 23 in a reciprocating motion. In this embodiment, the electromagnetic driving assembly 30 comprises two fastening portions 28 , a first driving component 24 and a second driving component 25 . The two fastening portions 28 surround the coil rod 26 . In this embodiment, the fastening portions are parallel to the coil rod 26 . Two openings 114 are separately provided on each of the fastening portions 28 , and are shaped as a half-circle in this embodiment. The fastening portions 28 are movably inserted into the openings 114 provided on the spherical shell 11 . It is understandable that a variety of ways to fasten the fastening portions 28 on the spherical shell 11 , and the insertion of the fastening portions 28 into the spherical shell 11 which illustrated in this embodiment is not a limitation to the present disclosure. In another application, the recessed portions 114 may be provided on the first surface 221 of the movable plate 22 , which can partially receive the elastic body 23 .
In this embodiment, the two first driving components 24 are permanent magnets, and the second driving component 25 is embodied as an electromagnetic coil corresponding to the first driving components 24 . The second driving component 25 winds around the coil rod 26 , and each of the first driving components 24 is fastened to the fastening portions 28 correspondingly. The second driving component 25 is provided around the coil rod 26 . The two first driving components 24 are separately formed on the two fastening portions 26 , and are spaced apart from the second driving component 25 . When the second driving components 25 are electrically powered, the resulting electric field generates a Lorentz force between the second driving components 25 and the first driving component 24 . The Lorentz force reciprocates the movable plate 22 backward and forward, nearing or moving away from the elastic body 23 . Thus, when movable plate 22 is impelled toward the elastic body 13 and away from the fastening portion 28 , the elastic body 13 is compressed by the first surface 221 , mimicking expansion of a pupil. When current is interrupted, the Lorentz force ceases, the coil rod 26 moves back to its original position, and the elastic body 13 returns to its original shape, mimicking contraction of the pupil.
For another exemplary application, the two first driving components 24 can be two electromagnetic coils, wound around the fastening portion 28 . Correspondingly, the second driving component 25 can be a permanent magnet provided on the coil rod 26 , and positioned relative to the first driving component 24 . The relative arrangement of the fastening portion 28 , the first driving component 24 , and the second driving component 25 constitutes no limitation to the disclosed scope of the appended claims.
The electromagnetic driving assembly of the disclosure eye drives the movable plate in a translational way, compressing the elastic body to mimic expansion of the artificial pupil.
FIG. 3 discloses a toy system with the disclosed eye. The toy system comprises a recession 101 configured for receiving the eye 100 as disclosed, and a mask 102 configured for imitating a doll's face. It should be noted that the mask can be varied to any shape or any outline according to the requirements of users, and is not limited to the shown shape.
Finally, it is to be understood that the above-described embodiments are intended to illustrate rather than limit the invention. Variations may be made to the embodiments without departing from the spirit of the invention as claimed. The above-described embodiments illustrate the scope of the invention but do not restrict the scope of the invention. | An eye is disclosed, which includes a spherical shell, a transparent body, a movable plate suspended inside the spherical shell, an elastic body disposed between the transparent body and the movable plate, and an electromagnetic driving device. The electromagnetic driving device drives the movable plate close to or away from the elastic body, and the elastic body is deformed when the electromagnetic driving assembly drives the movable plate. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a system for washing elongated objects. More particularly, it relates to a system for washing sticks or rods which have been used for cooking and/or chilling food products.
2. Background of the Art
In the processed meats industry, products such as hotdogs and sausages are typically suspended in link form from stainless steel sticks or rods for cooking and chilling. The sticks are usually three to four feet long and are either tubular or have a V-shaped cross-section. Following removal of the product from the sticks, the sticks must be cleaned before being reused. Typically, meat processors using a large quantity of sticks have employed drum-type washers to clean them. Such washers usually consist of a round or octagonal shaped drum with a side access door.
FIG. 1 shows an example of an octagonal shaped drum-type washer 10. Such a prior art washing system included a vessel 16 containing cleaning solution 18. The drum 12 is supported in the vessel 16 by a drive shaft 20. The sticks are loaded into the drum via door 14 and the cleaning process begins by turning the drum 12 via the drive shaft 20. The sticks may be either tubular 22 or have a V-shaped cross-section 24.
Thus, the sticks are manually placed in the drum and the drum is rotated in the cleaning solution. This produces some tumbling action between the sticks but tends to confine and block cleaning solution from effectively penetrating the core of the stick load in the drum. Further, the sticks with the V-shaped cross-section are prone to bunching and nesting which limits any mixing or migration of the sticks through the drum. Also, cleaning solution must be dumped after the wash cycle to allow refilling the unit with rinse water.
Another prior art apparatus for treating rods and pipes is disclosed in J. Moltrup, U.S. Pat. No. 1,393,633. The system disclosed in this patent includes a machine divided into separate pickling and washing compartments. The rods are organized into bundles or bunches and each bundle is inserted in a carrier. The carriers are placed on a runway which conveys the carrier into each compartment. As each carrier reaches the lower end of the runway, it is caught by conveyor with flights and conveyed out of the compartment. One drawback of this system is that the rods must be placed in individual carriers and must be moved therefrom after exiting the apparatus Also, there is no provision in the individual carriers for insuring that the rods and sticks are well mixed.
Another washing apparatus is disclosed by W. Morgan, U.S. Pat. No. 1,751,838. This apparatus is used for preparing cane stalks. The cleaning tank is provided with a hopper having inclined ends which direct the cane stalks onto a looped-shaped conveyor located adjacent to the bottom of the hopper. Another conveyor which shares a shaft with the loop-shaped conveyor conveys the cane stalks out of the hopper. Each of the conveyors is provided with a series of fingers which positively moves the cane stalks from the infeed of the hopper to the outfeed of the hopper. One drawback of this system is that the cane stalks can short circuit the desired tumbling action in the circular conveyor by being removed too soon by the outfeed conveyor.
It can be seen that an improved system is needed for washing elongated objects such as sticks, rods, or other similar items. Specifically, the need exists for a washing system which is convenient to load and unload and which insures the adequate mixing and tumbling of the sticks or the like.
BRIEF SUMMARY OF THE INVENTION
One aspect of the present invention provides an apparatus for cleaning elongated objects comprising: a tank having side and bottom walls for holding cleaning solution, wherein the tank also has a feed end and an exit end, both ends being adapted for the elongated objects; a first conveyor mounted inside the tank and downwardly inclined from the feed end toward the tank bottom, wherein the first conveyor has at least two spaced apart chains in which the spacing between the chains is adapted for supporting the elongated objects; a second conveyor mounted inside the tank and upwardly inclined from the bottom toward the exit end such that the planes of the first and second conveyors intersect near the tank bottom to form an angular section having an angle of less than 180°, wherein the second conveyor has at least two spaced apart chains in which the spacing between the chains is adapted for supporting the elongated objects and wherein the chains of the second conveyor have pusher flights; a jet manifold capable of producing a jet stream which is mounted in the tank such that the jet stream can be directed at the angular section formed by the planes of the first and second conveyors; a plate mounted between the chains of the second conveyor which can assume a first position below the plane of the second conveyor and a second position above the plane of the second conveyor; and a means for driving the conveyors.
Preferably, the angular section has an angle of about 90°, the chains of the first conveyor are inboard of the chains of the second conveyor, and the tank comprises an overflow means for maintaining a maximum level of cleaning solution.
Preferably, the second position of the plate is above the maximum level that can be assumed by the cleaning solution.
Preferably, the feed end includes a hopper for feeding the elongated objects into the angular section formed by the planes of the first and second conveyors and the exit end includes a rinse tank for receiving the elongated objects from the second conveyor.
Another aspect of the present invention provides an apparatus for cleaning elongated objects comprising: a tank having side and bottom walls for holding cleaning solution, wherein the tank also has a feed end and an exit end, both ends being adapted for the elongated objects; a first continuous loop conveyor mounted inside the tank around a first shaft and a second shaft such that the first conveyor is downwardly inclined from the feed end toward the tank bottom, wherein the first conveyor has at least two spaced apart chains in which the spacing between the chains is adapted for supporting the elongated objects; a second continuous loop conveyor mounted inside the tank around the second shaft and a third shaft such that the second conveyor is upwardly inclined from the second shaft toward the exit end such that the top loops of the first and second conveyors form an angular section having an angle of less than 180°, wherein the second conveyor has at least two spaced apart chains offset from those of the first conveyor and in which the spacing between the chains is adapted for supporting the elongated objects and wherein the chains of the second conveyor have pusher flights; a jet manifold capable of producing a jet stream which is mounted in the tank such that the jet stream can be directed at the angular section formed by the top loops of the first and second conveyors; a plate mounted between the second conveyor chains which can assume a first position below the plane of the top loop of the second conveyor and a second position above the plane of the top loop of the second conveyor; and a means for driving the conveyors.
Preferably, the angular section has an angle of about 90°, the chains of the first conveyor are inboard of the chains of the second conveyor, and the tank comprises an overflow means for maintaining a maximum level of cleaning solution.
Preferably, the second position of the plate is above the maximum level that can be assumed by the cleaning solution.
Preferably, the feed end includes a hopper for feeding the elongated objects into the angular section formed by the top loops of the conveyors and the exit end includes a rinse tank for receiving the elongated objects from the second conveyor.
It is preferred that a motor be linked to the third shaft for driving the first and second conveyors.
A still further aspect of the invention provides a method of cleaning elongated objects comprising feeding the elongated objects to the above apparatus; operating the conveyors with the plate in the second position for a predetermined time; and removing the elongated objects from the apparatus by placing the plate in its first position.
The objects of the present invention therefore include providing a washing system of the above kind:
(a) which efficiently cleans elongated objects without the stagnant zones common in the prior art;
(b) which provides efficient loading and unloading of the elongated objects; and
(c) which provides a system wherein the cleaning solution can be reused for subsequent loads.
These and still other objects and advantages of the present invention (e.g., methods of using the system) will be apparent from the description which follows. The following description is merely of the preferred embodiments. Thus, the claims should be looked to in order to understand the full scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic of a prior art washing system;
FIG. 2 is a schematic of the apparatus of the present invention;
FIG. 3 is a left side elevational view thereof;
FIG. 4 is a top plan view thereof;
FIG. 5 is a right side elevational view thereof;
FIG. 6 is an exit end view thereof;
FIG. 7 is a typical longitudinal cross-sectional view thereof;
FIG. 8 is a cross-sectional view thereof taken along the line 8--8 of FIG. 7;
FIG. 9 is a fragmentary blowup detail of the flipper plate assembly; and
FIG. 10 is a fragmentary blowup detail of the inlet hopper assembly.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 2 shows a schematic representation of the apparatus and method of the present invention. The washing system is designated as element 100. The present invention replaces the prior art drum 12 with two sets of conveyor chains disposed at about a 90° angle to each other and which share a common shaft at the bottom center of the vessel 104. The infeed conveyor 112 is installed around infeed conveyor shaft 118 and infeed/outfeed conveyor shaft 122. The infeed conveyor 112 has no flights or fingers.
The outfeed conveyor 114 is installed around outfeed conveyor shaft 120 and infeed/outfeed conveyor shaft 122. The outfeed conveyor 114 has pusher flights 116 which act to engage the tubular sticks 106 and/or the V-shaped cross-section sticks 108 to move the sticks out of the cleaning solution 110 contained in vessel 104. The flip back plate 126 when engaged in a raised position causes the sticks to eject from the outfeed conveyor 114 during the cleaning cycle. Direct impingement of the cleaning solution 110 is provided on the bottom of the stick pile by a jet manifold 124.
During operation of a cleaning cycle, the infeed conveyor 112 and the outfeed conveyor 114 are run simultaneously. The outfeed conveyor 114 with the pusher flights 116 pull sticks off the bottom of the pile and convey them upwards until they reach the flip back plate 126. The flip back plate 126 peels the sticks off the outfeed conveyor 114. The infeed conveyor 112 pulls the stick pile down towards the outfeed conveyor 114 so that a layer of sticks is being pulled off the bottom of the pile at all times. The shearing action at the bottom of the pile tends to separate and de-nest the sticks. At the end of the cleaning cycle, the flip back plate 126 is retracted and the sticks are conveyed out of the vessel 104 by the outfeed conveyor 114 into an adjacent tank for rinsing. Thus, the cleaning solution can be saved for the next batch of sticks.
As set forth below, the stick washing system of the present invention facilitates automatic loading and unloading of the sticks. Also the flip back plate 126 and outfeed conveyor 114 ensure that sticks are pulled off the bottom of the pile and returned to the top of the pile. Both of these advantages are surprising and unexpected improvements over the prior art drum type washer. The dynamics of the stick pile are not fully understood, but through testing it has been determined that the infeed conveyor 112 must be operated to get proper circulation of sticks in the pile. When the infeed conveyor 112 is shut off, the back of the stick pile stagnates and does not get pulled down into the outfeed conveyor 114.
Referring now to FIGS. 3-10, the stick washing system of the present invention is designated by element 100. The vessel 104 is designed to accommodate sticks having a typical length of 36-48 inches long. However, the apparatus can be modified in obvious ways to accommodate sticks of any size. The washing system 100 is equipped with a cover 105 which may be removed for easy access to the internals of the vessel 104. A control cabinet 128 is provided for housing the electrical components associated with pump motor, conveyor shaft motor, solenoid/regulators, etc.
Thermometer 130 is provided on the side of the vessel 104 which directly measures the temperature of the cleaning solution 110. Temperature control of the cleaning solution is accomplished by thermowell 150 which is operably connected to steam regulator 151. When the temperature of the cleaning solution falls below the desired set point, the steam regulator 151 will open allowing steam to be introduced into steam mixer 152 mounted inside the vessel 104.
The surprising and unexpected advantages of the present stick washing system resides in the configuration of conveyors 112 and 114. As shown in the figures, an infeed conveyor shaft 118 is located near the top of the tank 104 at the inlet end thereof. An infeed/outfeed conveyor shaft 122 is located on the wash tank near its center and bottom. Finally, an outfeed conveyor shaft 120 is located near the top of the tank 104 at the exit end thereof. The conveyor shafts 118, 120, and 122 are preferably equipped with hubs for accepting the conveyor chains.
Referring to FIG. 8, the infeed conveyors 112 are offset from the outfeed conveyors 114. As shown in FIG. 8, the two infeed conveyors 112 are inboard of the outfeed conveyors 114. Although the preferred embodiment shows two infeed conveyor chains 112 and two outfeed conveyor chains 114, any number of chains may be used as long as the infeed conveyors and outfeed conveyors are staggered. The conveyors are preferably made of polymeric chains but may be any acceptable material which is compatible with the cleaning solution.
As shown is FIGS. 7 and 8, tension is maintained on the conveyors by infeed conveyor tension bar 166, outfeed conveyor tensioner 170, and infeed conveyor tensioner 168. Tensioners 168 and 170 may be spring loaded arms with a roller in contact with its respective conveyor. Alternatively, the tensioners 168 and 170 can have arms secured with a nut and bolt.
Also, outfeed conveyor 114 includes pusher flights 116 for conveying the sticks out of the cleaning solution and into the discharge end of the wash tank 104.
The conveyor shafts are preferably arranged so that the planes of the infeed conveyor 112 and outfeed conveyor 114 form an angular section having an angle 113 from about 80° to about 110°. More preferred is an angle of about 90° to 100°. The angular section formed by the conveyor planes most preferably has an angle of about 90°. When the angle 113 is significantly less than about 90°, the infeed conveyor 112 pushes the sticks backward against the stick flow generated by the outfeed conveyor 114. If the angle 113 between the conveyors is reduced significantly below 90° (about 80°), a jam will occur as the conveyors attempt to move the sticks in opposite directions. At an angle 113 significantly greater than 100°(about 110°): (1) the stick pile flattens and reduces the number of sticks held by the conveyors; (2) the reduction in depth of the stick pile diminishes the ability of the pile to hold the sticks on the conveyors against the force of the water from the jet manifold 124; and (3) the stick pile begins to move up the outfeed conveyor 114 as a solid mass rather than a single layer of sticks causing erratic mixing of the stick pile and jams at the flip back plate 126.
The conveyors 112 and 114 may be propelled by applying power at any one of the conveyor shafts 118, 122, or 120, but preferably the driven shaft is the outfeed conveyor shaft 120. Motor 154 is used to drive shaft 120 and advantageously has a variable speed so that the conveyor speed may be adjusted to suit the particular washing application.
As shown in FIGS. 7-9, the flip back plate 126 is mounted on a flip back plate shaft 125 which is located just beneath the upper chains of the outfeed conveyor 114. In the retracted position, the flip back plate 126 is just below the plane formed by the upper chains of the outfeed conveyor 114. In the deployed position, flip back plate 126 protrudes above the plane formed by the upper chains of the outfeed conveyor 114. The flip back plate 126 is disposed on its shaft 125 and fills the gap between the chains of outfeed conveyor 114 (FIG. 8).
Turning to FIG. 9, a detail of the flip back plate mechanism is shown. The flip back plate arm 127 is pivotally attached to a flip back plate arm extension 123. The flip back plate arm extension 123 is fixedly attached in turn to the flip back plate 126. The end of the flip back plate arm 127 opposite the extension 123 includes notches 172.
As shown in FIG. 9, a latch plate 129 is attached to the wash tank wall 178. The length of the flip back plate arm 127 is such that when at least one of the notches 172 engages the latch plate 129 the flip back plate 126 is in a retracted position as shown by the dotted lines in FIG. 9. Similarly, at least one of the notches 172 will engage the latch plate 129 with the flip back plate 126 in the engaged position. Preferably, the flip back plate 126 has a concave lip 121 at the end opposite the flip back plate arm extension 123 to facilitate the flipping back of the sticks.
The angle 115 between the pusher flight 116 and the flip back plate 126 can be of any size as long as the sticks can be efficiently peeled off the outfeed conveyor 114 without the sticks hopping over the flip back plate 126. Preferably, the flip back plate 126 is vertical when deployed and the face of the pusher flight 116 is beveled at about 30°.
Preferably, the angle 115 between the flip back plate 126 and the face of the pusher flight 116 is about 75°. This prevents the sticks from jamming. The lip 121 of the flip back plate 126 forces the sticks to fall back in the desired direction.
Another important feature of the present invention is the jet manifold 124. As best seen in FIG. 7, it is situated just under the upper chain of the outfeed conveyor 114. As best seen in FIG. 8, the jet manifold 124 has a series of holes drilled along it. The jet manifold 124 is situated just above the V formed by the intersection of the planes of infeed conveyor 112 and the outfeed conveyor 114. In this manner, a jetstream can be directed at the sticks for effective cleaning because the pile of sticks on the conveyor chains prevent scattering of the lower sticks when impinged by the jetstream. The recirculation pump 134 takes cleaning solution from the pump suction nozzle 162 and pumps it through screen strainer 153 and then into the jet manifold 124. The suction line of the pump 134 is also supplied with a shutoff valve 148 and a basket strainer 155.
Referring to FIGS. 3, 4, 7, and 10 the wash system of the present invention is supplied with an inlet hopper 149 and inlet hopper door assembly 136. Inlet hopper 149 consists of an inlet hopper floor 144 and an inlet hopper door 140. The inlet hopper door 140 is hinged at inlet hopper door shaft 146. In the open position, the inlet hopper door 140 allows the sticks to fall into the V created by the intersection between the planes of the infeed conveyor 112 and outfeed conveyor 114. The inlet hopper door shaft 146 is further connected to a handle 138. Mounted between the handle 138 and the wall of vessel 104 is an arcuate end plate 137. The arcuate end plate 137 has a detent 145. The handle 138 is fitted with locking pin tabs 142 through which is fitted locking pin 141. Locking pin 141 is fitted with a spring 143 so that when the handle 138 is in a substantially horizontal position the end of the locking pin 141 engages the detent 145.
The level of the cleaning solution in the vessel 104 is maintained by the skimmer overflow standpipe 160 which empties into the overflow nozzle 158. If desired, the vessel 104 may be drained via vessel drain 164. The end of the vessel opposite the inlet hopper 149 is equipped with a rinse tub 131. Sticks discharge into the rinse tub 131 by falling off the outfeed conveyor 114 and over the conveyor discharge lip 135. The sticks fall onto the discharge rinse rack 147 which sits in the bottom of the rinse tub 131. The rinse tub is equipped with a water valve 132 for supplying the rinse tub 131 with water. The rinse tub has a drain 133 at its bottom. The level on the rinse tub is maintained by the overflow 156.
In general, all materials of construction for the present invention are 304 stainless steel. | A system for cleaning elongated objects is disclosed. The system utilizes an infeed conveyor without pusher flights and an outfeed conveyor with pusher flights. The conveyors are arranged to form an angular section near the bottom of the tank. A flip back plate rejects objects from the outfeed conveyor so that the objects are continuously circulated from the bottom of the angular section to the top of the angular section. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to endoscope couplers for optically and mechanically coupling an endoscope to a video camera. More particularly, the invention relates to endoscope couplers which enable relative rotation of the endoscope and camera about the endoscope axis.
2. Description of the Prior Art
Endoscopes have become widely utilized in surgery for viewing body cavities and organs to permit performance of diagnostic and surgical procedures internally without the need for invasive surgical procedures. An endoscope is typically inserted through a small incision or portal or natural body passage to provide access to the body cavity. A lens at a distal end of the endoscope is positioned to receive light reflected from a site to be observed, and images of the site can be viewed remotely to conduct diagnostic examinations and to perform closed, or endoscopic surgery. As used herein, the term endoscope refers generically to viewing devices for remotely observing otherwise inaccessible body cavities with minimal trauma and intrusion, including but not limited to arthroscopes, colonoscopes, bronchoscopes, hysteroscopes, cystoscopes, sigmoido-scopes, laparoscopes and ureterscopes, etc.
Endoscopes are sometimes supplied with an eyepiece at the proximal end thereof, and relay lenses in the endoscope typically produce an image for direct viewing through the eyepiece. However, adaptation of video camera technology to endoscopy imaging has enabled the output image of an endoscope to be viewed on a video monitor. Specifically, a video camera is electronically coupled to the video monitor and optically and mechanically coupled with the proximal end of the endoscope. Indirect or video monitor viewing of endoscopic images provides numerous benefits over direct viewing through an eyepiece, including: protection of a direct viewer's vision from high intensity illumination passed through the endoscope and reflecting off bodily tissue; enhancement of operator comfort and freedom of movement; increased endoscope utility and efficiency; reduction in the time required to conduct many endoscopic procedures; simultaneous viewing of endoscopic images by more than one person; and recordation and real time transmission of images of surgical procedures.
An endoscope coupler is required to couple the proximal end of the endoscope to the video camera and may be made as a separate device or in combination with either the endoscope or the video camera or both. Illustrative endoscope couplers are shown in U.S. Pat. No. 4,569,333 (Bel et al.); U.S. Pat. No. 4,611,888 (Prenovitz et al.); U.S. Pat. No. 4,740,058 (Hori et al.); U.S. Pat. No. 4,781,448 (Chatenever et al.); U.S. Pat. No. 4,807,594 (Chatenever); U.S. Pat. No. 4,844,071 (Chen et al.); U.S. Pat. No. 4,969,450 (Chinnock et al.); U.S. Pat. No. 5,056,902 (Chinnock et al.) and U.S. Pat. No. 5,359,992 (Hori et al.). Endoscope couplers sometimes include a cylindrical body which may be closed at opposing ends by end windows and contain a lens holder carrying one or more lenses longitudinally movable within the body to optically adjust an image from the endoscope onto a focal plane of the camera. The optical adjustments most commonly used may be a focus and/or zoom adjustment. Sometimes, endoscope couplers operate with the eyepiece of an endoscope and other times the eyepiece is replaced with an optical arrangement which must be viewed through the camera and monitor (that is, no eyepiece is available).
In addition to enabling optical adjustments, in certain applications such as the urology field, it is often necessary to maintain the camera in a fixed position while rotating the endoscope about its axis in order to view the surgical site. Therefore, rotatable endoscopic couplers have been developed to enable this rotation of the scope relative to the camera. Such couplers may not include any optical components although they serve to properly position the proximal end of the scope relative to the distal end of the camera so the image planes are properly spaced along their common axis. Known rotatable endoscopic couplers generally include a distal ring, which may be fixedly attached to the proximal end of the endoscope, a proximal ring, which may be fixedly attached to a camera, and a rotatable interface between the two rings. The rotatable interface often includes a plain bearing structure (not ball bearings) and a selectively actuatable lock (such as a lever with a pin or cam) to selectively prevent rotation.
Additionally, it is advantageous for the surgeon to use only one hand to manipulate the scope or the camera thereby leaving the other hand free to operate various instruments during surgical procedures. Therefore, rotatable couplers must be easy to operate.
Aforementioned U.S. Pat. No. 4,969,450 (Chinnock et al.) discloses a rotatable coupler for a video arthroscope which can be held and controlled with one hand. The rotatability is achieved by closely fitting cylindrical members including bores and counterbores which are rotatable about their common axes and sealed with several O-rings.
Another example of a rotatable coupler is shown in U.S. Pat. No. 4,611,888 (Prenovitz et al.). The Prenovitz coupler consists of two sections rotatable with respect to one another, the front section being non-rotatably mounted to the proximal end of an arthroscope and the rear section being non-rotatably mounted to the distal end of a video camera. The image produced by the scope is rotatable relative to the camera by simply rotating the front section relative to the rear section.
In order to maintain sterile surgical conditions, all imaging components, including endoscope couplers, whether rotatable or not, must be sterilized before and after each use. Steam autoclaving has long been the best accepted method of sterilization and is used for all instruments that can withstand the necessary high temperature and pressure. Instruments that will not survive the steam autoclave process, such as video cameras and prior art endoscopic couplers are treated by less effective or less efficient means such as immersion in sterilization liquid or gas sterilization. However, there is no known conventional rotatable endoscopic coupler which can withstand repeated steam or other sterilization and all known rotatable endoscopic couplers are adversely affected by such.
While known prior art couplers are available to enable the rotation of the endoscopic image relative to the camera, all known rotatable couplers utilize bearing surfaces, which are rotatable relative to each other, and locking mechanisms in the form of cams and pins to frictionally engage the rotatable elements to lock them together when the desired angular orientation is achieved. Over time, these known rotatable coupler designs become more and more difficult to operate because of the build up of residue caused by improper cleaning as well as the deterioration of the cooperating parts caused by their exposure to the harsh environments of autoclaves. This deterioration eventually leads to the inability to easily operate the rotatable coupler with one hand and eventually leads to the inability to rotate the coupler at all. These prior art couplers must then be totally rebuilt or replaced.
An improved rotatable coupler design is necessary in order to enable the autoclavability of rotatable endoscopic couplers and improve their performance over an extended period of time.
It is, therefore, an object of this invention to produce a rotatable endoscope coupler for joining an endoscope to a camera.
It is also an object of this invention to provide a rotatable endoscope coupler capable of being repeatedly subjected to an autoclave without significant deterioration of performance.
It is still another object of this invention to produce a rotatable endoscope coupler incorporating ball bearings which are adapted to withstand the autoclave environment.
It is still another object of this invention to produce a rotatable endoscope coupler capable of being easily disassembled for repair.
It is also an object of the present invention to provide an endoscope coupler that may be quickly and easily inserted between an endoscope and a video camera or may be formed as an integral part of either the endoscope or the video camera or both.
SUMMARY OF THE INVENTION
These and other objects are accomplished by the preferred embodiment disclosed herein which is a rotatable coupler for coupling a camera to an optical assembly, preferably an endoscopic optical assembly. The coupler comprises a proximal camera attachment means for fixedly securing the coupler to a camera, a distal optical assembly attachment means for fixedly securing the coupler to an optical assembly and a selectively rotatable coupling means interposed between the camera attachment means and the optical assembly attachment means. In one embodiment, the rotatable coupling means comprises a first annular member which is fixedly connected to the optical assembly attachment means and a second annular member is fixedly secured to the camera attachment means. An annular ball bearing means is interposed between the first and second annular members to permit relative rotation therebetween. The first annular member has a plurality of radially inwardly directed slots and a locking means attached to the second annular member annular member is adapted to selectively engage the slots to lock the first annular member to the second annular member.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational view of an endoscope, a camera and a rotatable coupler constructed in accordance with the principles of this invention.
FIG. 2 is a top plan view of a portion of FIG. 1 .
FIG. 3 is a cross-sectional perspective view taken generally along the line 3 - 3 of FIG. 2 .
FIG. 4 is an exploded view of a portion of FIG. 3 .
FIG. 5 is a cross-sectional view of FIG. 2 taken along the line 5 - 5 .
FIG. 6 is a front elevational view of the first annular ring (element 30 ) shown in FIG. 4 .
FIG. 7 is a side elevational view of FIG. 6 .
FIG. 8 is a rear elevational view of FIG. 6 .
FIG. 9 is a cross-sectional view of FIG. 6 taken along the line 9 - 9 .
FIG. 10 is a cross-sectional view of the second annular ring (element 32 ) shown in FIG. 4 .
FIG. 11 is an enlarged view of a portion of FIG. 10 .
FIG. 12 is a front elevational view of the locking tab element 92 shown in FIG. 4 .
FIG. 13 is a cross-sectional view of FIG. 12 taken along the line 13 - 13 .
FIG. 14 is a rear elevational view of FIG. 12 .
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIGS. 1 and 2 show an endoscope 10 releasably connected to a camera head 12 via an intermediate rotatable coupler assembly 14 constructed in accordance with the principles of this invention.
Coupler assembly 14 comprises a distal cylindrical “grabber” means 20 , which is releasably attachable to the eyepiece of scope 10 , and a proximal camera mount means 22 which, in the preferred embodiment is fixedly attached to camera 12 . Grabber means 20 is selectively rotatable relative to camera mount means 22 by virtue of interface or bearing means 24 interposed therebetween, as best seen in FIG. 3 . The freely rotatable grabber means enables a user to permit the camera head 12 (and, therefore, the monitor view) to remain fixed in selected orientation (e.g. upright), while rotating the scope about axis 46 . Either the scope or the camera may be rotated about the axis with the fingers of the hand holding the camera head. For applications such as urology, for example, the surgeon need only grasp the scope thereby allowing the camera to orient itself vertically by virtue of the weight of power cord 16 . Simply rotation of the scope about its axis will not affect the camera orientation. As will be explained below, for procedures requiring the scope and camera to be non-rotatable relative to each other, a locking feature is provided.
While the drawings are shown with an embodiment of the invention adapted to be used with an endoscope having an eyepiece, it will be understood that the invention could be adapted for use with any type of scope. The grabber means 20 may be replaced with an interface adapted to be affixed (permanently or removably) to the particular configuration of the proximal end of the scope to be coupled to the camera. Similarly, the rotatable coupler could be irremovably attached to the scope, or irremovably or removably attached to the camera, or removably or irremovably attachable to both.
As best seen in FIGS. 3 through 5 , bearing means 24 comprises a distal, first annular ring 30 fixedly attached to grabber means 20 , a proximally situated second annular ring 32 and a laterally situated, third annular ring 34 . Annular rings 30 , 32 , 34 have cooperating surfaces 36 , 38 and 40 , respectively, which, when assembled, serve as a race 42 for a plurality of balls 44 circumferentially situated about the axis 46 of the coupler assembly 14 . The assembly of the component parts of bearing means 24 may be understood by reference to the exploded view shown in FIG. 4 .
It is noted that, in the preferred embodiment, race 42 is defined by three cooperating and threadably assembled stainless steel surfaces 36 , 38 and 40 for ease of assembly and servicing. It will be understood that race 42 could be formed by more or fewer cooperating surfaces depending upon the design of the coupler, and could be assembled by means other than threads on rings 32 and 34 . In the preferred embodiment there are thirty five balls 44 , each made of ceramic and having a diameter of 0.125 inches. The ceramic material should be selected to withstand repeated sterilization cycles in an autoclave. However, should additional cleaning be required or should repairs or replacements be necessary, the rings 30 , 32 and 34 may be easily disassembled. In the preferred embodiment surface 36 is an annular groove having a radius of curvature adapted to receive balls 44 , and surfaces 38 and 40 each having planar annular portions 38 a and 40 a (best seen in FIG. 5 ).
Grabber means 20 has an outer cylindrical retaining member 50 that is provided with a fixed radial post 52 . Another radial post 54 is secured to the distal, first annular ring 30 . Retaining member 50 is secured to a spring member (not shown) interposed between the distal annular ring 30 and cylindrical member 50 . Cylindrical member 50 is rotatable about axis 46 when a user squeezes posts 52 and 54 together because post 54 is able to move in arcuate slot 58 . The circular opening 60 of flange 61 formed at the distal end of cylindrical member 50 has a diameter large enough to accept therethrough the eyepiece 62 of endoscope 10 . Three arcuate and radially pivotable retaining arms 64 a , 64 b and 64 c (the latter being hidden from view in FIG. 3 ) are pivotably attached to the distal surface of distal annular ring 30 at points 65 a , 65 b and 65 c (best seen in FIG. 2 ). Each arm has a longitudinally extending pin (not shown) riding in a radially and laterally extending slot (not shown) in the distal flange 61 of cylindrical retaining member 50 . As posts 52 and 54 are squeezed together, the relative rotation between the retaining member 50 and distal annular ring 30 causes the retaining arms to pivot about their attachment points to clear opening 60 to receive eyepiece 62 . Releasing pressure on the posts 52 and 54 allows arms 64 a , 64 b and 64 c to move radially inwardly behind the eyepiece to lock the eyepiece of the endoscope within the cylindrical retaining member 50 . The arms, in cooperation with radially inwardly extending tabs 70 a , 70 b and 70 c on distal ring 30 (best seen in FIG. 6 ) serve to position the eyepiece at the proper axial location relative to the optical components in camera 12 . Once the scope is so situated, it may rotate about axis 46 along with the distal annular ring 30 .
The proximal most rim 72 of annular ring 30 is provided with a plurality of radially inwardly extending slots 74 . Slots 74 extend longitudinally and in the preferred embodiment are open and proximally facing at rim 72 .
Proximally situated second annular ring 32 has an axially aligned opening 76 adapted to receive the distal end of camera 12 . Opening 76 is threaded at its proximal end to receive a camera adapter or to receive a camera mount directly. Ring 32 has an outer cylindrical annular wall 77 and a transverse proximal wall 78 , the latter provided with a plurality of circumferentially arranged ventilation apertures 80 . Annular wall 77 has a length along axis 46 sufficient to properly place bearing race surface 38 relative to bearing surfaces 36 and 40 to define race 42 when the proximal ring 32 is threadably engaged with lateral ring 34 . When fully assembled, the distally facing side 82 of proximal wall 78 will be adjacent to but spaced from the proximal most end of rim 72 , and all surfaces 36 , 38 and 40 will be contiguous with balls 44 .
Second annular ring 32 carries a locking mechanism 90 which serves to prevent the relative rotation between the camera mount means 22 and the grabber means 20 by engaging a pivotable projection with the slots 74 . Locking mechanism 90 , best seen in FIGS. 4 , 12 , 13 , and 14 , comprises a toggle lever 92 pivotably secured to and adjacent the radially outer surface of the proximal side of ring 32 by a shoulder screw 94 . Ring 32 has a screw-receiving threaded bore 96 . Lever 92 is thus situated transversely to axis 46 . The transverse length L of lever 92 is long enough so that when the lever is pivoted a predetermined amount clockwise or counterclockwise about its axis 98 , one corner 100 or 101 will extend radially beyond the outer surface of annular ring 34 . This enables one or the other corner of lever 92 to be easily pushed radially inwardly by the thumb (or other finger) of the hand holding the camera to toggle the lever from one extreme to the other, e.g. from locked to unlocked. Lever 92 is situated a predetermined arcuate lateral distance 93 from the top of the coupler to position it for easy accessibility.
The proximally facing surface 102 of lever 92 is provided with icons 104 and 106 (preferably molded, machined or otherwise form on the surface, or placed via a decal, paint, etc.) depicting a locked or unlocked condition and the direction in which the adjacent corner 100 or 101 must be pushed to achieve the desired condition.
The distally facing surface 108 of lever 92 is provided with a pair of detents 110 and 111 , and a pair of detents 112 and 113 . These detents are designed to cooperate with bores 114 and 115 formed in the proximally facing surface of ring 32 , and with balls 116 , 117 and springs 118 , 119 to frictionally engage lever 92 and hold it in the locked or unlocked position. In the preferred embodiment balls 116 and 117 each have a diameter of 0.063 inches and are made of ceramic. (Balls 116 , 117 and balls 44 are, in the preferred embodiment, also coated with a high temperature grease.) The distally facing surface 108 is also provided with a projection 120 extending distally and having an interference member or tooth 122 . Proximal surface 78 of annular ring 32 is provided with an aperture 124 in order to receive projection 120 and tooth 122 therethrough and enable the tooth to be positioned radially inwardly of slots 74 . When lever 92 is pivoted into a locked position, tooth 122 engages one of the slots 74 , thus preventing relative rotation between the two sides of coupler 14 .
It will be understood by those skilled in the art that numerous improvements and modifications may be made to the preferred embodiment of the invention disclosed herein without departing from the spirit and scope thereof. | A rotatable endoscope coupler which enables an endoscope to be rotatably attached to a camera and selectively locked in place. The coupler enables single handed rotation of the scope while the camera remains in a fixed orientation. A plurality of ceramic ball bearings riding in a stainless steel race enable the coupler to be repeatedly autoclaved. A locking mechanism allows the scope and camera to be fixed from relative rotation. | 0 |
BACKGROUND OF THE INVENTION
The invention disclosed and claimed herein generally pertains to automatic loading apparatus of the type which is capable of presenting cylindrical workpieces to a machining system in a particular, prespecified orientation, which may be critical for proper system operation. More particularly, the invention pertains to apparatus of the above type wherein workpieces may be initially received into the apparatus in orientations or positionings which are arbitrary. Even more particularly, the invention pertains to apparatus of the above type, wherein it is not necessary to notch, inscribe or otherwise vary the structure of a workpiece from the structure which it must have to perform its final intended purpose.
In order to join cylindrical workpieces such as camshaft bushings, or bushes, to certain types of engine blocks, a number of bushes are placed on respective arms or bars of an "H"-press, one bar corresponding to each of a number of bush positions on a block. After each bush has been placed upon a press bar, the press is manipulated so that each bush is first aligned with, and then pressed into, a bush position. Each bush is thereby brought into tight, immovable relationship with the engine block. In such operation, it is essential to maintain each bush in a particular, critical orientation with respect to the block, to insure that after the bush has been pressed onto the block, oil holes provided in the block will be in alignment with corresponding slots provided in the bush. If the oil holes and slots are not aligned, a camshaft mounted in the bush may not be properly lubricated, or may not be lubricated at all.
In the past, in order to insure that the above critical orientation of camshaft bushes was realized, the bushes would be placed upon respective press bars manually, one bush at a time, in a particular orientation with respect to the press bars. As far as is known, no device was available which could automatically load a bush onto a press bar so that the bush and the press bar would have a prespecified or pre-planned orientation in relation to one another. While an "H"-press could attach a number of camshaft bushes to an engine block in one movement or cycle, the efficiency of the press was limited, since a considerable amount of time and operator effort could be required, before the movement or cycle, to properly load the bushes onto the press.
SUMMARY OF THE INVENTION
The present invention provides apparatus for automatically loading cylindrical workpieces into a machining system, wherein the workpieces are presented to the machining system in a prespecified orientation which is necessary to achieve a desired interaction between the workpieces and the machining system. It is anticipated that such apparatus may be very usefully employed to significantly reduce the time, effort, and skill required to load camshaft bushes onto an "H"-press, in a prescribed orientation, whereby the efficiency of press operation may be substantially improved. Reference to such application, however, is by no means intended to limit either the scope or the utility of the present invention.
In the apparatus of the invention, feeder means are provided for placing a workpiece having a cylindrical outer surface in an initial position upon an upwardly inclined guideway, the cylindrical surface of the workpiece containing a number of holes, such as indentations or apertures. Usefully, such holes are present in a workpiece to enable the workpiece to perform its final intended purpose, whereby it is unnecessary to specially adapt the workpiece for use with the apparatus of the invention. If the workpiece comprises a camshaft bush, for example, the holes would comprise the aforementioned slots, which penetrate the wall of the bush to enable lubricating oil to pass through the bush after the bush has been pressed onto an engine block.
The apparatus is further provided with pin means, which alternatively contacts the cylindrical surface of the workpiece, and engages one of the holes in the cylindrical surface, to urge the workpiece up the guideway, the pin means applying a first frictional force to the workpiece when it is in contact with the cylindrical surface. Other means are provided for applying a second frictional force to the workpiece which interacts with the first frictional force to rotate the workpiece until the pin means engages one of the holes. A retaining means maintains the workpiece in a particular orientation, which is determined by the engagement of the pin means in one of the holes, until the workpiece has been presented to the machining system.
Preferably, the guideway includes a roughened inclined surface, and further includes two spaced apart walls, one wall being placed on each side of the inclined surface. The feeder means comprises means for receiving workpieces in arbitrary orientations, and for placing received workpieces at the lower end of the inclined surface. Preferably also, the pin means comprises means for urging the workpiece upwardly along the inclined surface between the walls, the cylindrical surface of the workpiece being maintained in contact with the inclined surface. The aforementioned second frictional force is generated by the contact between the cylindrical surface of the workpiece and the inclined surface of the guideway, and the walls of the guideway prevent lateral or sideward movement of the workpiece. The second frictional force exceeds the first frictional force by an amount which is great enough to insure that the workpiece will rotate until the pin means engages one of the holes in the cylindrical surface of the workpiece.
In a preferred embodiment of the invention, the workpiece comprises one of a number of parts having cylindrical wall, each of the parts being provided with a number of apertures which are selectively spaced around the circumference of its wall. The feeder means comprises means for receiving a number of parts in arbitrary orientations and positionings, for selectively aligning received parts, and for periodically enabling one of the aligned parts to be placed in the initial position. The pin means includes a pin which is sized to be receivable into each of the apertures of a part, and which is positioned, in relation to a part in the guideway, so that the pin is brought into alignment with one of the apertures of such part after the part has been rotated by the above frictional forces.
OBJECT OF THE INVENTION
An object of the present invention is to provide new and improved apparatus which is capable of receiving cylindrical workpieces in arbitrary orientations or positionings, and of presenting each received workpiece to a machining system in a prespecified orientation.
Another object is to provide apparatus of the above type, wherein it is not necessary to adapt or alter respective workpieces in any way in order to employ the apparatus to selectively orient and present the workpieces.
Another object is to provide a new and improved system for automatically loading camshaft bushes or bearings onto a press.
Another object is to substantially reduce the time and manual effort required to load camshaft bushes onto a press, while insuring that respective bushes will have a particular critical orientation, in relation to an engine block, after they have been attached to the engine block by the press.
These and other important objects and features of the invention will become more readily apparant by considering the following Detailed Description of the Preferred Embodiment, together with its accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an elevational view, a section being broken away therefrom, which shows an embodiment of the invention in its operational environment.
FIG. 2 is a plan view showing a system which is constructed from a number of the embodiments of FIG. 1.
FIGS. 3 and 4 are sectional views for illustrating the interaction between the embodiment of FIG. 1 and a cylindrical workpiece which has been received thereby.
FIG. 5 is a view showing an escapement unit for the embodiment of FIG. 1.
FIG. 6 is a sectional view taken along lines 6--6 of FIG. 5.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, there is shown a loading unit 10 provided with an inclined track 12, which receives cylindrical camshaft bushes or bearings 14 from a vibratory bowl feeder 16. Respective bushes 14 entering track 12 have their axes in horizontal planes and slide down track 12 to an escapement unit 18, where they are retained by an escapement finger 20. At prespecified intervals, escapement unit 18 pivots finger 20 to allow the downwardmost bush on track 12 to continue downwardly, until the bush comes to rest in a pre-orientation position. In FIG. 1, the reference number 14a is employed to represent a bush 14 which is in the pre-orientation position. The cylindrical outer surface of bush 14a is in contact with a roughened inclined surface 22, at the lower end thereof, and also abuts a bush advancement device 24.
After a bush 14 has traveled down track 12 to the pre-orientation position, loading unit 10 commences a bush orientation and load cycle. Such cycle is commenced by operating hydraulic cylinder 26 to drive advancement device 24 so that the advancement device moves bush 14a upwardly along inclined surface 22, and through a guideway 28. Guideway 28 is provided to prevent lateral or sideward movement of a bush as it moves upwardly, and may comprise two closely spaced parallel walls, one placed on each side of surface 22 so that a bush moves upwardly between the walls.
Each camshaft bush 14 has a cylindrical wall which is penetrated by several slots, the slots being of equal dimensions, and being spaced around the wall of a bush in equidistant relationship. As aforementioned, when a bush 14 is pressed onto an engine block, it is essential that each of the slots of the bush be in alignment with a corresponding oil hole provided in the block. Consequently, as advancement device 24 moves a bush upwardly along surface 22, structure included in the advancement device causes the bush to be rotated until the bush is so oriented, in a vertical plane, that the slots of the bush are in critical, prespecified angular positions, regardless of the angular positions of the slots when the bush is in the pre-orientation position. Such structure of advancement device 24 is described hereinafter in detail, and is capable of rotating a bush 14 to its critical orientation by the time the bush is advanced to a pre-load position, which is located at the upper end of inclined surface 22. In FIG. 1, a bush in the pre-load position is indicated by the reference number 14b.
After a bush 14 is placed in the pre-load position by the upward movement of device 24, a hydraulic cylinder 30 is operated to move a carriage 32 forward, advancement device 24, inclined surface 22, and guideway 28 being mounted upon the carriage. When carriage 32 is extended fully forward, a bush at the upper end of incline 22 is placed in a press engagement position, a bush in such position being indicated in FIG. 1 by the reference number 14c. Advancement device 24 is provided with further structure, hereinafter described, which becomes operative after a bush has been rotated to its critical orientation to prevent further rotation of the bush. Consequently, a bush 14 retains its critical orientation after it is placed in the press engagement position, and its orientation in relation to a press bar 34, of an "H"-press 36, will always be known. Press bar 34 is constrained by guide bars 38 to forward and backward motion, along the axis of bush 14c, and is provided with structure for grasping bush 14c so that the critical orientation of bush 14c is maintained. Movement of press bar 34 is co-ordinated with the operation of load unit 10 so that after carriage 32 has been extended fully forward, to place a bush in the press engagement position, press bar 34 is moved forward to grasp the bush. The grasping structure of bar 34 may comprise, for example, two spring plungers (not shown) which are mounted on press bar 34 so that each plunger will be received into one of the slots of a bush 14c, and will lockably engage the bush.
After press bar 34 has grasped bush 14c, carriage 32 and advancement device 24 are fully retracted, concluding a load and orientation cycle. Bar 34 is then moved backwardly, to allow an engine block 40 to be moved into a prespecified position in relation to press 36. The positioning of block 40 is such that if press bar 34 is moved forwardly once more, the bush grasped thereby will be pressed into a bush or bearing position on block 40, and each of the slots of the pressed bush will be in alignment with an oil hole in the block. After the bush has been pressed into the block, press bar 34 is moved backwardly a second time, and the block is removed.
Referring further to FIG. 1, there is shown carriage 32 provided with trip dogs 42 and 44. Trip dog 42 operates a forward limit switch 46, to indicate that carriage 32 has been extended fully forward, and trip dog 44 operates a backward limit switch 48, to indicate that carriage 32 has been fully retracted.
It is well known that an engine block generally requires more than one camshaft bush. It is further well known that all of the bushes required by a block may be applied thereto during a single operation or cycle of an "H"-press, by providing the "H"-press with a number of bars 34 which is equal to the number of bush positions on the block. All of the bars 34 are mounted on the press in parallel relationship, and move forwardly and backwardly in unison. In order to assure efficient utilization of a conventional "H"-press, the press bars thereof should be loaded with bushes 14 simultaneously. Simultaneous loading may be achieved by mounting a number of loading units 10 upon carriage 32, each loading unit having its own escapement unit 18, its own track 12 for receiving bushes from a vibratory bowl feeder, and its own advancement device 24, hydraulic cylinder 26 and guideway 28.
Referring to FIG. 2, there is shown a multiple bush loading system wherein five loading units 10 are mounted upon carriage 32, and bushes 14 are entered onto each of five tracks 12 from a vibratory bowl feeder 16 or 50. Both feeders 16 and 50 comprise commercially available devices, such as devices manufactured by the Valley Automation Company, and are capable of receiving bushes 14 in arbitrary orientations or positionings. For example, a press operator may randomly introduce bushes 14 into the bowl feeders by pouring them thereinto from a box or other container. The bowl feeders operate to move bushes 14 into alignment areas 52, which communicate with respective tracks 12 and which are provided with structure 54 for turning respective bushes onto their edges. Each bush 14 is thereby enabled to roll down a track 12 to an escapement unit 18 of one of the loading units 10 of the multiple loading system.
Loading units 10 are mounted upon carriage 32 in parallel relationship, and execute orientation and load cycles of the aforedescribed type in unison, whereby five bushings 14c are simultaneously presented to a press 36. By providing press 36 with five press bars 34, all of the presented bushes may be simultaneously grasped by the press, and may then be simultaneously pressed onto an engine block. It will be readily apparent that by judicious selection of the number and arrangement of loading units 10 mounted on carriage 32, virtually any number of camshaft bushes 14 may be simultaneously presented to a press 36, each bush being in the aforestated critical orientation.
Referring to FIGS. 3 and 4 together, there is shown advancement device 24 provided with a rigidly mounted pin 56. When a bush 14 is placed onto inclined surface 22, the pin will either be in contact with the cylindrical wall of the bush, or else will be in alignment with one of the slots 58 of the bush. Pin 56 is sized in relation to a slot so that if it is aligned therewith, a slight forward movement of advancement device 24 will cause the pin to enter the slot. In FIG. 4, reference number 14d indicates a bush having its wall in contact with pin 56, and reference number 14e indicates a bush having pin 56 inserted into one of its slots.
At the commencement of an orientation and load cycle, hydraulic cylinder 26 drives a piston rod 60 to move advancement device 24 forwardly, as aforedescribed. If a bush in the pre-orientation position is oriented so that pin 56 is in alignment with a slot thereof, the pin will enter the slot and then urge the bush upwardly, along surface 22. If the pin is in contact with the wall of the bush, it will urge the bush upwardly along surface 22, and in addition will cause the bush to be rotated. Rotation occurs by roughening surface 22 sufficiently to insure that the frictional force generated by the contact between surface 22 and the cylindrical wall of the bush will be substantially greater than the frictional force generated by the contact between the cylindrical wall and pin 56, as the bush is urged upwardly.
It will be apparent that regardless of the initial orientation of a bush 14a, rotation of the bush will eventually cause pin 56 to become aligned with one of the slots 58, if the length of surface 22 is sufficiently long in relation to the rotational force upon the bush. Referring to FIG. 4, such alignment occurs when any one of the slots 58 is at an angle φ, relative to a vertical axis V.
By judicious mounting of pin 56, a slot 58 will be at angle φ when a bush 14 is in its required critical orientation. Thereupon, pin 56 will enter the slot to prevent further rotation of the bush, and the bush will remain in its critical orientation as it is moved to the aforementioned pre-load position.
To further insure that a bush will retain its critical orientation, advancement device 24 is provided with a retention finger 62, which is pivotable about a point 64 and which is provided with a roller 66 at its rearward end 68. As advancement device 24 initially moves forward, roller 66 travels along a roller guide 70. After device 24 has moved a bush 14a a sufficient distance along surface 22 to insure that the bush has become critically oriented, roller 66 enters a groove 72 in guide 70, whereupon a spring 74 urges the forward end of retention finger 62 downwardly, to engage the bush. Further rotation of the bush is thereby prohibited, for the duration of the orientation and load cycle.
Referring further to FIG. 3, there are shown trip dogs 76 and 78 mounted upon the rearward end of piston 60. Trip dog 76 operates a forward limit switch 80, to indicate that advancement device 24 has been extended fully forward, and trip dog 78 operates a backward limit switch 82, to indicate that device 24 has been fully retracted. FIG. 3 also shows a latch 84, which is positioned to prevent a bush 14 from slipping out of loading unit 10 when the bush reaches the preload position.
Referring further to FIG. 4, there is shown the cylindrical wall of bush 14d spaced apart from a proximity switch 86, by pin 56, while the wall of bush 14e is shown to be in contact with the switch. Proximity switch 86 is activated when a bushing wall presses against it by reason of the entry of pin 56 into a slot and otherwise is deactivated. Consequently, activation of switch 86 provides notice that a bush 14 is critically oriented. FIG. 3 shows a blow-off tube 88, which is positioned to direct a stream of air upon switch 86 to prevent debris from collecting therearound.
Referring to FIG. 5, there is shown escapement finger 20 of escapement unit 18 in two operational positions, which are respectively indicated in FIG. 5 by reference numbers 20a and 20b. The escapement finger is in position 20a during an orientation and load cycle of unit 10, to prevent any bushings 14 from moving down track 12 during the cycle. At the conclusion of the cycle, an air cylinder 90 included an escapement unit 18 reciprocates a piston rod 92 in a first direction, causing the escapement finger to pivot from position 20a to 20b. Escapement finger 20 is structured so that as it moves from position 20a to position 20b, a single bush 14f is enabled to pass the escapement unit and proceed down track 12. Thereafter, cylinder 90 reciprocates cylinder rod 92 in the opposite direction, to return the escapement finger to position 20a. No bushes may pass the escapement unit during such movement.
Referring further to FIG. 5, there are shown trip dogs 94 and 96, attached to the rearward end of piston rod 92 to respectively operate forward limit switch 98 and backward limit switch 100.
Referring to FIG. 6, there is shown a cross section of respective components of escapement unit 18. The mechanical linkage between reciprocating piston rod 92 and escapement finger 20 is of any conventional design which will insure that a reciprocation of cylinder rod 92 in one direction will pivot escapement finger 20 into position 20a, and so that a reciprocation of piston rod 92 in the opposite direction will pivot escapement finger 20 into position 20b.
It is anticipated that modifications of the above embodiment, as well as other embodiments of the invention, will occur to those of skill in the art. It is the intent of Applicants to include all of such modifications and embodiments which come within the scope of their invention, as hereinafter claimed, within the bounds of patent protection arising out of this application. | Apparatus is provided for automatically loading a cylindrical workpiece into a machining system so that the workpiece is presented to the system in a prespecified orientation, the cylindrical surface of the workpiece containing a number of perforations, indentations or like apertures. The apparatus includes a feeding system for placing the workpiece in an initial position upon an upwardly inclined guideway, and further includes a pin, mounted in an advancement system, for alternatively contacting the cylindrical surface of the workpiece and engaging one of the apertures to urge the workpiece up through the guideway. The pin applies a frist frictional force to the workpiece when it is in contact with the cylindrical surface of the workpiece, and structure included in the guideway applies a second frictional force to the workpiece which interacts with the first frictional force to rotate the workpiece until the pin engages one of the apertures. A retaining system is provided for maintaining the workpiece in a position to which it is oriented by the engagement of the pin in one of the apertures, until the workpiece is presented to the machining system. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation application of international application No. PCT/EP2013/059570 having an international filing date of 8 May 2013 and designating the United States, the international application claiming a priority date of 9 Jul. 2012, based on prior filed European patent application No. 12 290 229.9, the entire contents of the aforesaid international application and the aforesaid European patent application being incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates to an air cleaner in particular of an internal combustion engine in particular of a motor vehicle, comprising a housing with a slide-in opening for inserting a slide-in filter element, a cover element for closing the slide-in opening, which comprises at least one one-piece snap element for fixing the cover element at the housing.
DE 10 2007 063 252 A1 discloses a slide-in air filter of an air conditioner of a vehicle. The air conditioner comprises an air blower for sucking in fresh ambient air or recirculating air from the vehicle interior. The air conditioner further comprises an air duct on the inlet side for the air in front of the air blower, which has a holding fixture for the slide-in air filter. The slide-in air filter comprises a slot and an air filter. The slot with the air filter is bendable around a bending axis. The bending axis is aligned parallel to a plane of insertion and at right angles to a direction of insertion.
It is an object of the invention to provide an air cleaner of the above-mentioned kind, which is capable of establishing an effective seal to impede a leakage of air in the air cleaner. Further, it should be easy to open and close the cover element.
SUMMARY OF THE INVENTION
The object is achieved in that an angle between a main plane of a sealing face of the housing for a sealing between the filter element and the housing and a main plane of a contact face of the cover element, at which a corresponding contact face of the housing abuts in a closing state of the cover element, is different from 90°.
Favorably, the main planes of the sealing face and the contact face are not perpendicular. So, a component of a force realized by the at least one snap element for pressing the cover element against the housing also can realize a pressure of the filter element against the sealing face. In this way, the tightness of the sealing between the filter element in the housing and the tightness of the connection of the cover element and the housing both are improved. The main planes define the average orientation of the according faces each. This means that the faces themselves can have areas which extend in an angle to the according main plane. In particular, the faces can have a profiling along the main plane. The at least one snap element is realized in one piece with the cover element and so is loss-proof connected to the cover element. This simplifies an opening and closing process of the cover element. Further, separate snap elements, in particular screws or tension springs, are not necessary. Favorably, the at least one snap element can be easily realized in one production step together with the cover element. Advantageously, the cover element and the at least one snap element are made of plastic. With plastic, elastic snap elements can be realized easily. The cover element with the at least one snap element also can be made of a material different from plastic.
According to a favorable embodiment of the invention, a tension force of the at least one snap element can realize a first force component, which is perpendicular to the main plane of the contact face of the cover element, and a second force component, which is perpendicular to the main plane of the sealing face of the housing. Advantageously, the tension force of the at least one snap element can be perpendicular to the main plane of the sealing face so that the second force component is identical with the tension force itself. The first force component can effect the pressure of the cover element against the housing so that the tightness of the connection between the cover element and the housing can be improved. The second force component can cause the pressure of the filter element against the sealing face of the housing so that the compression of the sealing between the filter element and the housing and thus the tightness can be improved.
Advantageously, an angle between a direction of a tension force of the at least one snap element and the main plane of the contact face of the cover element can be different from 90°, in particular the angle can be between 20° and 70°, preferably approximately 45°. Experiments have shown that at an angle between 20° and 70°, preferably approximately 45°, the effect of the tension force can improve the gas tightness of the contact area between the filter element and the sealing face as well as the gas tightness of the contact area between the cover element and the housing.
Favorably, an angle between a direction of a tension force of the at least one snap element and the main plane of the sealing face of the housing for the sealing between the filter element and the housing can be approximately 90°. So, a pressure for compressing the sealing and improving the sealing function between the filter element and the housing can be maximized.
According to a further favorable embodiment of the invention, a sealing element can be arranged between the contact face of the housing and the cover element. Advantageously, the sealing element can be flexible. Preferably, the sealing element can be made of an elastomer. With the sealing element, tolerances of the shape of the according contact faces of the cover element and the housing and/or the position of the cover element relative to the housing can be compensated. Further, the sealing function can be increased. Additionally, the sealing element can effect an acoustical decoupling of the cover element and the housing. Advantageously, the sealing element and the cover element can be realized as a two-component part. So, the sealing element can be loss-proof attached to the cover element. Additionally, the opening and closing of the cover element can be further simplified.
Advantageously, the slide-in opening can be arranged on a raw-gas side of the filter element. So, a suction of leak air into the housing through the slide-in opening to the clean-air side of the filter element can be impeded.
According to a further favorable embodiment of the invention, the cover element can be part of a drawer in which the slide-in filter element can be placed and which can be slid through the slide-in opening into the housing. The filter element can be placed easily and stably in the drawer. The drawer together with the filter element can be slid into the housing and placed precisely in its end position. So, even a filter element whose internal strength is not sufficient for pushing it on its own can be placed precisely and stably in the housing. Favorably, the drawer can have a frame for holding the filter element. The drawer can be permeable to gas at least in direction of the air flow through the filter element.
Favorably, at least one snap face, which can act as a counterpart for the at least one snap element, can be arranged at the housing. With this snap face, the tension force of the snap element can be transferred to the housing.
Further, at least one counter support for connecting the housing and the cover element can be arranged on an opposite side of the at least one snap face and the at least one snap element. In this way, the cover element can be clamped between the counter support and the at least one snap element. So the cover element can be pressed against the housing on opposite sides. Thus, the pressure of the cover element against the housing can be distributed all over the contact face. So, the tightness of the sealing further can be improved.
Advantageously, the at least one snap element can have at least one unlocking element for unlocking the fixation of the cover element at the housing. With the at least one unlocking element, the at least one snap element easily can be unlocked so that the cover element easily can be opened in particular for removing the filter element.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention together with the above-mentioned and other objects and advantages may best be understood from the following detailed description of the embodiments, without being restricted to the embodiments.
FIG. 1 is a first perspective view of an air cleaner of an internal combustion engine of a motor vehicle with a housing in which a drawer with a slide-in filter element is placed.
FIG. 2 is a second perspective view of the air cleaner of FIG. 1 .
FIG. 3 is a cross-section of the air cleaner of FIG. 2 along the section line III-III of FIG. 2 .
FIG. 4 is an enlarged view of the cross-section of the air cleaner of FIG. 3 of an area of a snap element for fixing a cover element of the drawer at the housing.
FIG. 5 is a third perspective view of the air cleaner of FIGS. 1 to 4 wherein the snap elements are shown in an unlocked state.
FIG. 6 is a perspective view of the air cleaner of FIG. 5 with the unlocked snap elements, with the view angle of FIG. 2 .
FIG. 7 is a cross-section of the air cleaner of FIG. 6 along a section line VII-VII of FIG. 6 .
FIG. 8 is an enlarged view of the cross-section of the air cleaner of FIG. 7 of the area of the unlocked snap element.
In the drawings, same or similar elements are referred to by same reference numerals. The drawings are merely schematic representations, not intended to portray specific parameters of the invention. Moreover, the drawings are intended to depict only typical embodiments of the invention and therefore should not be considered as limiting the scope of the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
In FIGS. 1 to 8 , an air cleaner 10 of an internal combustion engine of a motor vehicle is depicted.
The air cleaner 10 has a housing 12 which comprises of an upper housing part 14 , a lower housing part 16 , and an inlet housing part 18 . The upper housing part 14 is fixed at the lower housing part 16 , for example, by welding. On the opposite side of the upper housing part 14 , the inlet housing part 18 is fixed at the lower housing part 16 , for example, by welding.
The inlet housing part 18 has an inlet 20 for ambient air which has to be cleaned. The upper housing part 14 has an outlet 22 for the cleaned air. The lower housing part 16 has an air duct 24 , which is shown in FIGS. 3 and 7 , with a holding fixture 26 for a drawer 28 . In the drawer 28 , a slide-in filter element 30 is placed. The lower housing part 16 has a slide-in opening 32 for inserting the drawer 28 with the filter element 30 into the holding fixture 26 .
An inlet chamber 34 of the lower housing part 16 is connected by an opening 38 with an outlet chamber 36 of the upper housing part 14 . The filter element 30 is covering the opening 38 and so separates the inlet chamber 34 from the outlet chamber 36 . The inlet 20 leads into the inlet chamber 34 . The outlet 22 comes from the outlet chamber 36 . The inlet chamber 34 and the slide-in opening 32 are on a raw-gas side 40 of the filter element 30 . The outlet chamber 36 and the opening 38 are on a clean-gas side 42 of the filter element 30 .
The filter element 30 has a pleated filter medium 44 which has an approximately cuboid shape. A circumferential elastic sealing 48 is fixed tight at an edge of the filter medium 44 . The sealing 48 is faced toward a sealing face 46 of the housing part 14 . In a locked state of the drawer 28 , which is shown in FIGS. 1 to 4 , the sealing 48 abuts gas-tightly against the sealing face 46 . The sealing face 46 is surrounding the opening 38 . The sealing 48 preferably can be made of polyurethane foam. The sealing face 46 has a main plane depicted in FIGS. 3 and 5 in broken line 50 . The main plane 50 defines a main orientation of the sealing face 46 . Preferably, the sealing face 46 is flat.
The slide-in opening 32 is surrounded by a contact face 52 . The contact face 52 has a main plane is depicted in broken line 54 in FIGS. 3 and 4 . The main plane 54 defines a main orientation of the contact face 52 . Preferably, the contact face 52 is flat.
The drawer 28 is made of plastic. It has a frame 56 for holding the filter element 30 . In flow direction of the air, the frame 56 is permeable to gas. The flow direction of the air is indicated in FIG. 3 with an arrow 57 . Further the drawer 28 has a cover element 58 , which is arranged in one piece with the frame 56 . The cover element 58 has approximately the shape of a hollow cuboid, which is halved along one of its space diagonals. At its open edge, it has an elastomeric sealing element 60 , which is realized as a two component part with the cover element 58 . The face of the sealing element 60 realizes a contact face 62 of the cover element 58 .
In a locked state of the drawer 28 , the cover element 58 closes tightly the slide-in opening 32 of the lower housing part 16 . The contact face 62 of the sealing element 60 abuts tightly on the contact face 52 , which surrounds the slide-in opening 32 . In the locked state, a main plane of the contact face 62 extends more or less along the main plane 54 of the contact face 52 . For reason of clarity, in FIGS. 3 and 4 the main plane of the contact face 62 is indicated by the same broken line and has the same reference number as the main plane 54 .
An angle 64 between the main plane 50 of the sealing face 46 and the main plane 54 of the contact face 62 of the cover element 58 is different from 90°. For example, the angle 64 is between 20° and 70°, preferably about 45°.
The cover element 58 comprises two snap elements 66 for fixing the cover element 58 at the housing 12 . The snap elements 66 are realized in one piece each with a common plate 68 . The common plate 68 is realized in one piece with the outer surface of the cover element 58 . The common plate 68 with the snap elements 66 is flexibly pivoted at the cover element 68 . Each snap element 66 has a snap tab 70 which extend in the locked state of the drawer 28 parallel to the main plane 50 of the sealing face 46 .
A snap face 72 which acts as a counterpart for the snap elements 66 is connected to the upper housing part 14 . The snap face 72 extends parallel to the main plane 50 of the sealing face 46 . In the locked state of the drawer 28 , the snap face 72 passes through a gap 74 between the snap elements 66 and an upper edge of the cover element 58 .
The snap elements 66 each have an unlocking element 76 for unlocking the fixation of the cover element 58 at the housing 12 .
A counter support 78 for connecting the lower housing part 16 and the cover element 58 is arranged on an opposite side of the snap face 72 and the snap elements 66 . The counter support 78 comprises a support element on the side of the lower housing part 16 and a corresponding support element on the side of the cover element 58 .
In the locked state of the drawer 28 , a tension force 80 of the snap elements 66 each cause a first force component 82 which is perpendicular to the main plane 54 of the contact face 62 of the cover element 58 . The tension forces 80 of the snap elements 66 themselves are perpendicular to the main plane 50 of the sealing face 46 of the housing 12 and so realize a second force component each. The angles between the tension forces 80 and the main plane 50 are indicated with the reference numeral 86 .
An angle 84 between the direction of the tension force 80 of the snap elements 66 each and the main plane 54 of the contact face 52 of the cover element 58 are different from 90°. The angles 84 favorably are between 20° and 70°, preferably approximately 45°.
For replacing the filter element 30 , the unlocking elements 76 are pulled away from the upper housing part 14 . So, the snap tabs 70 are separated from the snap faces 72 each. The snap faces 72 get out of the gaps 74 . This situation is shown in FIGS. 5 to 8 . The drawer 28 with the filter element 30 is pivoting away from the sealing face 46 so that the sealing 48 can relax. A bar 88 for positioning, which is fixed at the opposite side of the snap face 72 , gets out of an according groove 90 which is arranged in the upper edge of the cover element 68 . The corresponding support elements of the counter support 78 on the side of the housing part 16 and the cover element 58 are separated. The drawer 28 is pulled out of the holding fixture 26 of the lower housing part 16 against a direction 92 of insertion. The filter element 30 is being replaced.
For closing, the drawer 28 is pushed in the direction 92 of insertion until the snap tabs 70 reach the snap faces 72 . Then, the drawer 28 is pivoted towards the sealing face 46 . Thereby, a front face 94 of the snap tabs 70 , which are sloped like ramps, each are gliding along the according front faces 96 of the snap faces 72 . The front faces 96 of the snap faces 72 are sloped accordingly. The snap tabs 70 engage the snap faces 72 , the bar 88 for positioning engages the groove 90 , and the support elements of the counter support 78 are combined. The sealing 48 and the sealing element 60 are compressed so that the opening 38 and the slide-in opening 32 are sealed tightly.
The invention is not limited to an air cleaner 10 of an internal combustion engine of a motor vehicle. The invention can also be applied to other kinds of air cleaners in particularly for vehicles. The invention can further be applied to other kinds of internal combustion engines, in particular for industrial engines.
The angle 86 between the direction of the tension forces 80 of the snap elements 66 each and the main plane 50 also can be different from 90°.
Instead of being pleated with an approximately cuboid shape, the filter medium 44 also can be shaped in a different kind. The filter medium 44 can also be flat without pleats.
The housing 12 can also have more or fewer than three housing parts 14 , 16 , 18 .
Instead of welding, the housing parts 14 , 16 , 18 can be fixed together in another way, for example by gluing or by use of mechanical fixing parts, for example, screws or springs.
Instead of ambient air, also another gas, for example, recirculating air or recirculating exhaust gas can be cleaned by the air cleaner 10 .
The sealing 48 can be made of a material different from polyurethane foam.
Instead of being flat, the sealing face 46 also can have a profiling or can be sloped relative to the main plane 50 .
Instead of being flat, the contact face 52 also can have a profiling or can be sloped relative to the main plane 54 .
More or fewer than two snap elements 66 can be used.
The cover element 58 can be realized without the sealing element 64 .
The slide-in opening 32 also can be arranged on the clean-gas side 42 of the filter element 30 .
The drawer 28 also can be made of a material different from plastic.
While specific embodiments of the invention have been shown and described in detail to illustrate the inventive principles, it will be understood that the invention may be embodied otherwise without departing from such principles. | An air cleaner of an internal combustion engine has a housing with a slide-in opening and receives a slide-in filter element through this opening. A cover element closes off the slide-in opening. The cover element has a snap element for fixing the cover element at the housing. The cover element has a contact face defining a first main plane. A sealing is disposed between the filter element and the housing and seals between filter element and housing. A sealing face provided at the housing interacts with the sealing and defines a second main plane. The housing has a contact face abutting the contact face of the cover element in the closing state of the cover element. An angle between the second main plane of the sealing face of the housing and the first main plane of the contact face of the cover element is different from 90°. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to co-pending German Patent Application No. DE 10 2011 002 129.9 entitled “Kupplungskopf mit einem Filterelement”, filed Apr. 18, 2011.
FIELD OF THE INVENTION
The invention relates to a coupling head for a commercial vehicle having a filter element. Compressed air flows through the filter element which in particular is designed as a filter insert. Coupling heads of this kind are used for pneumatically charging a compressed air system of a commercial vehicle, in particular a unit of a multiple unit commercial vehicle or tractor-trailer-combination. Here, compressed air is fed, for example via a coupling head, to supply the compressed air system of a trailer with compressed air and/or to deliver a control pressure, in particular for a brake actuation.
BACKGROUND
CH 317732 discloses a coupling head (also called “Glad hand”) assigned to a towing vehicle and a coupling head assigned to a trailer, which each have a mussel shell shape with an overlapping flange, by means of which the two coupling heads can be pneumatically connected to one another in a sealing manner. Each coupling head has a sealing ring, these sealing rings being pressed against one another to seal the coupling heads. A non-return valve, which blocks in the direction towards the trailer, is integrated into the coupling head on the towing vehicle side. This non-return valve is, when both coupling heads are fitted, automatically transferred into a permanent open position wherein this transfer is controlled by the movement via a cam drive. A filter element has the form of a screen basket with compressed air flowing therethrough. The filter element serves to collect contaminants. The filter element is integrated into the coupling head on the trailer side.
DE 1 767 438 U (which relates to another technical field) describes a coupling head for railway vehicles, into which a sealing ring is integrated. The sealing ring consists of an annular body made of rubber or a rubber-like material. The sealing ring has an inner annular groove, into which a thin cover is inserted. The thin cover is divided by slots, running radially, into flexible sectors in the form of circular segments having the same segment angles. When the coupling head is not pressurized, the circular segments due to their stiffness are held in an plane orientation in relation to one another, whereby the coupling head is closed in outward direction. In the coupled state and with compressed air applied, the circular segments bend in the direction of flow without producing a relevant resistance against the flow of the compressed air.
DE-OS 2 037 008 discloses coupling heads for a two or multiple line compressed air braking system for operating a trailer. Between the tractor and the trailer detachable connections by coupling heads are required for a supply line, a brake control line and also, where appropriate, an auxiliary brake line. The coupling head on the towing vehicle side and assigned to the supply line has a sealing and control piston which is tensioned via a spring into a shut-off position when no coupling head is fitted on the trailer side. When coupled to the coupling head on the trailing side via a ring seal of the coupling head on the trailer side, the sealing and control piston is transferred from a shut-off position into an open position, which is effected against the tensioning by the spring. The sealing and control piston has an inclined or cam surface. Via this inclined or cam surface the sealing or control piston on the way from the shut-off position to the open position actuates a stem of a shut-off valve of the coupling head on the towing vehicle side into the opening direction of the shut-off valve. The seal of the coupling head on the trailer side is formed as an elastic ring seal. The elastic ring seal is pressed onto the upper surface of the sealing and control piston of the coupling head on the towing vehicle side when the coupling heads are twisted with each other. The coupled position of the coupling heads is secured by bayonet elements. The seal of the coupling head on the trailer side has an L-shaped semi-longitudinal section. One leg of the L is oriented parallel to the longitudinal axis and forms a guiding surface for the compressed air flow. The other leg of the L extends radially outwards and is accommodated and held in a form-fit manner by a housing of the coupling head on the trailer side. The coupling head on the towing vehicle side and assigned to the brake control line, generally also has a sealing and control piston which interacts with the seal with the L-shaped semi-longitudinal section of the coupling head on the trailer side. Here, however, the sealing and control piston is additionally equipped with a valve seat which together with a valve body forms a shut-off valve. The coupling head on the towing vehicle side comprises a control piston located in a control chamber. The control chamber is coupled to the coupling head on the towing vehicle side and assigned to the supply line, and is located downstream of the shut-off valve of this coupling head. The control piston is designed as a differential piston, on which both the brake control pressure on the towing vehicle side and the supply line pressure downstream of the shut-off valve act. If the connection of both of the coupling heads assigned to the supply line is detached and as a result the pressure in the control chamber drops down, this pressure drop and a closing movement of the control piston result in a shut-off of the shut-off valve in the coupling head on the tow vehicle side and assigned to the brake control line. This is done by pressing the valve body against the assigned valve seat. Here, the coupling heads are referred to as “automatic coupling heads”.
DE 199 31 162 B4 underlines the importance of the use of filter elements in coupling heads in order to protect compressed air braking systems and auxiliary consumers in commercial vehicles from contaminants. Here, the filter element is in each case integrated into the coupling head of the trailer. The coupling heads of the trailer, in contrast to those of the towing vehicle, have no stop valve or shut-off valve which in the uncoupled state causes the assigned pneumatic line to close. The filter element is generally situated in a separate housing. However, also embodiments are known, in which a cup-shaped filter insert opens against the force of a pretensioning pressure spring and frees a by-pass connection. This by-pass connection is only freed if the filter element is sufficiently blocked with contaminative particles such that upstream of the filter element the required opening pressure for the by-pass connection is produced. With the opening of the by-pass connection, it is accepted that contaminated compressed air might be transferred to the trailer. DE 199 31 162 B4 discloses a coupling head having a housing, an upper claw, a cover and a guide element, wherein claw and guide element serve to connect and guide the other assigned coupling head when assemblying or detaching the coupling heads. A spring element formed as a filter insert is inserted into the coupling head. The filter insert is formed with a cage-like base body. The interior space of the base body is freely accessible through an internal bore of a ring surface in the direction of flow of the compressed air, while an escape from the interior space in the direction of flow is only possible through the screen made of a fine-meshed, plastic filter material. The filter material is bonded to the filter insert cage or fused as a result of a heat treatment. The ring surface is formed by a ring of the cage. A first pressure spring is supported at the ring of the cage on one side. On the ring on the opposite side a stop ring is supported which is acted upon by a second pressure spring opposed to the first pressure spring. The stop ring is a valve body for a double valve in which, in a closed position of a first valve, the valve body tightly contacts the ring and, in a closed position of the second valve, tightly contacts a valve seat formed by the housing of the coupling head, which is arranged radially outwardly from the ring. If the filter insert is not blocked due to contaminants, both valves are closed. If with increasing blockage of the filter insert a greater pressure builds up upstream of the filter insert, this pressure when exceeding an opening pressure lifts the filter insert together with the stop ring under the additional bias of the second pressure spring from the valve seat formed by the housing. Accordingly, a by-pass is created dependent on the build-up of pressure and on the amount of blockage. The coupling head is, however, also adapted for a reverse direction of flow, for which, when there is no contamination of the filter insert, the compressed air must also flow through the filter insert. If a pressure decrease builds up for this reverse direction of flow with a blockage of the filter insert, a by-pass can also be brought into effect for the reverse flow, which in this case is provided by opening the first valve. Under the additional bias of the first pressure spring, the filter insert with the ring is moved away from the stop ring, whereby a by-pass in the form of a cross-over section is created between the ring and the stop ring. DE 199 31 162 B4 discloses different embodiments and installation options for the filter insert and the double valve. The assembly of the coupling head requires the insertion of two pressure springs, the filter insert and the stop ring into an interior space of the housing. Subsequently the interior space must then be closed with a screwed-in cover comprising an additional sealing element. Alternatively, instead of using a cover which is screwed in, the use of an alternative cover having a quickly detachable securing ring or another securing wire is suggested in this document. Detaching the cover serves to allow access to the interior of the coupling head, so that the filter insert might be replaced quickly after it has become clogged or so that the pressure springs can be replaced.
EP 2 281 700 A1 is also based on the fundamental idea of opening a valve for a by-pass when there is an increase in pressure upstream due to an increased restriction effect of a blocked filter insert. In this case, the valve is formed with a valve lip of the seal. When there is no throttle effect due to a blockage the seal tightly abuts a limiting ring of the filter insert. However, the seal elastically deforms when due to the restriction effect there is an increase in the pressure above an opening pressure, so that the by-pass is freed.
OBJECT OF THE INVENTION
The invention is based on the object to provide a coupling head for a commercial vehicle having a filter element (in particular a filter insert) which (taking account of production and/or assembly costs and effort) allows for the possibility of an at least partial blockage of the filter insert as a result of contaminated compressed air conveyed through the filter element.
SUMMARY OF THE INVENTION
The present invention is based on the perception that the person skilled in the art, in accordance with the prior art mentioned above, proceeds from the preconception that for “normal operation” of the coupling head with a clean filter element (i.e. a filter element which is not or not sufficiently blocked) the presence of a by-pass which bypasses the filter element is to be avoided as far as possible. On the other hand, a by-pass is required which must be selectively brought into effect, when a blockage or partial clogging of the filter element occurs. However, the by-pass should not impair the functioning of the compressed air system by an at least partial closure or increased restriction of the cross-over section for the compressed air in the coupling head. In the worst case, this partial closure or restriction could lead to an inadequate braking action of the commercial vehicle with the risk of an accident, an immobilisation of the vehicle or the need for the filter element to be replaced or cleaned.
According to the invention, it was recognized for the first time that the by-pass bypassing the filter element can be permanently open. According to the invention, the additional design measures required according to the prior art for enabling the pressure and clogging controlled opening of a by-pass can then be omitted. Thus, in particular pressure springs for acting on a valve element in a closed position, valve seats and the like, which are known from the prior art mentioned above, can be dispensed with.
In addition, forming the seal according to EP 2 281 700 A1 with an elastic valve lip can, in some cases, also be omitted, whereby the production of this seal can be simplified. Furthermore, a problem with the embodiments known from this prior art is that providing the seal with the valve lip represents a deviation from standardized sealing rings, such as those prescribed in ISO 1728 for coupling heads. The dimensional stability of the sealing lip presents a further problem. Due to aging or other effects, the behaviour of the material can change over the course of time, whereby a creeping increase or reduction in the opening pressure for the by-pass can occur. All these problems can be eliminated according to the invention.
Basically, for one embodiment, the invention suggests a division of the compressed air flows in a first flow through the filter element and in a second flow through the permanently open by-pass. The relation between the two flows might be fixed or also dependent on the degree of the extent of the blockage of the filter element. To simply name a non-limiting example, basically a restriction effect for the filter element which is not or not sufficiently blocked can be less than the restriction effect for the by-pass, so that without exceeding a certain degree of contamination of the filter element a certain proportion or a large part of the compressed air does not bypass the filter element via the by-pass but flows through the filter element. In so doing, passing on a certain amount of contamination through the by-pass can, in some cases be, accepted.
The by-pass is preferably a free and open channel. However, in terms of the present invention, a by-pass should also be included under a “permanently open by-pass”, in which possibly filtering (in particular reduced filtering with reduced throttling effect with respect to the filter element) also might take place, as long as here no switchable valve element opens closes the by-pass. In addition, it is understood that the by-pass according to the invention can have any geometry of flow, wherein the by-pass can be formed with at least one by-pass opening to admit the compressed air to enter into the by-pass and/or with at least one by-pass channel.
A further embodiment of the invention additionally takes care that the extent of the contaminants which could bypass the filter element via the by-pass is kept to an acceptable level. For this embodiment, basically the compressed air is guided over a guiding surface in a guiding direction, wherein the guiding direction can, for example, be directed in the direction of the filter element. The by-pass has (at least) one by-pass opening for admitting the compressed air to enter into the by-pass. The by-pass opening is arranged in such a way that the compressed air does not directly reach the by-pass opening in the guiding direction which would mean that the compressed air flow with the contaminants would be able to reach the by-pass opening. Instead, the by-pass opening is arranged in such a way that the compressed air can only reach the by-pass opening from the guiding surface by being redirected from the guiding direction. The redirection can be effected by corresponding conducting elements or guiding surfaces. The invention also covers an at least partial redirection of the flow to the by-pass opening by pneumatic forces, in particular by the flow conditions in the coupling head. It is also possible for the compressed air not to reach the by-pass opening directly via the flow, but rather to reach the by-pass opening in a region of reduced flow as a result of the pressure conditions. The redirection referred to results in the contaminants contained in the flow owing to their inertia being redirected less or not at all. Accordingly a separation of air and contaminants occurs such that compressed air with contaminants originally oriented in the guiding direction is divided into contaminants which do not reach the by-pass opening and compressed air which reaches the by-pass opening without contaminants or only with a reduced proportion of contaminants. It is understood that within the scope of the present invention, a complete separation of the compressed air, on the one hand, and the contaminants, on the other hand, does not necessarily have to take place. Instead, the proportion of contaminants reaching the by-pass opening can be reduced by the redirection. It is also possible for only heavier contaminants to be kept away from the by-pass opening by the redirection, while lighter or smaller contaminants, which conceivably do not impair operation of the compressed air system, are directed to the by-pass opening by the redirection. The by-pass opening can be “covered” in the flow or guiding direction, so that the compressed air with the contaminants can only reach the by-pass opening “around the corner”, namely around the cover.
Any type of embodiment might be used for inducing the redirection. For one embodiment of the invention, the by-pass opening is formed in the region of an undercut or in a back tapered region. This can be arranged at any position, for example in the flow channels of the compressed air or inlet regions of chambers. To simply name a few non-limiting examples, the undercut might (at least partly) be formed with the seal which is responsible for sealing the coupling of the two assigned coupling heads. For another example the undercut is (at least partly) formed with a housing of the coupling head. Also embodiments are possible, in which the undercut is formed together with the seal and the housing.
In a further embodiment of the invention, the by-pass is formed with at least one by-pass channel and/or at least one by-pass opening. Here, the by-pass channels and/or by-pass openings can be arranged arbitrarily in the flow channels. These can also be arranged at different positions along the direction of flow. For one particular proposal of the invention, the by-pass channels or by-pass openings are distributed over the circumference of a line or flow cross-section, wherein the distribution can occur evenly or unevenly. By-pass openings and/or by-pass channels can be employed which can all have the same or different cross-sectional and/or longitudinal forms.
There are various possibilities for the type of flow guidance when the redirection is carried out. In one particular embodiment of the invention, the flow conditions in the coupling head for an at least partly blocked filter element are specified in such a way that the compressed air reaches the by-pass and/or flows through it via the following partial flow regions:
From a guiding flow in the region of a guiding surface, the compressed air flow is initially redirected in the region of a redirection flow, in which region contaminants can already be eliminated. The prevention of contaminants passing through the by-pass can be increased if another redirection occurs, but this time in another direction, in a region of a counter redirection flow. A turning region is arranged between the region of the redirection flow and the region of the counter redirection flow.
In principle, the redirection can take place along any curved flow courses, wherein flow contours for bringing about the redirection can also be provided with projections, edges and the like. It has proved particularly effective, in some cases, with respect to keeping contaminants from passing through the by-pass, if the compressed air for an at least partly blocked filter element flows through the by-pass in an (roughly approximated) S-shaped flow.
According to a further proposal of the invention, the compressed air flowing through the by-pass must flow around a protrusion, an edge or a projection which extends into the filter element. The compressed air with the contaminants contained therein must thereby already enter the interior of the filter element, in particular the filter insert. The compressed air can only reach the by-pass if it flows back around the protrusion, the edge or the projection again. This flow back is accompanied by a large change in direction right up to a reversal in the sense of direction. Contaminants here strive to continue the direction of flow into the filter element and not to participate in the above mentioned change in the direction of flow. Accordingly, the contaminants do not reach, or only to a reduced extent reach, the by-pass.
The invention comprises embodiments, in which the contours delimiting the flow are independent of the flow conditions. For another proposal of the invention, however, a contour effect occurs which is dependent on the flow conditions. An elastic guiding or passing element is provided for this embodiment. The guiding or passing element can, in some cases, be elastically deformed by the flow of the compressed air dependent on a flow speed, a volumetric flow or a pressure. In a further embodiment of the invention, the extent of the elastic deformation of the guiding or passing element alters the extent of the redirection of the compressed air on the way to the at least one by-pass opening of the by-pass.
Guiding or passing elements of this kind can be built by elastic circular segments. For example corresponding to the prior art DE 1 767 438 U these elastic circular segments might be closed when they are not flowed through, but undergo bending in an opening direction when flowed through. Where guiding or passing elements in the form of elastic ring segments are used, these segments delimit a permanently free circular cross-section which can be flowed through independently of an elastic deformation of the ring segments for further opening of the free cross section.
It is possible for the guiding or passing element to be formed as a separate component. According to a particular proposal of the invention, however, at least one guiding or passing element is an integral component of the seal which is responsible for the sealing connection when coupling the two coupling heads to one another. This embodiment is based on the understanding that the elasticity of the seal (which can consist of a single material or a composite material) can be used in a multifunctional way: on the one hand the seal is used for the required elastic sealing of the two coupling heads whereas on the other hand the seal is used for the elastic deformability of the guiding or passing element. Furthermore, for this embodiment of the invention the range of parts is reduced and hence also the production, stocking and assembly costs and effort are reduced.
Whilst, in principle, any configuration of the seal with regard to the shape and structure might be used, a seal according to ISO 1728 for coupling heads can also be used within the scope of the invention.
The filter element can be secured in place by any method, in particular by a pretension, with a certain play or with a fixation of the filter element. A particularly compact configuration is produced if the filter element in a coupling head according to the invention is secured in place by the seal. The seal hence takes on another function. As a further advantage, securing the filter element in place is “automatically” dispensed when removing the seal (for example in the course of maintenance with cyclical replacement of the seal). In the case of a seal which is detached, the filter element can then possibly be removed from the coupling head without further disassemblying steps, whereby the filter element can then be cleaned particularly easily or can be replaced by a new filter element.
According to a further embodiment of the invention, (at least) one collecting space for contaminants is provided in the coupling head. For one embodiment the filter element or the filter insert forms the collecting space. This is due to the fact that the compressed air as such is guided in the guiding direction to the filter insert and compressed air reaches the by-pass opening due to the redirection, while contaminants are deposited in the interior of the filter insert (which hence forms the collecting space). This embodiment might have the advantage that when cleaning or replacing the filter element, contaminants located therein can also be removed. However, it is also possible that on the way to the by-pass or in the by-pass itself additional collecting spaces are built with recesses, grooves, undercuts and the like, in which, for example as a result of redirections, the contaminants can be deposited, so that they are not transported further.
Advantageous further embodiments of the invention result from the claims, the description and the drawings. The advantages of features and of combinations of several features mentioned above are only provided by way of example and can alternatively or cumulatively come into effect. However, the mentioned advantages not necessarily have to be achieved by embodiments according to the invention. Further features are to be derived from the drawings—in particular from the illustrated geometries and the relative dimensions of a plurality of components in relation to one another and their relative arrangement and operative connection. The combination of features of different embodiments of the invention or of features of different claims is also possible and is hereby encouraged. This also relates to those features which are illustrated in separate drawings or are mentioned in the description thereof. These features can also be combined with features of different claims. Equally, features specified in the claims can be omitted for further embodiments.
The features mentioned in the claims and the description are in terms of their number to be understood such that exactly this number or a larger number than the stated number is present, without necessarily requiring the explicit use of the adverb “at least”. Therefore if, for example, a by-pass channel is mentioned, this is to be understood such that exactly one by-pass channel, two or more by-pass channels might be present.
Other features and advantages of the present invention will become apparent to one with skill in the art upon examination of the following drawings and the detailed description. It is intended that all such additional features and advantages be included herein within the scope of the present invention, as defined by the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is explained and described further below by means of preferred exemplary embodiments illustrated in the figures.
FIG. 1 shows a first embodiment of a coupling head according to the invention in a vertical section.
FIG. 2 shows a detail II of FIG. 1 , in which the flow through the coupling head according to the invention is illustrated.
FIGS. 3 and 4 show further embodiments of coupling heads according to the invention in a vertical section.
FIG. 5 shows a detail V of FIG. 4 , in which the flow through the coupling head according to the invention is illustrated.
FIGS. 6 and 7 show a further embodiment of a coupling head according to the invention in a vertical section.
FIG. 8 shows a top view of a seal which is inserted into the coupling head according to FIGS. 6 and 7 .
FIG. 9 shows a further embodiment of a coupling head according to the invention in a vertical section.
FIG. 10 shows a top view of a seal which is inserted into the coupling head according to FIG. 9 .
FIG. 11 shows a further embodiment of a coupling head according to the invention in a vertical section
DETAILED DESCRIPTION
The coupling head 1 according to the invention can be used as a coupling head for any pneumatic coupling, in particular for a supply line or a brake control line of a towing vehicle or a trailer. It is by all means possible, in addition to the features disclosed below, for further components and technical functions to be integrated into the coupling head, such as those for example explained for the prior art mentioned at the outset, e.g. stop valves or the like. The flow through the coupling head 1 in one direction is described below. This can constitute the only direction of the flow through the coupling head. However, it is also quite possible for the coupling head to be used with an opposing direction of flow, see also in particular the embodiments relating to this in DE 199 31 162 B4, wherein in this case the measures according to the invention with the redirection of the compressed air flow only take effect in one direction of flow or alternatively preferably by means of additional measures in both directions of flow.
The coupling head 1 according to FIG. 1 has a housing 2 which for the illustrated exemplary embodiment integrally forms a connection region 3 , a straight pneumatic line region 4 and a chamber 5 which has a longitudinal axis 6 . The longitudinal axis 6 is oriented transverse to the longitudinal axis 7 of the connection region 3 and the line 4 . The line 4 runs laterally into the chamber 5 . The chamber 5 only has one further opening 8 to the top and in the direction of the longitudinal axis 6 . Preferably, the housing is formed as a cast part.
For the exemplary embodiment illustrated in FIG. 1 , the upper half of the chamber 5 is formed with a cylindrical enveloping surface 9 . The chamber 5 tapers in a straight line with a truncated cone-shaped enveloping surface 10 to a base region 11 of the chamber 5 . A filter element 12 , here in the form of a filter insert 13 , is inserted into the chamber 5 .
The filter insert 13 can be of any design, for instance also corresponding to the filter insert with cage and screen according to DE 199 31 162 B4. The contour of the filter insert 13 is, for example, formed rotationally symmetrically to the longitudinal axis 6 . For the exemplary embodiment illustrated, the filter insert 13 has a truncated cone-shaped geometry and is supported on the base region 11 .
An elastomeric, elastic seal 14 is pressed from above onto the housing 2 and ensures a pneumatically tight connection between the seal 14 and the housing 2 in the region of the opening 8 . A guide element 15 can also be identified in FIG. 1 , like the one also described in DE 199 31 162 B4.
The seal 14 is formed in an L-shape in half-section, having one leg 16 oriented parallel to the longitudinal axis 6 and one leg 17 oriented transverse to the longitudinal axis 6 and extending outwards from the leg 16 . The leg 16 delimits a cylindrical inner wall which forms a guiding surface 18 for the compressed air flowing in. The guiding surface 18 is arranged inside the upper edge 19 of the filter insert 13 (radially inside with respect to the longitudinal axis 3 ). Preferably, the seal 14 abuts under elastic pretension in the direction of the longitudinal axis 6 on the edge 19 of the filter insert 13 , whereby the filter insert 13 is fixed in place at least in the direction of the longitudinal axis 6 . For the exemplary embodiment illustrated in FIG. 1 , the base region 11 is formed with an elevation which can fit into a corresponding depression in the filter insert 13 in a form-fit manner, whereby the filter insert 13 is also guided in lateral direction. In the chamber 5 , an interior space 20 of the filter insert is separated by the filter insert from a cross-over space 21 . The cross-over space 21 is delimited radially on the inner side by the filter insert 13 and radially on the outer side by the housing 2 with the enveloping surfaces 9 , 10 .
Compressed air flows guided through the guiding surface 18 in a guiding direction 22 into the interior space 20 and through the filter insert 13 to the cross-over space 21 , from which the compressed air reaches the line 4 .
In the region of an inner corner or edge of the seal 14 , the seal has a plurality of recesses 23 distributed over the circumference, each of which forms an undercut 24 of the guiding surface 18 ( FIG. 2 ). The undercuts 24 lead to by-pass openings 25 which are formed between the edge 19 of the filter insert 13 and the enveloping surface 9 or the seal 14 . The by-pass openings 25 run into by-pass channels 26 which run into the cross-over space 21 or are formed with it. (In the figures, the pluralities of recesses 23 , undercuts 24 , by-pass openings 25 and by-pass channels 26 are in some cases differentiated by supplementing letters a, b, c, d.)
In FIG. 1 , the arrows 27 , 28 illustrate that the compressed air reaches the cross-over space 21 and the line 4 from the guiding direction 22 via two alternative paths, namely,
on the one hand, through the filter insert 13 and, on the other hand, by bypassing the filter insert 13 through the by-pass openings 25 and the by-pass channels 26 .
The redirection which must be present so that compressed air can enter from the guiding direction 22 through the by-pass opening 25 into the by-pass channel 26 is illustrated in FIG. 2 with the arrows. Firstly, the flow is redirected away from the longitudinal axis 6 in a redirection region 31 downstream from a flow region 29 . Before reaching a turning region 30 due to the redirection a flow component directed radially outwards increases in size. By contrast, downstream from the turning region 30 as far as a flow region 32 , a redirection occurs in the opposite direction in a counter redirection region 33 . Here, the flow component is directed radially outwards decreasing in size. The flow is hence guided “around the corner” with the result that contaminants contained in the compressed air do not follow the flow path of the compressed air outlined in FIG. 2 with the redirection region 31 and the counter redirection region 33 , but rather enter the interior space 20 of the filter insert 13 where these can be deposited. It is to be understood that the flow path outlined in FIG. 2 is only an exemplary illustration. Other flow paths are also possible without altering the design, for which, for example, the compressed air first enters the interior space of the filter insert 13 and the redirection only then takes place in such a way that the compressed air exits again from the interior space 20 and reaches the by-pass channel 26 via the by-pass opening 25 . It can be identified in FIG. 2 that the redirection in the redirection region 31 does not occur by means of a physical guiding contour but rather by pneumatic forces.
For the exemplary embodiment illustrated in FIGS. 1 and 2 , the recesses 23 have a rectangular or square cross-section, wherein the height of the recesses decreases in radial outward direction. E.g. the recess 23 d is in the detail section according to FIG. 2 formed in the fashion of a chamfer 34 . Away from the recesses 23 , the seal 16 abuts on the edge 19 of the filter insert 13 under pretension.
For the following exemplary embodiments, components and their design features are identified by the same reference numerals as those used in FIGS. 1 and 2 , provided that these in terms of their design and/or function at least partly correspond or are comparable to the components and design features denoted with this reference numeral according to FIGS. 1 and 2 .
The embodiment according to FIG. 3 substantially corresponds to the embodiment according to FIGS. 1 and 2 . However, here the housing 2 has at least one recess 35 in the upper end region of the enveloping surface 9 . It is also possible that one single continuous recess 35 as a kind of annular groove is built in the enveloping surface 9 . Alternatively, a plurality of recesses 35 can be provided at circumferential positions which correspond to the circumferential positions of the recesses 23 . In this case, the undercuts 24 are formed jointly by the recesses 23 of the seal 14 and the at least one recess 35 of the housing. Accordingly, the recesses 35 can form the by-pass channel 26 and the by-pass opening 25 . As illustrated in FIG. 3 , in this case the edge 19 of the filter insert 13 can have an outer diameter which (with a transition fit) can correspond to the diameter of the enveloping surface 9 , without this resulting in the compressed air not being able to laterally flow past the filter insert 13 . It is, however, also possible for a recess 25 to be provided in the enveloping surface 9 , if the dimensions of the enveloping surface 9 , on the one hand, and of the edge 19 of the filter insert 13 are chosen according to FIG. 1 , whereby then the restriction effect of the by-pass opening 25 and the by-pass channel 26 can be reduced, provided that this is desired.
According to the exemplary embodiment illustrated in FIGS. 4 and 5 , the housing 2 of the coupling head 1 is substantially formed corresponding to FIG. 3 . Here, the enveloping surface 9 is also provided with a, for example, circumferential recess 35 . Here, however, the seal 16 is not provided with recesses 23 according to the previous figures. Instead, the seal 16 has a circumferential, annular projection 36 which extends with an extension 37 into the interior space 20 of the filter insert 13 and thereby extends the guiding surface 18 into the interior space 20 of the filter insert 13 . An annular channel 38 is formed lying radially outside the projection 36 . The annular channel 38 is defined by the outer circumference of the projection 36 and the filter insert 13 . The annular channel 38 runs into an annular groove 39 introduced into the leg 17 of the seal 14 , via which the annular channel 38 is pneumatically connected to the recess 35 . For the exemplary embodiment according to FIG. 4 , the guiding surface 18 is a (truncated) cone shape tapering in the direction of the filter insert 13 , wherein preferably the opening angle of the guiding surface 18 corresponds to the opening angle of the filter insert 13 .
FIG. 5 shows the division of the flow of, on the one hand, compressed air with contaminants as per arrow 28 and, on the other hand, compressed air with a reduced proportion of contaminants as per arrow 27 . Here a redirection occurs from the flow region 29 via the redirection region 31 to the turning region 30 and the counter redirection region 33 to the flow region 32 . Put simply, the redirection can take place according to FIG. 5 in the form of a “horizontal S”.
FIGS. 6 and 7 show an embodiment, in which the housing 2 , corresponding to the embodiments according to FIGS. 3 and 4 , is provided with a preferably annular recess 35 . The seal 14 is formed differently here: As can be identified in FIG. 8 , an elastic guiding or passing element 41 extends transverse to the inlet channel 40 . The guiding and passing element 41 is integrally formed by the seal 14 . Here, the guiding or passing element 41 is formed with eight circular segments 41 , which have axes oriented radially to the longitudinal axis 6 and which sit as close as possible to one another with their lateral edges. With a flat alignment of the circular segments 42 according to FIG. 8 , which corresponds to the unpressurised state of the inlet channel 40 , a certain closing function, for example against the entry of contaminants without further compressed air flow, is provided. With the application of compressed air, the circular segments 42 are bent in the direction of flow, as illustrated in FIG. 7 , so that compressed air can enter the interior space 20 of the filter insert 13 . According to the degree of bending of the circular segments 42 , these more or less in the shape of a cone concentrate the compressed air flow in the direction of the longitudinal axis 6 . On the other hand, with an increased degree of bending the circular segments 42 enter the interior space 20 of the filter insert 13 , similar to the projection 36 according to the exemplary embodiment illustrated in FIG. 4 , so that the flow can only reach the by-pass opening 25 and the by-pass channel 26 with a redirection according to FIG. 5 . Accordingly, for this embodiment the required redirection depends on the extent of the bending of the circular segments 42 . In addition, as illustrated in FIG. 7 , with the bending of the circular segments 42 gaps 43 can form between adjacent circular segments 42 , through which the compressed air with an altered redirection can cross over to the by-pass opening 25 and the by-pass channel 26 . While the annular groove 39 in the seal 14 according to FIG. 4 has an approximately rectangular cross-section, FIG. 7 shows an annular groove 39 with a triangular cross-section, wherein the corner responsible for the redirection is rounded, which can automatically result from the bending line of the ring segments 42 . The seal 14 can be provided with ribs 44 which can be pressed from above onto the edge 19 of the filter insert 13 for the purpose of fixing them in place. In FIG. 7 , in the left half plane the circular segments 42 are illustrated being flowed through and bent, while those in the right half plane are illustrated with no flow through and unbent.
In the exemplary embodiment illustrated in FIGS. 9 and 10 , the function of the seal 14 which is emphasised here is designed corresponding to the exemplary embodiment according to FIGS. 6 to 8 , but with the difference that the guiding or passing element 42 in this case is formed with ring segments 45 . The ring segments 45 radially on the inner side and also without elastic bending delimit a circular, permanently open opening cross-section 46 . While for the previous exemplary embodiments the guide element 15 was fitted or pressed from above onto the leg 17 of the seal 14 , for the exemplary embodiment according to FIG. 9 a ring-shaped connection region 47 is accommodated and held in an annular groove 48 of the enveloping surface 49 of the seal 14 . This represents a form of the seal 14 and of the connection with the guide element 15 as is in particular employed in the USA.
FIG. 11 shows an exemplary embodiment, in which the guide element 15 is integrally formed with the housing 2 . In order to accommodate the seal 14 , the housing 2 here has an undercut 50 in a form of a circumferential groove which can, for example, be manufactured by machining. When being fitted, preferably the seal 14 is inserted by elastic deformation with the leg 17 into the undercut 50 . In addition, it can be identified in FIG. 11 that the recess 35 of the housing does not have to be circumferentially formed for the purpose of forming the by-pass 51 . Instead, a plurality of recesses 35 a , 35 b , etc. distributed over the circumference is used here.
Preferably, the diameters of the filter insert 13 are dimensioned in such a way that with a regularly occurring exchange of the seal 14 the filter insert 13 is arranged unfixed in the chamber 5 and can be taken out without difficulty for cleaning or replacement. A seal change of this kind can take place without further components of the coupling head 1 other than the guide element 15 and/or the seal 14 having to be disassembled.
A by-pass 51 is formed with the recesses 23 , undercuts 24 , chambers 34 , by-pass channels 26 , by-pass openings 25 , recesses 35 and/or a section of the cross-over space 21 . The contaminants in the compressed air can be of any kind, for example in the form of particles, dirt, drops or vapour. The edge 19 of the filter insert 13 forms a separating element for dividing the compressed air flows into a first flow in the direction of the filter element 12 , on the one hand, and into a second flow through the by-pass 51 , on the other hand. Here, the edge 19 delimits radially on the inner side the by-pass opening(s).
It is understood that the present invention can also comprise embodiments with other redirections of the compressed air to eliminate the contaminants, wherein a repeated redirection back and forth can also take place, and wherein labyrinthine guiding of the compressed air can also take place. Here, the redirection to isolate contaminants can take place upstream from the by-pass opening, i.e. outside the by-pass itself, and/or inside the by-pass.
For the illustrated exemplary embodiments, the at least one by-pass 51 or the at least one by-pass channel 26 is formed with a recess or undercut 24 of the seal 14 and/or of the housing 2 , while the filter insert 13 has a circumferential edge 19 which delimits the by-pass 51 or by-pass channel 26 . It is quite possible for the at least one by-pass channel 26 or at least one by-pass 51 to be formed by the filter element 12 or the filter insert 13 , without the seal 14 and/or the housing 2 having a recess or undercut for this purpose. To simply name an example, depressions oriented in the axial direction can be formed in the edge 19 of the filter insert 13 to form the by-pass 51 . It is also possible for radial recesses, holes or the like to be provided in the upper end region of the filter insert 13
Many variations and modifications may be made to the preferred embodiments of the invention without departing substantially from the spirit and principles of the invention. All such modifications and variations are intended to be included herein within the scope of the present invention, as defined by the following claims. | The present invention relates to a coupling head for coupling a towing vehicle to a trailer.
According to the invention, in the coupling head a filter element is used. The filter element is bypassed by a continuously open by-pass. Preferably, the path through the by-pass has at least one redirection in the region of an undercut. As a result of the redirection, contaminants in the compressed air are not or not fully transferred through the by-pass. The by-pass might also ensure a supply of compressed air to the trailer, for example, when the filter element is at least partly blocked due to the contaminants. According to the invention, a valve element used to open the by-pass in the case of increasing blockage of the filter element is not required. | 1 |
This application is a continuation, of application Ser. No. 07/738,517 filed Jul. 31, 1991, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention describes an efficient method for assaying nucleic acids employing fluorescence.
2. Related Art
In medical and biological fields, a DNA or RNA probe complexed with a radioactive isotope has been employed as a means of detecting nucleic acids. This technique comprises hybridizing the labeled probe with a target nucleic acid, followed by detecting the target nucleic acid by autoradiography. This isotope method has numerous drawbacks which are serious obstacles to the application and development of this technology. The drawbacks of the isotope method are as follows:
(a) The nucleic acid hybridization method lacks spatial resolution sufficient to reveal the relative positional relationship between contiguous signals.
(b) Experimental procedures using isotope can only be performed in isotope laboratories equipped with special facilities. This hinders the application of the hybridization method, particularly for clinical applications.
(c) Use of isotope is dangerous for laboratory workers even under controlled laboratory conditions. In addition, a danger for non-laboratory workers also exists because of radioactive wastes.
(d) An extended period (several weeks to several months) may be required for detection, such that application to rapid clinical diagnosis is difficult.
(e) Radioactivity decays with a definite half-life period. Accordingly, experiments must be scheduled around a purchase date of isotope. If the schedule chart is slightly altered, there is a danger of wasting isotope or experimental results on a large scale.
(f) To enhance detection sensitivity, significant quantities of radioactivity must be incorporated in a nucleic acid probe. However, this highly radioactive nucleic acid is unstable and easily suffers from radioactive disintegration.
(g) In general, isotope is extremely expensive. This prevents general use of the hybridization method.
In view of such drawbacks, DNA or RNA labeling methods in place of employing radioactive isotope have been developed. For example, BLU GENE KIT™, commercially available from Bethesda Research Laboratories Inc. (BRL Inc.), is known. Additionally, "Nucleic Acid Probe And Use Thereof" is disclosed in Japanese Patent Application Laid-Open No. 60-226888.
However, these techniques do not eliminate all of the drawbacks described above. In particular, detection sensitivity is not comparable to that of the isotope method. In the above labeling, the detection sensitivity is "10 -12 g DNA," slightly inferior to the "10 -13 g DNA" of the isotope method.
An object of the present invention is to provide a method for assaying nucleic acids which eliminates the drawbacks of the isotope method and which also provides excellent detection sensitivity.
SUMMARY OF THE INVENTION
The present invention provides a method for assaying nucleic acids or similar compounds comprising binding phosphatase to a sample (e.g. nucleic acids), reacting the phosphatase with 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate, irradiating the reaction products with an excited light, and detecting the fluorescence emitting therefrom.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows the test results obtained in Example 1.
FIG. 2 shows the test results obtained in Example 1.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It is preferable in the present invention to employ a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate to which a phosphatase is bound. Examples of phosphatases include alkali phosphatase and acid phosphatase.
Sample compounds which can be detected by the method of the present invention comprise nucleic acid (DNA or RNA), protein, and immunological detection of a chemical compound using antibody.
An example of a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate includes the basic skeleton shown by Formula (I). ##STR1##
In the assay method according to the present invention, a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate is reacted with a phosphatase, followed by irradiation with an excited light, whereby the dephosphating product of the 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate emits fluorescence. The emitted fluorescence can then be detected.
The 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate is reacted with a phosphatase combined with a sample (e.g. nucleic acids) on a membrane filter made of nylon. This produces a dephosphating product of the 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate, which adheres to the nylon membrane filter and displays fluorescence. The fluorescence and the pattern thereof (spots, and bands produced by electrophoresis) are then detected by irradiation with an excited light.
In the present invention, intense fluorescence can be obtained by employing a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate to improve detection sensitivity; for example, 3×10 -14 g (0.03 pg) of DNA is detectable. No isotope is used in this method, and therefore, the drawbacks of the prior art are eliminated.
Thus, a method for assaying nucleic acids or similar compounds which provides excellent detection sensitivity is described. Further, the present invention provides the dephosphating product of a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate in a high yield.
EXAMPLES
Example 1
To verify the effectiveness of a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate as a probe for nucleic acids, the DNA Labeling and Detection Kit of Boehringer Mannheim and 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate were used to detect DNA on a nylon membrane filter.
DNA was labeled with digoxigenin (Dig), diluted, and spotted on the nylon membrane filter. Each of the spots included 50 ng (50×10 -9 g) DNA of herring spermatozoa. 0.08 to 25 pg of Dig-labeled DNA was employed. The results are shown in FIG. 1. 0 pg in the Figure represents a blank test. Reference numeral 1 designates a carrier filter for a specimen of nucleic acids, and reference numeral 11 designates fluorescence sensitized portions. "+" represents detection of DNA; "±" represents that DNA cannot distinctly be detected; and "-" represents that DNA cannot be detected. The results shown in FIG. 1 demonstrate that DNA could satisfactorily be detected in 0.08 pg of sample.
Using a smaller amount of DNA, a second experiment was conducted on 0.015 to 0.25 pg of Dig-labeled DNA in the same manner as described above. The test results are shown in FIG. 2. Satisfactory detection was obtained in a 0.03 pg (30 fg) sample.
In the first experiment, a conventional color development detection using azo-color, Fast Blue BB™ (of POLYSCIENCE, INC.) was employed. The detectable spot included 0.5 pg (0.5×10 -12 g) of DNA.
Example 2
A 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate was produced by the following processes.
According to the description of Enzyme Histochemistry, 5 g (0.027 mol) of 2-hydroxy-3-naphthoic acid, 40 ml of dehydrated xylene, and 0.023 mol of 3,5-dimethyl aniline were stirred in a 100 ml NASU flask provided with a Graham condenser at 80° C. for 10 minutes. 0.01 mol of phosphorous trichloride was then added to the flask and the resultant mixture was refluxed for 2 hours. Thereafter, the reaction solution was decanted in the hot state to skim the supernatant fluid. After cooling the fluid at 4° C., the fluid was filtered, and the precipitates thus obtained were eluted with xylene and then water. The precipitates were then neutralized with a 2% aqueous solution of sodium carbonate, and xylene was removed from the precipitates by boiling.
The precipitates were brought to pH 9 with a 2% aqueous solution of sodium carbonate, filtered, and cooled. The precipitates thus obtained were eluted with water and added to a 3% HCl solution, heated, filtered, and cooled. The precipitates were then washed with hot water and dried.
Next, the precipitates were recrystalized to produce 3-hydroxy-2-naphthoic acid-2'-biphenyl anilide, shown by the following formula (II). ##STR2##
1 g of this naphthol AS derivative was dissolved in 8 ml of pylidine. After stirring this solution at 0° C. for 30 minutes, phosphorus oxychloride (2.5 eg), cooled similarly, was added and stirred at 0° C. for 4 hours. Ice was then added to the solution to terminate the reaction.
The reaction product obtained was purified on a reverse phase silica gel column, followed by purification on a normal phase silica gel column, to produce 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate, shown by the following formula (III). ##STR3## | A method for assaying nucleic acids or similar compounds comprises binding a sample such as a nucleic acid to phosphatase; reacting the phosphatase with a 3-hydroxy-2-naphthoic acid-2'-phenyl anilide phosphate; irradiating the reaction product with an excited light; and detecting fluorescence emitted therefrom. | 2 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an exercise bike, and more particularly to an exercise bike which provides multiple track modes.
[0003] 2. Description of Related Art
[0004] A conventional exercise bike includes a main body having a transmission mechanism mounted in a parallel part thereof, a unidirectional swing arm clutch mounted thereon for controlling a rotation of a wheel, and a damping generator mounted thereon. A four-connection rod mechanism is operated with the transmission mechanism. A spring-restored mechanism is operated with the four-connection rod mechanism. The main body has a handlebar disposed on a vertical part thereof and an operational panel mounted on the vertical part thereof, and a liquid crystal display screen disposed on the panel thereof. The wheel is rotated by a connection of pedals, gears, one-way bearings and connection rods. An idle damping is provided for adjusting a tension of the wheel for providing different users.
[0005] The conventional exercise bike only provides a single exercise mode. A user feels boring, tired in the single exercise mode after long time using, such that the exercise effect will be decreased.
[0006] The present invention has arisen to mitigate and/or obviate the disadvantages of the conventional exercise bike.
SUMMARY OF THE INVENTION
[0007] The main objective of the present invention is to provide an improved exercise bike, and more particular to a multi-mode exercise bike.
[0008] To achieve the objective, the multi-mode exercise bike in accordance with the present invention includes a main body. The main body has two supporting arm assemblies symmetrically mounted on two sides thereof. Each supporting arm assembly comprises a first arm having one end pivotally connected with the main body, a second arm having one end pivotally connected with the main body, a third arm having one end pivotally connected with the other end of the first arm, and a fourth arm having one end pivotally connected with the other end of the third arm and the other end pivotally connected with the other end of the second arm. The first arm has a first jointer located between the main body and the first arm. The second arm has a second jointer located between the main body and the second arm. The second arm and the first arm are arranged in a crisscross manner without directly contacting to each other. The second jointer positioned lower than the first jointer. The third arm has a third jointer located between the third arm and the first arm. The third arm has a pedal mounted thereon. The fourth arm has a fourth jointer located between the third arm and the fourth arm. The fourth jointer is positioned adjacent to the pedal of third arm. A fifth jointer is located between the fourth arm and the second arm. The main body has a guiding wheel set mounted thereon for guiding the second arm swinging as a pivot of the second jointer. The guiding wheel set includes a rotating disc and two connecting rods respectively connected with two sides of the rotating disc. The two connecting rods are respectively connected with the two supporting arm assemblies. Each connecting rod has one end eccentrically pivotally connected with the rotating disc and the other end pivotally connected with a middle section of the second arm located between the second jointer and the fifth jointer.
[0009] Further, each first arm has a connector extending from the first jointer. The main body has a second guiding wheel set mounted therein for guiding the first arm reciprocatingly swinging as the pivot of the first jointer. The second guiding wheel set includes a second rotating disc and two second connecting rods respectively connected with two sides of the second rotating disc. Each second connecting rod has one end eccentrically pivotally connected with the second rotating disc and the other end pivotally connected with the connector.
[0010] Further, the main body has two set of damping mechanisms respectively relatively connected with the guiding wheel set and the second guiding wheel set. Each damping mechanism has a idle wheel connected with the rotating disc/second rotating disc and a magnet unit mounted on the idle wheel for controlling a damping force of the idle wheel.
[0011] Further, the first arm has a handle extending from the first jointer. The handle is pivotable as the pivot of the first jointer.
[0012] Further, the two pedals of the two third arms are faced to each other.
[0013] Further benefits and advantages of the present invention will become apparent after a careful reading of the detailed description with appropriate reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a perspective view of a multi-mode exercise bike in accordance with the present invention;
[0015] FIG. 2 is a perspective view of the multi-mode exercise bike in accordance with the present invention in another direction;
[0016] FIG. 3 is a side plan view of the multi-mode exercise bike in accordance with the present invention;
[0017] FIG. 4 is an operational view of the multi-mode exercise bike in accordance with the present invention in a vertical exercise mode;
[0018] FIG. 5 is an operational view of the multi-mode exercise bike in accordance with the present invention in a parallel exercise mode; and
[0019] FIG. 6 is an operational view of the multi-mode exercise bike in accordance with the present invention in a circular exercise mode.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Referring to the drawings and initially to FIGS. 1-6 , a multi-mode exercise bike in accordance with the present invention comprises a main body 1 . The main body 1 has two supporting arm assemblies 2 symmetrically mounted on two sides thereof. Each supporting arm assembly 2 comprises a first arm 21 having one end pivotally connected with the main body 1 , a second arm 22 having one end pivotally connected with the main body 1 , a third arm 23 having one end pivotally connected with the other end of the first arm 21 , and a fourth arm 24 having one end pivotally connected with the other end of the third arm 23 and the other end pivotally connected with the other end of the second arm 22 .
[0021] The first arm 21 has a first jointer 31 located between the main body 1 and the first arm 21 .
[0022] The second arm 22 has a second jointer 32 located between the main body 1 and the second arm 22 . The second arm 22 and the first arm 21 are arranged in a crisscross manner without directly contacting to each other. The second jointer 32 positioned lower than the first jointer 31 .
[0023] The third arm 23 has a third jointer 33 located between the third arm 23 and the first arm 21 . The third arm 23 has a pedal 231 mounted thereon.
[0024] The fourth arm 24 has a fourth jointer 34 located between the third arm 23 and the fourth arm 24 . The fourth jointer 34 is positioned adjacent to the pedal 231 of third arm 23 . A fifth jointer 35 is located between the fourth arm 24 and the second arm 22 .
[0025] The main body 1 has a guiding wheel set 11 mounted thereon for guiding the second arm 22 swinging as a pivot of the second jointer 32 . The guiding wheel set 11 includes a rotating disc 111 and two connecting rods 112 respectively connected with two sides of the rotating disc 111 . The two connecting rods 112 are respectively connected with the two supporting arm assemblies 2 . Each connecting rod 112 has one end eccentrically pivotally connected with the rotating disc 111 and the other end pivotally connected with a middle section of the second arm 22 located between the second jointer 32 and the fifth jointer 35 .
[0026] Referring to FIG. 4 , when a user alternatively steps on the pedals 231 along a vertical direction, the guiding wheel set 11 guides the second arm 22 reciprocatingly swinging up and down as the pivot of the second jointer 32 . The fourth arm 24 pivotally pulls the third arm 23 such that the third arm 23 is swung up and down as the pivot of the third jointer 33 .
[0027] Referring to FIG. 5 , when the user alternatively steps on the pedals 231 along a parallel direction, the third arm 23 is suspended on the first arm 21 and the fourth arm 24 such that the third arm 23 is swung along the parallel direction as the pivots of the first jointer 31 and the fifth jointer 34 .
[0028] Referring FIG. 6 , when the user alternatively steps on the pedals 231 along a circular direction, the guiding wheel set 11 guides the second arm 22 reciprocatingly swinging up and down as the pivot of the second jointer 32 such that the third arm 23 is able to be swung up and down. The third arm 23 is also suspensibly swung along the parallel direction as the pivots of the first jointer 31 and the fifth jointer 35 such that the fifth jointer 35 and the third jointer 33 are moved to-and-fro relative to each other to form a circular track of the pedal 231 .
[0029] Further description as the following, each first arm 21 has a connector 211 extending from the first jointer 31 . The main body 1 has a second guiding wheel set 12 mounted therein for guiding the first arm 21 reciprocatingly swinging as the pivot of the first jointer 31 . The second guiding wheel set 12 includes a second rotating disc 12 and two second connecting rods 122 respectively connected with two sides of the second rotating disc 121 . Each second connecting rod 122 has one end eccentrically pivotally connected with the second rotating disc 121 and the other end pivotally connected with the connector 211 .
[0030] Referring to FIGS. 1-2 , the rotating disc 111 and the second rotating disc 121 respectively have a extender A and a extender B radially extending therefrom. Each of the extender A and the extender B is pivotally connected with connecting rod 112 and the second connecting rod 122 . The extenders A and B are increased a width of the rotating disc 111 and a width of the second rotating disc 121 .
[0031] Further, the main body 1 has two set of damping mechanisms 13 respectively relatively connected with the guiding wheel set 11 and the second guiding wheel set 12 . Each damping mechanism 13 has a idle wheel 131 connected with the rotating disc 111 /second rotating disc 121 and a magnet unit 132 mounted on the idle wheel 131 for controlling a damping force of the idle wheel 131 .
[0032] Further, the first arm 21 has a handle 212 extending from the first jointer 31 . The handle 212 is pivotable as the pivot of the first jointer 31 .
[0033] Further, the two pedals 231 of the two third arms 23 are faced to each other.
[0034] The multi-mode exercise bike in accordance with the present invention is depended on the user's force for providing a vertical directional mode, a parallel directional mode, and a circular directional mode. The three modes are related to human foot. The user can change various exercise modes to prevent from a long time single exercise mode bringing unexciting and tired felling.
[0035] Although the invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention as hereinafter claimed. | A tool with quick pop-up tool head includes a body. The body has a handle, a telescopic portion telescopically mounted in the handle, and an operational portion mounted on the telescopic portion such that the operational portion is able to telescopically move relative to the handle. The operational portion has a shoulder disposed on an interior thereof. The telescopic portion has a tool head means mounted therein. The tool head means is selectively engaged with the shoulder and is extendable from the telescopic portion. | 0 |
This application is a continuation of U.S. application Ser. No. 12/762,051, filed on Apr. 16, 2010, now published, which is a continuation of U.S. application Ser. No. 11/416,460, filed on May 1, 2006, now abandoned, which is a continuation of U.S. application Ser. No. 10/026,925, filed on Dec. 18, 2001, now abandoned, which claims the benefit under 35 USC §120 of U.S. provisional application 60/256,380, filed Dec. 18, 2000 the entire content of each of which is herein incorporated by reference. The provisional application and the Tables attached to it are specifically incorporated by reference herein.
The present invention relates to focused libraries of genetic packages that each display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The focused diversity of the libraries of this invention comprises both sequence diversity and length diversity. In a preferred embodiment, the focused diversity of the libraries of this invention is biased toward the natural diversity of the selected family. In more preferred embodiment, the libraries are biased toward the natural diversity of human antibodies and are characterized by variegation in their heavy chain and light chain complementarity determining regions (“CDRs”).
The present invention further relates to vectors and genetic packages (e.g., cells, spores or viruses) for displaying, or displaying and expressing a focused diverse family of peptides, polypeptides or proteins. In a preferred embodiment the genetic packages are filamentous phage or phagemids or yeast. Again, the focused diversity of the family comprises diversity in sequence and diversity in length.
The present invention further relates to methods of screening the focused libraries of the invention and to the peptides, polypeptides and proteins identified by such screening.
BACKGROUND OF THE INVENTION
It is now common practice in the art to prepare libraries of genetic packages that individually display, display and express, or comprise a member of a diverse family of peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the amino acid diversity of the family. In many common libraries, the peptides, polypeptides or proteins are related to antibodies (e.g., single chain Fv (scFv), Fv, Fab, whole antibodies or minibodies (i.e., dimers that consist of V H linked to V L )). Often, they comprise one or more of the CDRs and framework regions of the heavy and light chains of human antibodies.
Peptide, polypeptide or protein libraries have been produced in several ways in the prior art. See e.g., Knappik et al., J. Mol. Biol., 296, pp. 57-86 (20004, which is incorporated herein by references. One method is to capture the diversity of native donors, either naive or immunized. Another way is to generate libraries having synthetic diversity. A third method is combination of the first two. Typically, the diversity produced by these methods is limited to sequence diversity, i.e., each member of the library differs from the other members of the family by having different amino acids or variegation at a given position in the peptide, polypeptide or protein chain. Naturally diverse peptides, polypeptides or proteins, however, are not limited to diversity only in their amino acid sequences. For example, human antibodies are not limited to sequence diversity in their amino acids, they are also diverse in the lengths of their amino acid chains.
For antibodies, diversity in length occurs, for example, during variable region rearrangements. See e.g., Corbett et al., J. Mol. Biol., 270, pp. 587-97 (1997). The joining of V genes to J genes, for example, results in the inclusion of a recognizable D segment in CDR3 in about half of the heavy chain antibody sequences, thus creating regions encoding varying lengths of amino-acids. The following also may occur during joining of antibody gene segments: (i) the end of the V gene may have zero to several base deleted or changed; (ii) the end of the D segment may have zero to many bases removed or changed; (iii) a number of random bases may be inserted between V and D or between D and J; and (iv) the 5′ end of J may be edited to remove or to change several bases. These rearrangements result in antibodies that are diverse both in amino acid sequence and in length.
Libraries that contain only amino acid sequence diversity are, thus disadvantaged in that they do not reflect the natural diversity of the peptide, polypeptide or protein that the library is intended to mimic. Further, diversity in length may be important to the ultimate functioning of the protein, peptide or polypeptide. For example, with regard to a library comprising antibody regions, many of the peptides, polypeptides, proteins displayed, displayed and expressed, or comprised by the genetic packages of the library may not fold properly or their binding to an antigen may be disadvantaged, if diversity both in sequence and length are not represented in the library.
An additional disadvantage of prior art libraries of genetic packages that display, display and express, or comprise peptides, polypeptides and proteins is that they are not focused on those members that are based on natural occurring diversity and thus on members that are most likely to be functional. Rather, the prior art libraries, typically, attempt to include as much diversity or variegation at every amino acid residue as possible. This makes library construction time-consuming and less efficient than possible. The large number of members that are produced by trying to capture complete diversity also makes screening more cumbersome than it needs to be This is particularly true given that many members of the library will not be functional.
SUMMARY OF THE INVENTION
One objective of this invention is focused libraries of vectors or genetic packages that encode members of a diverse family of peptides, polypeptides or proteins wherein the libraries encode populations that are diverse in both length and sequence. The diverse length comprising components contain motifs that are likely to fold and function in the context of the parental peptide, polypeptide or protein.
Another object of this invention is focused libraries of genetic packages that display, display and express, or comprise a member of a diverse family of peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. These libraries are diverse not only in their amino acid sequences, but also in their lengths. And, their diversity is focused so as to more closely mimic or take into account the naturally-occurring diversity of the specific family that the library represents.
Another object of this invention is diverse, but focused, populations of DNA sequences encoding peptides, polypeptides or proteins suitable for display or display and expression using genetic packages (such as phage or phagemids) or other regimens that allow selection of specific binding components of a library.
A further object of this invention is focused libraries comprising the CDRs of human antibodies that are diverse in both their amino acid sequence and in their length (examples of such libraries include libraries of single chain Fv(scFv), Fv, Fab, whole antibodies or minibodies (i.e., dimers that consist of V H linked to V L ). Such regions may be from the heavy or light chains or both and may include one or, more of the CDRs of those chains. More preferably, they diversity or variegation occurs in all of the heavy chain and light chain CDRs.
It is another object of this invention to provide methods of making and screening the above libraries and the peptides, polypeptides and proteins obtained in such screening.
Among the preferred embodiments of this invention are the following:
1. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR1 selected from the group consisting of:
(1) <1> 1 Y 2 <1> 3 M 4 <1> 5 (SEQ ID NO:100), wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; (2) (S/T) 1 (S/G/X) 2 (S/G/X) 3 Y 4 Y 5 W 6 (S/G/X) 7 (SEQ ID NO:101) wherein (S/T) is a 1:1 mixture of S and T residues, (S/G/X) is a mixture of 0.2025 S, 0.2025 G and 0.035 of each of amino acid residues A, D, E, F, H, I, K, L, H, N, P, Q, R, T, V, W, and Y; (3) V 1 S 2 G 3 G 4 S 5 I 6 S 7 <1><1> < 1> 10 Y 11 Y 12 W 13 <1> 14 (SEQ ID NO:1), wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; and (4) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio: HC CDR1s (1):(2):(3)::0.80:0.17:0.02.
2. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express or comprise at least a portion of the diversity of the antibody facility, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR2 selected from the group consisting of:
(1) <2>I<2><3>SGG<1>T<1>YADSVKG (SEQ ID NO:2), wherein <1> is an equimolar mixture of each of amino acid residues 2 1 1, 0, E, F, G, H, I, K, L, M, N, P, 0, P, S, T, V, W, and Y; <2> is an equimolar mixture of each of amino acid residues Y, R, W, V, G, and S; and <3> is an equimolar mixture of each of amino acid residues P, S, and G or an equimolar mixture of P and S; (2) <1>I<4><1><1><G><5><1><1><1>YADSVKG (SEQ ID NO:3), wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; <4> is an equimolar mixture of residues D, I, N, S, W, Y; and <5> is an equimolar mixture of residues S, G, D and N; (3) <1>I<4><1><1>G<5><1><1>YNPSLKG (SEQ ID NO:4), wherein <1> is an equimolar mixture of each of amino acid residues A, D, E, F, G, H, I, K, L, M, N; P, Q, R, S, T, V, W and Y, and <4> and <5> are as defined above; (4) <1>I<8>S<1><1><1>GGYY<1>YAASVKG (SEQ ID NO:5), wherein <1> is an equimolar mixture of each amino acid residues A, D, E, F, Gill, I, K, L, M, N, P, Q, R, S, T, V, and Y; <8> is 0.27 R and 0.027 of each of ADEFGHIKLMNPQSTVWY; and (5) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio: HC CDR2s: (1)/(2) (equimolar): (3):(4)::0.54:0.43:0.03.
3. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a heavy chain CDR3 was selected from the group consisting of:
(1) YYCA21111YFDYWG (SEQ ID NO:6), Wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (2) YYCA2111111YFDYWG (SEQ ID NO:7), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (3) YYCA211111111YFDAYTG (SEQ ID NO:8), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, 1, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (4) YYCAR111S2S3111YFDYWG (SEQ ID NO:9), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of Y and W; (5) YYCA2111CSG11CY1YFDYWG (SEQ ID NO:10), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R; (6) YYCA211S1TIFG11111YFDYWG (SEQ ID NO:11), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; and 2 is an equimolar mixture of K and R. (7) YYCAR111YY2S3344111YFDYWG (SEQ ID NO:12), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of D and S; and 3 is an equimolar mixture of S and G; (8) YYCAR1111YC2231CY111YFDYWG (SEQ ID NO:13), wherein 1 is an equimolar mixture of each amino acid residues A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y; 2 is an equimolar mixture of S and G; and 3 is an equimolar mixture of T, D and G; and (9) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture: (1) 0.10 (2) 0.14 (3) 0.25 (4) 0.13 (5) 0.13 (6) 0.11 (7) 0.04 and (8) 0.10; and more preferably the HC CDR3s (1) through (8) are in the following proportions in the mixture: (1) 0.02 (2) 0.14 (3) 0.25 (4) 0.14 (5) 0.14 (6) 0.12 (7) 0.08 and (8) 0.11.
Preferably, 1 in one or all of HC CDR3s (1) through (8) is 0.095 of each of G and Y and 0.048 of each of A, D, E, F H, 1, K, L, M, N, P, Q, R, S, T, V, and W.
4. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encodes a kappa light chain CDR1 selected from the group consisting of:
(1) RASQ<1>V<2><2><3>LA (SEQ ID NO:14)
(2) RASQ<1>V<2><2><2><3>LA (SEQ ID NO:15); wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <3> is 0.2Y and 0.044 each of ADEFGHIKLMNPQRTVW and S; and
(3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDR1s (1):(2)::0.68:0.32.
5. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the-antibody family the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light-chain CDR2 having the sequence:
<1>AS<2>R<4><1> (SEQ ID NO:102), wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY; and <4> is 0.2.A and 0.044 each of DEFGHIKLMNPQRSTVWY.
6. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a kappa light chain CDR3 selected from the groups consisting of:
(1) QQ<3><1><1><1>P<1>T (SEQ ID NO:16), wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <3> is 0.2 Y and 0.044 each of ADEFGHIKIMNPQRTVW; (2) QQ33111P (SEQ ID NO:103), wherein 1 and 3 are as defined in (1) above; (3) QQ3211PP1T (SEQ ID NO:17), wherein 1 and 3 are as defined in (1) above and 2 is 0.2 S and 0.044 each of ADEFGHIKLMNPQRTVWY; and (4) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDA3s (1):(2):(3)::0.65:0.1:0.25.
7. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR1 selected from the group consisting of:
(1) TG<1>SS<2>VG<1><3><2><3>VS(SEQ ID NO:18), wherein <1> is 0.27 T, 0.27 G and 0.027 each of ADEFRIKLMNPQRSVWY: <2> is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY, and <3> is 0.36 Y and 0.036 each of ADEFGHIKLMNPQRSTVW; (2) G<2><4>L<4><4><4><3><4><4> (SEQ ID NO:104), wherein <2> is as defined in (1) above and <4> is an equimolar mixture of amino acid residues ADEFGHIKIMNPQRSTVWY; and (3) mixtures of vectors or genetic packages 5 characterized by any of the above DNA sequences, preferably in the ratio CDR1 (1):(2)::0.67:0.33;
8. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR2 has the sequence:
<4><4><4><2>RPS (SEQ ID NO:105) wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKIMPQRSTVWY and <4> is an equimolar mixture of amino acid residues ADEFGHIKLONPQRSTVW.
9. A focused library of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of human antibody related peptides, polypeptides and proteins and collectively display, display and express, or comprise at least a portion of the diversity of the antibody family, the vectors or genetic packages being characterized by variegated DNA sequences that encode a lambda light chain CDR3 selected from the group consisting of:
(1) <4><5><4><2><4>S<4><4><4><4>V (SEQ ID NO:106), wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKIMPQRSTVWY; <4> is an equimolar mixture of amino acid residues ADEFGHIKLMVPQRSTVW; and <5> is 0.36 S and 0.6355 each of ADEFGHIKLMNPQRTVWY; (2) <5>SY<1><5>S<5><1><4>V (SEQ ID NO:19), wherein <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and <4> and 5 <5> are as defined in (1) above; and (3) mixtures of vectors or genetic packages characterized by any of the above DNA sequences, preferably in the ratio CDR3s
10. A focused library comprising variegated-DNA sequences that encode a heavy chain CDR selected from the group consisting of:
(1) one or more of the heavy chain CDR's of paragraph 1 above; (2) one or more of the heavy chin CDR2s of paragraph 2 above; (3) one or more of the heavy chain CDR3s of paragraph 3 above; and (4) mixtures of vectors or genetic-packages characterized by (1), (2) and (3).
11. The focused library comprising one or more of the variegated DNA sequences that encodes a heavy chain CDR of paragraphs 1, 2 and 3 and further comprising variegated DNA sequences that encodes a light chain CDR selected from the group consisting of
(1) one or more the kappa light chain CDR1s of paragraph 4; (2) the kappa light chain. CDR2 of paragraph 5; (3) one or more of the kappa light chain CDR3s of paragraph 6; (4) one or more of the kappa light chain CDR1s of paragraph 7; (5) the lambda light chain ‘CDR2’ of paragraph 8 (6) one or more of the lambda light chain CDR3s of paragraph. 9; and (7) mixtures of vectors and genetic packages characterized by one or more of (1) through (6).
12. A population of variegated DNA sequences as. described in paragraphs 1-11 above.
13. A population of vectors comprising the variegated DNA sequences as described in paragraphs 1-11 above.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Antibodies (“Ab”) concentrate their diversity into those regions that are involved in determining affinity and specificity of the Ab for particular targets. These regions may be diverse in sequence or in length. Generally, they are diverse In both ways. However, within families of human antibodies the diversities, both in sequence and in length, are not truly random. Rather, some amino acid residues are preferred at certain positions of the CDRs and some CDR lengths are preferred. These preferred diversities account for the natural diversity of the antibody family.
According to this invention, and as more fully described below, libraries of vectors and genetic packages that more closely mirror the natural diversity, both in sequence and in length, of antibody families, or portions thereof are prepared and used.
Human Antibody Heavy Chain Sequence and Length Diversity
(a) Framework
The heavy chain (“HC”) Germ-Line Gene (GLG) 3-23 (also known as 1/1)-47) accounts for about 12% of all human Abs and is preferred as the framework in the preferred embodiment of the invention. It should, however, be understood that other well-known frameworks, such as 4-34, 3-30, 3-30.3 and 4-30.1, may also be used without departing from the principles of the focused diversities of this invention.
In addition, JH4(YFDYWGQGTLVTVSS; SEQ ID NO:20) occurs more often than JH3 in native antibodies. Hence, it is preferred for the focused libraries of this invention. However, JH3 (AFDIWGQGTMVTVSS; SEQ ID NO:21) could as well be used.
(b) Focused Length Diversity: CDR1, 2 and 3
(i) CDR1
For CDR1, GLGs provide CDR1s only Of the lengths 5, 6, and 7. Mutations during the maturation of the v-domain gene, however, can lead to CDR1s having lengths as short as 2 and as long as 16. Nevertheless, length 5, predominates. Accordingly, in the preferred embodiment of this invention the preferred HC CDR1 is 5 amino acids, with less preferred CDR1s having lengths of 7 and 14. In the most preferred libraries of this invention, all three lengths are used in proportions similar to those found in natural antibodies.
(ii) CDR2
GLGs provide CDR2s only of the lengths 15:19, but mutations during maturation may result in CDR2s of lengths from 16 to 28 amino acids. The lengths 16 and 17 predominate in mature Ab genes. Accordingly, length 17 is the preferred length for HC CDR2 of the present invention. Less preferred HC CDR2s of this invention have lengths 16 and 19. In the most preferred focused libraries of this invention, all three lengths are included in proportions similar to those found in natural antibody families.
(iii) CDR3
HC CDR3s vary in length. About half of human HCs consist of the components: V::nz::D::ny::JHn where V is a V gene, nz is a series of bases (mean 12) that are essentially random, D is a D segment, often with heavy editing at both ends, ny is a series of bases (mean 6) that are essentially random, and JH is one of the six JH segments, often with heavy editing at the 5′ end. The D segments appear to provide spacer segments that allow folding of the IgG. The greatest diversity is at the junctions of y with D and of D with JH.
In the preferred-libraries of this invention both types of HC CDR3s are used. In HC CDR3s that have no identifiable D segment, the structure is V::nz::JHn where JH is usually edited at the 5′ end. In HC CDR3s that have an identifiable D segment, the structure is V::nz::D::ny::JHn.
(c) Focused Sequence Diversity: CDR1, 2 and 3
(i) CDR1
In 5 amino acid length CDR1, examination of a 3D model of a humanized Ab showed that the side groups of residues 1, 3, and 5 were directed toward the combining pocket. Consequently, in the focused libraries of this invention, each of these positions may be selected from any of the native amino acid residues, except cysteine (“C”). Cysteine can form disulfide bonds, which are an important component of the canonical Ig fold. Having free thiol groups Could, thus, interfere with proper folding of the HC and could lead to problems in production or manipulation of selected Abs. Thus, in the focused libraries of this invention cysteine is excluded from positions 1; 3 and 5 of the preferred 5 amino acid CDR1s. The other 19 natural amino acids residues may be used at positions 1, 3 and 5. Preferably, each is present in equimolar ratios in the variegated libraries of this invention.
3D modeling also suggests that the side groups of residue 2 in a 5 amino acid CDR1 are directed away from the combining pocket. Although this position shows substantial diversity, both in GLG and mature genes, in the focused libraries of this invention this residue is preferably Tyr (Y) because it occurs in 681/820 mature antibody genes. However, any of the other native amino acid residues, except Cys (C), could also be used at this position.
For position 4, there is also some diversity in GLG and mature antibody genes. However, almost all mature genes have uncharged hydrophobic amino acid residues: A, G, L, P, F, M, W, I, V, at this position. Inspection of a 3D model also shows that the side group of residue 4 is packed into the innards of the HC. Thus, in the preferred embodiment of this invention which uses framework 3-23, residue 4 is preferably Met because it Is likely to fit very well into the framework of 3-23. With other frameworks, a similar fit consideration is used to assign residue 4.
Thus, the most preferred HC CDR1 of this invention consists of the amino acid sequence <1>Y<I>M<1> where <1> can be any one of amino acid residues: A, D, E, G, H, I, K, L, M, N, R, Q, S, T, V, W, Y (not C), preferably present at each position in an equimolar amount. This diversity is shown in the context of a framework 3-23:JH4 in Table 1. It has a diversity of 6859-fold.
The two less preferred HC CDR1s of this invention have length 7 and length 14. For length 7, a preferred variegation is (S/T) (S/G/<1>) 2 (S/G/<1>) 3 Y 4 Y 5 W 6 (S/G/<1>) 7 (SEQ ID NO:107); where (S/T) indicates an equimolar mixture of Ser and Thr codons; (S/G/<1>) indicates a mixture Of 0.2025 S, 0.2025 G, and 0.035 for each of A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, Y. This design gives a predominance of Ser and Gly at positions 2, 3, and 7, as occurs in mature HC genes. For length 14, a preferred variegation is VSGGSIS<1><1><1>YYW<1> (SEQ ID NO:108), where <1> is an equimolar mixture of the 19 native amino acid residues, except Cys (C).
The DNA that encodes these preferred HC CDR1s is preferably synthesized using trinucleotide building blocks so that each amino acid residue ii present in essentially equimolar or other described amounts. The preferred codons for the <1> amino acid residues are gct, gat, gag, ttt, ggt, cat, att, aag, ctt, atg, aat, cct, cag, cgt, tct, act, gtt, tgg, and tat. Of course, other codons for the chosen amino acid residue could also be used.
The diversity oligonucleotide (ON) is preferably synthesized from BspEI to BstXI (as shown in Table 1) and can, therefore, be incorporated either by PCR synthesis using overlapping ONs or introduced by ligation of BspEI/BstXI-cut fragments. Table 2 shows the oligonucleotides that embody the specified variegations of the preferred length 5 HC CDR1s of this invention. PCR using ON-R1V1vg, ON-R1top, and ON-R1bot gives a dsDNA product of 73 base-pairs, cleavage with 14spEI and BstXI trims 11 and 13 bases from the ends and provides cohesive ends that can be ligated to similarly cut vector having the 3-23 domain shown in Table 1. Replacement of ON-R1V1vg with either ONR1V2vg or ONR1V3vg (see Table 2) allows synthesis of the two alternative diversity patterns—the 7 residue length and the 14 residue length HC CDR1.
The more preferred libraries of this invention comprise the 3 preferred HC CDR1 length diversities. Most preferably, the 3 lengths should be incorporated in approximately the ratios in which they are observed in antibodies selected without reference to the length of the CDRs. For example, one sample of 1095 HC genes have the three lengths present in the ratio: L=5:L=7:L=14::820:175:23::0.80:0.17:0.02. This is the preferred ratio in accordance with this invention.
(ii) CDR2
Diversity in HC CDR2 was designed with the same considerations as for HC CORI: GLG sequences, mature sequences and 3D structure. A preferred length for CDR2 is 17, as shown in Table 1. For this preferred 17 length CDR2, the preferred variegation in accordance with the invention is: <2>I<2><3>SGG<1>T<1>YADSVKG (SEQ ID NO:2), where <2> indicates any amino acid residue selected from the group of Y, R, W, V, G and S (equimolar mixture), <3> is P, S and G or P and S only (equimolar mixture), and <1> is any native amino acid residue except C (equimolar mixture).
ON-R2V1vg shown in Table 3 embodies this diversity pattern. It is preferably synthesized so that fragments of dsDNA containing the BstXI and XbaI site can be generated by PCR. PCR with ON-R2V1vg, ON-R2top, and ONR2bot gives a dsDNA product of 122 base pairs. Cleavage with BstXI and XbaI removes about 10 bases from each end and produces cohesive ends that can be ligated to similarly cut vector that contains the 3-23 gene-shown in Table 1.
In an alternative embodiment for a 17 length HC CDR2, the following variegation may be used; <1>I<4><1><1>G<5><1><1><1>YADSVKG (SEQ ID NO:3), where <1> is as described above for the more preferred alternative of HC CDR2; <4> indicates an equimolar mixture of DINSWY, and <5> indicates an equimolar mixture of SGDN. This diversity pattern is embodied in ON-R2V2vg shown in Table 3. Preferably, the two embodiments are used in equimolar mixtures in the libraries of this invention.
Other preferred HC CDR2s have lengths 16 and 19. Length 16: <1>I<4><1><1>G<5<1><1>YNPSLKG (SEQ ID NO:4); Length:19: <1>I<8>S<1><1><1>GGYY<1>YAASVKG (SEQ ID NO:5), wherein <1> is an equimolar mixture of all native amino acid residues except C; <4> is a equimolar mixture of DINSWY; <5> is an equimolar mixture of SGDN; and <8> is 0.27 R and 0:0 7 of each of residues ADEFGHIKLMNPQSTVWY. Table 3 shows ON-R2V3vg which embodies a preferred aDR2 variegation of length 16 and ON7R2V4vg which embodies a preferred CDR2 variegation of length 19. To prepare these variegations ON-R2V3vg may be PCR amplified with ON-A2top and ON-R2bo3 and ON-R2V4vg may be PCR amplified with ON-R2top and ON-R2-bo4. See Table 3. In the most preferred embodiment of this invention, all three HC CDR2 lengths are used. Preferably, they are present in a ratio 17:16:19::579:464:31::0.54:0.43:0.03.
(iii) CDR3
The preferred libraries of this invention comprise several BC CDR3 components. Some of these will have only sequence diversity. Others will have sequence diversity with embedded D segments to extend the length, while also incorporating sequences known to allow Igs to fold. The HC CDR3 components of the preferred libraries of this invention and their diversities are depicted in Table 4: Components 1-8.
This set of components was chosen after studying the sequences of 1383 human BC sequences. The proposed components are meant to fulfill the following goals:
1) approximately the same distribution of lengths as seen in native Ab genes;
2) high level of sequence diversity at places having high diversity in native Ab genes; and
3) incorporation of constant sequences often seen in native Ab genes.
Component 1 represents all the genes having lengths 0 to 8 (counting from the YYCAR motif at the end of FR3 to the WG dipeptide motif near the start of the J region, i.e., FR4). Component 2 corresponds the all the genes having lengths 9 or 10. Component 3. corresponds to the genes having lengths 11 or 12 plus half the genes having length 13. Component 4 corresponds to those having length 14 plus half those having length 13. Component 5 corresponds to the genes having length 15 and half of those having length 16. Component 6 corresponds to genes of length 17 plus half of those with length 16. Component 7 corresponds to those with length 18. Component 8 corresponds to those having length 19 and greater. See Table 4.
For each HC CDR3 residue having the diversity <1>, equimolar ratios are preferably not used. Rather, the following ratios are used 0.095 [G and Y] and 0.048 [A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, and W]. Thus, there is a double dose of G and Y with the other residues being in equimolar ratios. For the other diversities, e.g., KR or SG, the residues are present in equimolar mixtures.
In the preferred libraries of this invention the eight components are present in the following fractions: 1 (0.10), 2 (0.14), 3 (0.25), 4 (0.13), 5 (0.13), 6 (0.11), 7 (0.04) and 8 (0.10). See Table 4.
In the more preferred embodiment of this invention, the amounts of the eight components is adjusted because the first component is not complex enough to justify including it as 10% of the library. For example, if the final library were to have 1×10 9 members, then 1×10 8 sequences would come from component 1, but it has only 2.6×10 5 CDR3 sequences so that each one would occur in ˜385 CDR1/2 contexts. Therefore, the more preferred amounts of the eight components are 1(0.02), 2(0.14), 3(0.25), 4(0.14), 510.14), 6(0.12), 7(0.68), 8(0.11). In accordance with the more preferred embodiment component 1 occurs in ˜77 CDR1/2 contexts and the other, longer CDR3s occur more often.
Table 5 shows vgDNA that embodies each of the eight HC CDR3 components shown in Table 4. In Table 5, the oligonucleotides (ON) Ctop25, CtprmA, C8prmB, and CBot25 allow PCR amplification of each of the variegated ONs (vgDNA): C1t08, C2t10, C3t12, C4t14, C5t15, C6t17, C7t18, and C8t19. After amplification, the dsDNA can be cleaved with AfiII and BstEII (or KpnI) and ligated to similarly cleaved vector that contains the remainder of the 3-23 domain. Preferably, this vector already contains diversity in one, or both, of CDR1 and CDR2 as disclosed herein. Most preferably, it contains diversity in both the CDR1 and CDR2 regions. It is, of course, to be understood that the various diversities can be incorporated into the vector in any order.
Preferably, the recipient vector originally contains a stuffer in place of CDR1, CDR2 and CDR3 so that there will be no parental sequence that would then occur in the resulting library. Table 6 shows a version of the V3-23 gene segment with each CDR replaced by a short segment that contains both stop codons and restriction sites that will allow specific cleavage of any vector that does not have the stuffer removed. The stuffer can either be short and contain a restriction enzyme site that will not occur in the finished library, allowing removal of vectors that are not cleaved by both AfiII and BstEII (or AionI) and religated. Alternatively, the stuffer could be 200-400 bases long so that uncleaned or once-cleaved vector can be readily separated from doubly cleaved vector.
Human Antibody Light Chain: Sequence and Length Diversity
(i) Kappa Chain
(a) Framework
In the preferred embodiment of this invention, the kappa light chain is built in an A27 framework with a JK1 region. These are the most common V and J regions in the native genes. Other frameworks, such as 012, L2, and All, and other J regions, such as JK4, however, may be used without departing from the scope of this invention.
(b) CDR1
In native human kappa chains, CDR1s with lengths of 11, 12, 13, 16, and 17 were observed with length 11 being predominant and length 12 being well represented. Thus, in the preferred embodiments of this invention LC CDR1s of length 11 and 12 are used in an and mixture similar to that observed in native antibodies), length 11 being most preferred. Length 11 has the following sequence: RASQ<1>V<2><2><3>LA (SEQ ID NO:14) and Length 12 hag the following sequence: RASQ<1>V<25<2><2><3>LA (SEQ ID NO:15), wherein <1> is an equimolar mixture of ill of the native-amino acid residues, except C, <2> is 0.2 S and 0.044 of each of ADEFGHIKLMNPQRTVWY, and <3> is 0.2.Y and 0.044 each of A, D, E, F, G, H, 1, K, L, M, N, Q, R, T, V, W and S. In the most preferred embodiment of this invention, both CDR1. lengths are used. Preferably, they are present in a ratio of 11:12::154:73:0.68:0.32.
(c) CDR2
In native kappa, CDR2 exhibits only length 7. This length is used in the preferred embodiments of-this invention. It has the sequence <1>AS<2>R<4><1>, wherein <1> is an-equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY; <2> is 0.2 S and 0.004 of each of ADEFGHIKLMNPQRTVWY; and <4> is 0.2 A and 0.044 of each of DEFGHIKLMNPQRSTUWY.
(d) CDR3
In native kappa, CDR3 exhibits lengths of 4, 6, 7; 8, 9, 10, 11, 12, 13, 0.0 . . . and 19. While any of these lengths and mixtures of them can be employed in this invention, we prefer lengths 8, 9 and 10, length 9 being more preferred. For the preferred Length 9, the sequence is, QQ<3><1><1><1>P<1>T, wherein <1> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY and <3> is 0.2? and 0.044 each of ADEFGHIKLWQRSVW. Length 8 is preferably QQ33111P and Length 10 is Preferably QQ3211PP1T, wherein 1 and 3 are as defined for Length 9 and 2 is S (0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY. A mixture of all 3 lengths being most preferred (ratios as in native antibodies), i.e., 8:9:10i28:166:63::0.1:0.65:0.25.
Table 7 shows a kappa chain gene of this invention, including a PlacZ promoter a ribosome-binding site, and signal sequence (M13 III signal). The DNA sequence encodes the GLG amino acid sequence but does not comprise the GLG DNA sequence. Restriction sites are designed to fall within each framework region so that diversity can be cloned into the CDRs. XmaI and Esp1 are in FR1, SexAI is in FR2, RsrII is in FR3, and KpnI (or Acc65I), are in FR4. Additional sites are provided in the constant kappa chain to facilitate construction of the gene.
Table 7 also shows a suitable scheme of variegation for kappa. In CDR1, the most preferred length 11 is depicted. However, most preferably both lengths 11 and 12 are used. Length 12 in CDR1 can be construed by introducing codon 51 as <2> (i.e. a Ser-biased mixture). CDR2 of kappa is always 7 codons. Table 7 shows a preferred variegation scheme for CDR2. Table 7 Shows a variegation scheme for the most preferred CDR3 (length 9). Similar variegations can be lied for CDRs of length 8 and 10. In the preferred embodiment of this invention, those three lengths (8, 9 and 10) are included in the libraries of this invention in the native ratios, as described above.
Table 9 shows series of diversity oligonucleotides and primers that may be used to construct the kappa chain diversities depicted in Table 7.
(ii) Lambda Chain
(a) Framework
The lambda chain is preferably built in a 2a2 framework with an L2J region. These are the most common V and J regions in the native genes. Other frameworks, such as 31, 4b, 1a and 6a, and other J regions, such as L1J, L3J and L7J, however, may be used without departing from the scope of this invention.
(b) CDR1
In native human lambda chains, CDR1s with length 14 predominate, lengths 11, 12 and 13 also occur. While any of these can be used in this invention, lengths 11 and 14 are preferred. For length 11 the sequence is: TG<2><4>L<4><4><4><3><4><4> (SEQ ID NO:22) and for Length 14 the sequence is: TG<1>SS<2>VG<1><3><2><3>VS (SEQ ID NO:18), wherein <1> is 0.27 T, 0.21 G and 0.027 each of ADEFHIKLMNPQRSVWY; <2> is 0.27 D, 0.27 N and 0.027 each of AEFGHIKLMPQRSTVWY; <3> is 0.36 Y and 0.0355 each of ADEFGHIKLMNPQRSTVW; and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVWY. Most preferably, Mixtures (similar to those occurring in native antibodies) preferably, the ratio is 11:14::23:46::0.33: 0.67 of the three lengths are used.
(c) CDR2
In native human lambda chains 4 .CDR2s with length 7 are by far the most common. This length is preferred in this invention. The sequence of this Length 7 CDR2 is <4><4><4><2>RPS, wherein <2> is 0.27 D, 0.27 N, and 0.027 each of AEFGHIKLMPQRTVWY and <4> is an equimolar mixture of amino acid residues ADEFGHIKLMNPQRSTVW.
(d) CDR3
In native human lambda chains, CDR3s of length 10 and 11 predominate, while length 9 is also common. Any of these three lengths can be used in the invention. Length 11 is preferred and mixtures of 10 and 11 more preferred. The sequence of Length 11 is <4><5><4><2><4>S<4><4><4><4>V, where <2> and <4> are as defined for the lambda CORI and <5> is 0.36 S and 0.0355 each of ADFFGHIKLMNFORTVWY. The sequence of Length 10 is <5>SY<1><5>S<5><1><4>V (SEQ ID NO:19), wherein <1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY; and <4> and <5> are as defined for Length 11. The preferred mixtures of this invention comprise an equimolar mixture of Length 10 and Length 11. Table 8 shows a preferred focused lambda light chain diversity in accordance with this invention.
Table 9 shows a series of diversity oligonucleotides and primers that may be used to construct 10 the lambda chain diversities depicted in Table 7.
Method of Construction of the Genetic Package
The diversities of heavy chain and the kappa and lambda light chains are best constructed in separate vector's. First a synthetic gene is designed to embody each of the synthetic variable domains. The light chains are bounded by restriction sites for ApaLI (positioned at the very end of the signal sequence) and AscI (positioned after the stop codon). The heavy chain is bounded by SfiI (positioned within the PelB signal sequence) and NotI (positioned in the linker between CH1 and the anchor protein). Signal sequences other than PelB may also need, e.g., a M13 pIII signal sequence.
The initial genes are made with “stuffer” sequences in place of the desired CDRs. A “stuffer” is a sequence that is to be cut away and replaced by diverse DNA but which does not allow expression ‘of a functional antibody gene. For example, the stuffer may contain several stop codons and restriction sites that will not occur in the correct finished library vector. For example, in Table 10, the stuffer for CDR1 of kappa A27 contains a StuI site. The vgDNA for CDR1 is introduced as a cassette from EspI, XmaI, or Af1II to dither SexAI or KasI. After the ligation, the DNA is cleaved with Still; there should be no StuI sites in the desired vectors.
The sequences of the heavy chain gene with stuffers is depicted in Table 6. The sequences of the kappa light chain gene with stuffers is depicted in Table 10. The sequence of the lambda light chain gene with stuffers is depicted in Table 11.
In another embodiment of the present invention the diversities of heavy chain and the kappa or lambda light chains are constructed in a single vector or genetic packages (e.g., for display or display and expression) having appropriate restriction sites that allow cloning of these chains. The processes to construct such vectors are well known and widely used in the art. Preferably, a heavy chain and Kappa light Chain library and a heavy chain and lambda light chain library would be prepared separately. The two libraries, most preferably, will then be mixed in equimolar amounts to attain maximum diversity.
Most preferably, the display is had on the surface of a derivative of M13 phage. The most preferred vector contains all the genes of M13, an antibiotic resistance-gene, and the display cassette. The preferred vector is provided with restriction sites that allow introduction and excision of members of the diverse family of genes, as cassettes. The preferred vector is stable against rearrangement under the growth conditions used to amplify phage.
In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a phagemid vector (e.g., pCES1) that displays and/or expresses the peptide, polypeptide or protein. Such vectors may also be used to store the diversity for subsequent display and/or expression using other vectors or phage.
In another embodiment of this invention, the diversity captured by the methods of the present invention may be displayed and/or expressed in a yeast vector.
TABLE 1
3-23: JH4 CDR1/2 diversity = 1.78 × 10 8
FR1(VP47/V3-23)---------------
20 21 22 23 24 25 26 27 28 29 30
A M A E V Q L L E S G
(SEQ ID NO: 99)
ctgtctgaac cc atg gcc gaa/gtt/caa/ttg/tta/gag/tct/ggt/
Scab...... NcoI.... MfeI
--------------FR1--------------------------------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
G G L V Q P G G S L R L S C A
/ggc/ggt/ctt/gtt/cag/cct/ggt/ggt/tct/tta/cgt/ctt/tct/tgc/gct/
Sites of variegation <1> <1> <1> <1> 6859-fold diversity
----FR1-------------------->/.....CDR1..................../---FR2------
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
A S G F T F S - Y - M - W V R
/gct/tcc/gga/ttc/act/ttc/tct/ - /tac/ - /atg/ - /tgg/gtt/cgc/
BspEI BsiWI BstXI.
Sites of variegation-><2> <2> <3>
-------FR2-------------------------------->/...CDR2.........
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
Q A P G K G L E W V S - I - -
/caa/gct/cct/ggt/aaa/ggt/ttg/gag/tgg/gtt/tct/ - /atc/ - / - /
...BstXI
<1> <1> 25992-fold diversity in CDR2
.....CDR2............................................/---FR3---
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
S G G - T - Y A D S V K G R F
/tct/ggt/ggc/ - /act/ - /tat/gct/gac/tcc/gtt/aaa/ggt/cgc/ttc/
--------FR3--------------------------------------------------
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
T I S R D N S K N T L Y L Q M
/act/atc/tct/aga/gac/aac/tct/aag/aat/act/ctc/tac/ttg/cag/atg/
XbaI
---FR3----------------------------------------------------->/
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
N S L R A E D T A V Y Y C A K
/aac/agc/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc/aaa/
AflII
.......CDR3................./ Replaced by the various components!
121 122 123 124 125 126 127
D Y E G T G Y
/gac/tat/gaa/ggt/act/ggt/tat/
/----- FR4 ---(JH4)-----------------------------------------
Y F D Y W G Q G T L V T V S S (SEQ ID NO: 26)
/tat/ttc/gat/tat/tgg/ggt/caa/ggt/acc/ctg/gtc/acc/gtc/tct/agt/. (SEQ ID NO: 25)
KpnI BstEII
<1> = Codons for ADEFGHIKLMNPQRSTVWY (equimolar mixture)
<2> = Codons for YRWVGS (equimolar mixture)
<3> = Codons for PS or PS and G (equimolar mixture)
TABLE 2
Oligonucleotides used to variegate CDR1 of human HC
CDR1 - 5 residues
(ON-R1V1vg):
5′-ct/tcc/gga/ttc/act/ttc/tct/<1>/tac/<1>/atg/<1>/tgg/gtt/cgc/caa/gct/cct/
gg-3′
(SEQ ID NO: 27)
<1> = Codons of ADEFGHIKLMNPQRSTVWY 1:1
(ON-R1top):
5′-cctactgtct/tcc/gga/ttc/act/ttc/tct-3′
(SEQ ID NO: 28)
(ON-R1bot)[RC]:
5′-tgg/gtt/cgc/caa/gct/cct/ggttgctcactc-3′
(SEQ ID NO: 29)
CDR1 - 7 residues
(ON-R1V2vg):
5′-ct/tcc/gga/ttc/act/ttc/tct/<6>/<7>/<7>/tac/tac/tgg/<7>/tgg/gtt/cgc/caa/gct/
cct/gg-3′
(SEQ ID NO: 30)
<6> = Codons for ST, 1:1
<7> = 0.2025(Codons for SG) + 0.035(Codons for ADEFHIKLMNPQRTVWY)
CDR1 - 14 residues
(ON-R1V3vg):
5′-ct/tcc/gga/ttc/act/ttc/tct/atc/agc/ggt/ggt/tct/atc/tcc/<1>/<1>/<1>/-
tac/tac/tgg/<1>/tgg/gtt/cgc/caa/gct/cct/gg-3′
(SEQ ID NO: 31)
<1> = Codons for ADEFGHIKLMNPQRSTVWY 1:1
TABLE 3
Oligonucleotides used to variegate CDR2 of human HC
CDR2 - 17 residues
(ON-R2V1vg):
5′-ggt/ttg/gag/tgg/gtt/tct/<2>/atc/<2>/<3>/tct/ggt/ggc/<1>/act/<1>/tat/gct/-
gac/tcc/gtt/aaa/gg-3′
(SEQ ID NO: 32)
(ON-R2top):
5′-ct/tgg/gtt/cgc/caa/gct/cct/ggt/aaa/ggt/ttg/gag/tgg/gtt/tct-3′
(SEQ ID NO: 33)
(ON-R2bot)[RC]:
5′-tat/gct/gac/tcc/gtt/aaa/ggt/cgc/ttc/act/atc/tct/aga/ttcctgtcac-3′
(SEQ ID NO: 34)
<1> = Codons for A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W and Y (equimolar mixture)
<2> = Codons for Y, R, W, V, G and S (equimolar mixture)
<3> = Codons for P and S (equimolar mixture) or P, S and G (equimolar mixture)
(ON-R2V2vg):
5′-ggt/ttg/gag/tgg/gtt/tct/<1>/atc/<4>/<1>/<1>/ggt/<5>/<1>/<1>/<1>/tat/gct/-
gac/tcc/gtt/aaa/gg-3′
(SEQ ID NO: 35)
<4> = Codons for DINSWY (equimolar mixture)
<5> = Codons for SGDN, (equimolar mixture)
CDR2 - 16 residues
(ON-R2V3vg):
5′-ggt/ttg/gag/tgg/gtt/tct/<1>/atc/<4>/<1>/<1>/ggt/
<5>/<1>/<1>/tat/aac/cct/tcc/ctt/aag/gg-3′
(SEQ ID NO: 36)
(ON-R2bo3)[RC]:
5′-tat/aac/cct/tcc/ctt/aag/ggt/cgc/ttc/act/atc/tct/aga/tcctgtcac-3′
(SEQ ID NO: 37)
CDR2 - 19 residues
(ON-R2V4vg):
5′-ggt/ttg/gag/tgg/gtt/tct/<1>/atc/<8>/agt/<1>/<1>/
<1>/ggt/ggt/act/act/<1>/tat/gcc/gct/tcc/gtt/aag/gg-3′
(SEQ ID NO: 38)
(ON7R2bo4)[RC]:
5′-tat/gcc/gct/tcc/gtt/aag/ggt/cgc/ttc/act/atc/tct/aga/ttcctgtcac-3′
(SEQ ID NO: 39)
<1>, <2>, <3>, <4> and <5> are as defined above
<8> is 0.27 R and 0.027 each of ADEFGHIKLMNPQSTVWY
TABLE 4
Preferred Components of HC CDR3
Preferred
Fraction of
Adjusted
Component
Length
Complexity
Library
Fraction
1
YYCA21111YFDYWG.
8
2.6 × 10 5
.10
.02
(SEQ ID NO: 6)
(1 = any amino acid residue, except C; 2 = K and R)
2
YYCA2111111YFDYWG.
10
9.4 × 10 7
.14
.14
(SEQ ID NO: 7)
(1 = any amino acid residue, except C; 2 = K and R)
3
YYCA211111111YFDYTG.
12
3.4 × 10 10
.25
.25
(SEQ ID NO: 8)
(1 = any amino acid residue, except C; 2 = K and R)
4
YYCAR111S2S3111YFDYWG.
14
1.9 × 10 8
.13
.14
(SEQ ID NO: 9)
(1 = any amino acid residue, except C; 2 = S and G
3 = Y and W)
5
YYCA2111CSG11CY1YFDYWG.
15
9.4 × 10 7
.13
.14
(SEQ ID NO: 10)
(1 = any amino acid residue, except C; 2 = K and R)
6
YYCA211S1TIFG11111YFDYWG.
17
1.7 × 10 10
.11
.12
(SEQ ID NO: 11)
(1 = any amino acid residue, except C; 2 = K and R)
7
YYCAR111YY2S33YY111YFDYWG.
18
3.8 × 10 8
.04
.08
(SEQ ID NO: 12)
(1 = any amino acid residue, except C; 2 = D or G;
3 = S and G)
8
YYCAR1111YC2231CY111YFDYWG.
19
2.0 × 10 11
.10
.11
(SEQ ID NO: 13)
(1 = any amino acid residue, except C; 2 = S and G;
3 = T, D and G)
TABLE 5
Oligonucleotides used to variegate the eight components of HC CDR3
(Ctop25):
5′-gctctggtcaac/tta/agg/gct/gag/g-3′
(SEQ ID NO: 40)
(CtprmA):
5′-gctctggtcaac/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc-3′
AflII...
(SEQ ID NO: 41)
(CBprmB) [RC]:
5′-/tac/ttc/gat/tac/tgg/ggc/caa/ggt/acc/ctg/gtc/acc/tcgctccacc-3′
BstEII...
(SEQ ID NO: 42)
(CBot25) [RC]:
5′-/ggt/acc/ctg/gtc/acc/tcgctccacc-3′
(SEQ ID NO: 43)
The 20 bases at 3′ end of CtprmA are identical to the most 5′ 20 bases
of each of the vgDNA molecules.
Ctop25 is identical to the most 5′ 25 bases of CtprmA.
The 23 most 3′ bases of CBprmB are the reverse complement of the
most 3′ 23 bases of each of the vgDNA molecules.
CBot25 is identical to the 25 bases at the 5′ end of CBprmB.
Component 1
(C1t08):
5′-cc/gct/gtc/tac/tac/tgc/gcc/<2>/<1>/<1>/<1>/<1>/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 44)
<1> = 0.095 Y + 0.095 G + 0.048 each of the residues ADEFHIKLMNPQRSTVW,
no C; <2> = K and R (equimolar mixture)
Component 2
(C2t10):
5′-cc/gct/gtc/tac/tac/tgc/gcc/<2>/<1>/<1>/<1>/<1>/<1>/<1>/tac/ttc/gat/tac/
tgg/ggc/caa/gg-3′
(SEQ ID NO: 45)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = K and R (equimolar mixture)
Component 3
(C3t12):
5′-cc/gct/gtc/tac/tac/tgc/gcc/<2>/<1>/<1>/<1>/<1>/<1>/<1>/<1>/<1>/tac/ttc/gat/tac/-
tgg/ggc/caa/gg-3′
(SEQ ID NO: 46)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = K and R (equimolar mixture)
Component 4
(C4t140):
5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/<1>/<1>/<1>/tct/<2>/tct/<3>/<1>/<1>/<1>/tac/ttc/gat/-
tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 47)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = S and G (equimolar mixture); <3> = Y
and W (equimolar mixture)
Component 5
(C5t15):
5′-cc/gct/gtc/tac/tac/tgc/gcc/<2>/<1>/<1>/<1>/tgc/tct/ggt/<1>/<1>/tgc/tat/<1>/tac/-
ttc/gat/tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 48)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = K and R (equimolar mixture)
Component 6
(C6t17):
5′-cc/gct/gtc/tac/tac/tgc/gcc/<2>/<1>/<1>/tct/<1>/act/atc/ttc/ggt/<1>/<1>/<1>/<1>/-
<1>/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 49)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = K and R (equimolar mixture)
Component 7
(C7t18):
5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/<1>/<1>/<1>/tat/tac/<2>/tct/<3>/<3>/tac/tat/-
<1>/<1>/<1>/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 50)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = D and G (equimolar mixture); <3> = S
and G (equimolar mixture)
Component 8
(c8t19):
5′-cc/gct/gtc/tac/tac/tgc/gcc/cgt/<1>/<1>/<1>/<1>/tat/tgc/<2>/<2>/<3>/<1>/tgc/tat/-
<1>/<1>/<1>/tac/ttc/gat/tac/tgg/ggc/caa/gg-3′
(SEQ ID NO: 51)
<1> = 0.095 Y + 0.095 G + 0.048 each of ADEFHIKLMNPQRSTVW,
no C; <2> = S and G (equimolar mixture); <3> = TDG
(equimolar mixture);
TABLE 6
3-23::JH4 Stuffers in place of CDRs
FR1(DP47/V3-23)---------------
20 21 22 23 24 25 26 27 28 29 30
A M A E V Q L L E S G
ctgtctgaac cc atg gcc gaa/gtt/caa/ttg/tta/gag/tct/ggt/
(SEQ ID NO: 99)
Scab...... NcoI.... MfeI
--------------FR1--------------------------------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
G G L V Q P G G S L R L S C A
/ggc/ggt/ctt/gtt/cag/cct/ggt/ggt/tct/tta/cgt/ctt/tct/tgc/gct/
----FR1-------------------->/...CDR1 stuffer..../---FR2------
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
A S G F T F S S Y A / / W V R
/gct/tcc/gga/ttc/act/ttc/tct/tcg/tac/gct/tag/taa/tgg/gtt/cgc/
BspEI BsiWI BstXI.
-------FR2-------------------------------->/...CDR2 stuffer.
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
Q A P G K G L E W V S / p r /
/caa/gct/cct/ggt/aaa/ggt/ttg/gag/tgg/gtt/tct/taa/cct/agg/tag/
...BstXI AvrII..
.....CDR2 stuffer..................................../---FR3---
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
T I S R D N S K N T L Y L Q M
/act/atc/tct/aga/gac/aac/tct/aag/aat/act/ctc/tac/ttg/cag/atg/
XbaI
---FR3-----------..> CDR3 Stuffer------------->/
106 107 108 109 110
N S L R A (SEQ ID NO: 53)
/aac/agc/tta/agg/gct/tag taa agg cct taa (SEQ ID NO: 52)
AflII StuI...
/----- FR4 ---(JH4)-----------------------------------------
Y F D Y W G Q G T L V T V S S
(SEQ ID NO: 26)
/tat/ttc/gat/tat/tgg/ggt/caa/ggt/acc/ctg/gtc/acc/gtc/tct/agt/...
(SEQ ID NO: 25)
KpnI BstEII
TABLE 7
A27:JH1 Human Kappa light chain gene
gaggacc attgggcccc ctccgagact ctcgagcgca
Scab...... EcoO109I XhoI..
ApaI.
acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc
..-35.. Plac ..-10.
cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga
aacagctatg accatgatta
cgccaagctt tggagccttt tttttggaga ttttcaac (SEQ ID NO: 54)
PflMI.......
Hind III
M13 III signal sequence (AA seq)--------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
M K K L L F A I P L V V P F Y
gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac
--Signal-->FR1------------------------------------------->
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
S H S A Q S V L T Q S P G T L
/agc/cat/agt/gca/caa/tcc/gtc/ctt/act/caa/tct/cct/ggc/act/ctt/
ApaLI...
----- FR1 ------------------------------------->/ CDR1------>
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
S L S P G E R A T L S C R A S (SEQ ID NO: 55)
/tcg/cta/agc/ccg/ggt/gaa/cgt/gct/acc/tta/agt/tgc/cgt/gct/tcc/ (SEQ ID NO: 54; Cont'd)
EspI..... AflII...
XmaI....
For CDR1:
<1> ADEFGHIKLMNPQRSTVWY 1:1
<2> S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each)
<3> Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each)
(CDR1 installed as AflII-(SexAI or KasI) cassette.) For the most preferred 11 length codon 51
(XXX) is omitted; for the preferred 12 length this codon is <2>
------- CDR1 --------------------->/--- FR2 --------------->
<1> <2> <2> xxx <3>
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Q - V - - - - L A W Y Q Q K P (SEQ ID NO: 55; Cont'd)
/cag/ - /gtt/ - / - / - / - /ctt/gct/tgg/tat/caa/cag/aaa/cct/ (SEQ ID NO: 54; Cont'd)
SexAI...
For CDR2:
<1> ADEFGHIKLMNPQRSTVWY 1:1
<2> S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each)
<4> A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each)
CDR2 installed as (SexAI or KasI) to (BamHI or RsrII) cassette.)
----- FR2 ------------------------->/------- CDR2 ---------->
<1> <2> <4>
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
G Q A P R L L I Y - A S - R - (SEQ ID NO: 55; Cont'd)
/ggt/cag/gcg/ccg/cgt/tta/ctt/att/tat/ - /gct/tct/ - /cgc/ - (SEQ ID NO: 54; Cont'd)
SexAI.... KasI....
CDR2-->/--- FR3 ----------------------------------------------->
<1>
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
- G I P D R F S G S G S G T D
/ - /ggg/atc/ccg/gac/cgt/ttc/tct/ggc/tct/ggt/tca/ggt/act/gac/
BamHI...
RsrII.....
------ FR3 ------------------------------------------------->
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
F T L T I S R L E P E D F A V (SEQ ID NO: 55; Cont'd)
/ttt/acc/ctt/act/att/tct/aga/ttg/gaa/cct/gaa/gac/ttc/gct/gtt/ (SEQ ID NO: 54; Cont'd)
XbaI...
For CDR3 (Length 9):
<1> ADEFGHIKLMNPQRSTVWY 1:1
<3> Y(0.2) ADEFGHIKLMNPQRTVW (0.044 each)
For CDR3 (Length 8): QQ33111P
1 and 3 as defined for Length 9
For CDR3 (Length 10): QQ3211PP1T
1 and 3 as defined for Length 9
2 S(0.2) and 0.044 each of ADEFGHIKLMNPQRTVWY
CDR3 installed as XbaI to (StyI or BsiWI) cassette.
----------->/----CDR3-------------------------->/-----FR4--->
<3> <1> <1> <1> <1>
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
Y Y C Q Q - - - - P - T F G Q (SEQ ID NO: 55; Cont'd)
/tat/tat/tgc/caa/cag/ - / - / - / - /cct/ - /act/ttc/ggt/caa/ (SEQ ID NO: 54; Cont'd)
BstXI...........
-----FR4------------------->/ <------- Ckappa ------------
121 122 123 124 125 126 127 128 129 130 131 132 133 134
G T K V E I K R T V A A P S
/ggt/acc/aag/gtt/gaa/atc/aag/ /cgt/acg/gtt/gcc/gct/cct/agt/
StyI.... BsiWI..
135 136 137 138 139 140 141 142 143 144 145 146 147 148 149
V F I F P P S D E Q L K S G T
/gtg/ttt/atc/ttt/cct/cct/tct/gac/gaa/caa/ttg/aag/tca/ggt/act/
MfeI...
150 151 152 153 154 155 156 157 158 159 160 161 162 163 164
A S V V C L L N N F Y P R E A (SEQ ID NO: 55; Cont'd)
/gct/tct/gtc/gta/tgt/ttg/ctc/aac/aat/ttc/tac/cct/cgt/gaa/gct/ (SEQ ID NO: 54; Cont'd)
BssSI...
165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
K V Q W K V D N A L Q S G N S
/aaa/gtt/cag/tgg/aaa/gtc/gat/aac/gcg/ttg/cag/tcg/ggt/aac/agt/
MluI....
180 181 182 183 184 185 186 187 188 189 190 191 192 193 194
Q E S V T E Q D S K D S T Y S
/caa/gaa/tcc/gtc/act/gaa/cag/gat/agt/aag/gac/tct/acc/tac/tct/
195 196 197 198 199 200 201 202 203 204 205 206 207 208 209
L S S T L T L S K A D Y E K H
/ttg/tcc/tct/act/ctt/act/tta/tca/aag/gct/gat/tat/gag/aag/cat/
210 211 212 213 214 215 216 217 218 219 220 221 222 223 224
K V Y A C E V T H Q G L S S P (SEQ ID NO: 55; Cont'd)
/aag/gtc/tat/GCt/TGC/gaa/gtt/acc/cac/cag/ggt/ctg/agc/tcc/cct/ (SEQ ID NO: 54; Cont'd)
SacI....
225 226 227 228 229 230 231 232 233 234
V T K S F N R G E C (SEQ ID NO: 55; Cont'd)
/gtt/acc/aaa/agt/ttc/aac/cgt/ggt/gaa/tgc/taa/tag ggcgcgcc
DsaI.... AscI....
BssHII
acgcatctctaa gcggccgc aacaggaggag (SEQ ID NO: 54; Cont'd)
NotI....
TABLE 8
2a2:JH2 Human lambda-chain gene
gaggaccatt gggcccc ttactccgtgac
Scab...... EcoO109I
ApaI..
-----------FR1-------------------------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
S A Q S A L T Q P A S V S G S P G
(SEQ ID NO: 57)
agt/gca/caa/tcc/gct/ctc/act/cag/cct/gct/agc/gtt/tcc/ggg/tca/cct/ggt/
(SEQ ID NO: 56)
ApaLI... NheI... BstEII...
SexAI....
For CDR1 (length 14):
<1> = 0.27 T, 0.27 G, 0.027 each of ADEFHIKLMNPQRSVWY, no C
<2> = 0.27 D, 0.27 N, 0.027 each of AEFGHIKLMPQRSTVWY, no C
<3> = 0.36 Y, 0.0355 each of ADEFGHIKLMNPQRSTVW, no C
T G <1> S S <2> V G
------FR1------------------> /-----CDR1---------------------
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Q S I T I S C T G - S S - V G
/caa/agt/atc/act/att/tct/tgt/aca/ggt/ - /tct/tct/ - /gtt/ggc/
BsrGI..
<1> <3> <2> <3> V S = vg Scheme #1, length = 14
-----CDR1------------->/--------FR2-------------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
- - - - V S W Y Q Q H P G K A
(SEQ ID NO: 57; Cont'd)
/ - / - / - / - /gtt/tct/tgg/tat/caa/caa/cac/ccg/ggc/aag/gcg/
(SEQ ID NO: 56; Cont'd)
XmaI.... KasI.....
AvaI....
A second Vg scheme for CDR1 gives segments of length 11:
T 22 G<2><4>L<4><4><4><3><4><4> where
<4> = equimolar mixture of each of ADEFGHIKLMNPQRSTVWY, no C
<3> = as defined above for the alternative CDR1
For CDR2:
<2> and <4> are the same variegation as for CDR1
<4> <4> <4> <2> R P S
--FR2-----------------> /------CDR2--------------->/-----FR3-
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
P K L M I Y - - - - R P S G V
/ccg/aag/ttg/atg/atc/tac/ - / - / - / - /cgt/cct/tct/ggt/gtt/
KasI....
-------FR3----------------------------------------------------
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
S N R F S G S K S G N T A S L
(SEQ ID NO: 57; Cont'd)
/agc/aat/cgt/ttc/tcc/gga/tct/aaa/tcc/ggt/aat/acc/gca/agc/tta/
(SEQ ID NO: 56; Cont'd)
BspEI.. HindIII.
BsaBI........(blunt)
-------FR3-------------------------------------------------->/
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T I S G L Q A E D E A D Y Y C
(SEQ ID NO: 57; Cont'd)
/act/atc/tct/ggt/ctg/cag/gct/gaa/gac/gag/gct/gac/tac/tat/tgt/
(SEQ ID NO: 56; Cont'd)
PstI...
CDR3 (Length 11):
<2> and <4> are the same variegation as for CDR1
<5> = 0.36 S, 0.0355 each of ADEFGHIKLMNPQRTVWY no C
CDR3 (Length 10): <5> SY <1> <5> S <5> <1> <4> V
<1> is an equimolar mixture of ADEFGHIKLMNPQRSTVWY, no C
<4> and <5> are as defined for Length 11
<4> <5> <4> <2> <4> S <4> <4> <4> <4> V
-----CDR3---------------------------------->/---FR4---------
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
- - - - - S - - - - V F G G G
/ - / - / - / - / - /tct/ - / - / - / - /gtc/ttc/ggc/ggt/ggt/
KpnI...
-------FR4-------------->
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
T K L T V L G Q P K A A P S V
/acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/gct/gct/cct/tcc/gtt/
KpnI... HincII..
Bsu36I...
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
T L F P P S S E E L Q A N K A
(SEQ ID NO: 57; Cont'd)
/act/ctc/ttc/cct/cct/agt/tct/gaa/gag/ctt/caa/gct/aac/aag/gct/
(SEQ ID NO: 56; Cont'd)
SapI.....
136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
T L V C L I S D F Y P G A V T
/act/ctt/gtt/tgc/ttg/atc/agt/gac/ttt/tat/cct/ggt/gct/gtt/act/
BclI....
151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
V A W K A D S S P V K A G V E
/gtc/gct/tgg/aaa/gcc/gat/tct/tct/cct/gtt/aaa/gct/ggt/gtt/gag/
BsmBI...
166 167 168 169 170 171 172 173 174 175 176 177 178 179 180
T T T P S K Q S N N K Y A A S
/acg/acc/act/cct/tct/aaa/caa/tct/aac/aat/aag/tac/gct/gcg/agc/
BsmBI.... SacI....
181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
S Y L S L T P E Q W K S H K S
(SEQ ID NO: 57; Cont'd)
/tct/tat/ctt/tct/ctc/acc/cct/gaa/caa/tgg/aag/tct/cat/aaa/tcc/
(SEQ ID NO: 56; Cont'd)
SacI...
196 197 198 199 200 201 202 203 204 205 206 207 208 209 210
Y S C Q V T H E G S T V E K T
/tat/tcc/tgt/caa/gtt/act/cat/gaa/ggt/tct/acc/gtt/gaa/aag/act/
BspHI...
211 212 213 214 215 216 217 218 219
V A P T E C S (SEQ ID NO: 57; Cont'd)
/gtt/gcc/cct/act/gag/tgt/tct/tag/tga/ggcgcgcc
AscI....
BssHII
aacgatgttc aag gcggccgc aacaggaggag (SEQ ID NO: 56; Cont'd)
NotI.... Scab.......
TABLE 9
Oligonucleotides For Kappa and Lambda Light Chain Variegation
(Ctop25):
5′-gctctggtcaac/tta/agg/gct/gag/g-3′
(SEQ ID NO: 58)
(CtprmA):
5′-gctctggtcaac/tta/agg/gct/gag/gac/acc/gct/gtc/tac/tac/tgc/gcc-3′
(SEQ ID NO: 59)
AflII...
(CBprmB) [RC]:
5′-/tac/ttc/gat/tac/ttg/ggc/caa/ggt/acc/ctg/gtc/acc/tcgctccacc-3′
(SEQ ID NO: 60)
BstEII...
(CBot25) [RC]:
5′-/ggt/acc/ctg/gtc/acc/tcgctccacc-3′
(SEQ ID NO: 61)
Kappa chains:
CDR1 (“1”), CDR2 (“2”), CDR3 (“3”)
CDR1
(Ka1Top610):
5′-ggtctcagttg/cta/agc/ccg/ggt/gaa/cgt/gct/acc/tta/agt/tgc/cgt/gct/tcc/cag-3′
(SEQ ID NO: 62)
(Ka1STp615):
5′-ggtctcagttg/cta/agc/ccg/ggt/g-3′
(SEQ ID NO: 63)
(Ka1Bot620) [RC]:
5′-ctt/gct/tgg/tat/caa/cag/aaa/cct/ggt/cag/gcg/ccaagtcgtgtc-3′
(SEQ ID NO: 64)
(Ka1SB625) [RC]:
5′-cct/ggt/cag/gcg/ccaagtcgtgtc-3′
(SEQ ID NO: 65)
(Ka1vg600):
5′-gct/acc/tta/agt/tgc/cgt/gct/tcc/cag-
/<1>/gtt/<2>/<2>/<3>/ctt/gct/tgg/tat/caa/cag/aaa/cc-3′
(SEQ ID NO: 66)
(Ka1vg600-12):
5′-gct/acc/tta/agt/tgc/cgt/gct/tcc/cag-
/<1>/gtt/<2>/<2>/<2>/<3>/ctt/gct/tgg/tat/caa/cag/aaa/cc-3′
(SEQ ID NO: 67)
CDR2
(Ka2Tshort657):
5′-cacgagtccta/cct/ggt/cag/gc-3′
(SEQ ID NO: 68)
(Ka2Tlong655):
5′-cacgagtccta/cct/ggt/cag/gcg/ccg/cgt/tta/ctt/att/tat-3′
(SEQ ID NO: 69)
(Ka2Bshort660): [RC]:
5′-/gac/cgt/ttc/tct/ggt/tctcacc-3′
(SEQ ID NO: 70)
(Ka2vg650):
5′-cag/gcg/ccg/cgt/tta/ctt/att/tat/<1>/gct/tct/<2>/-
/cgc/<4>/<1>/ggg/atc/ccg/gac/cgt/ttc/tct/ggt/tctcacc-3′
(SEQ ID NO: 71)
CDR3
(Ka3Tlon672):
5′-gacgagtccttct/aga/ttg/gaa/cct/gaa/gac/ttc/gct/gtt/tat/tat/tgc/caa/c-3′
(SEQ ID NO: 72)
(Ka3BotL682) [RC]:
5′-act/ttc/ggt/caa/ggt/acc/aag/gtt/gaa/atc/aag/cgt/acg/tcacaggtgag-3′
(SEQ ID NO: 73)
(Ka3Bsho694) [RC]:
5′-gaa/atc/aag/cgt/acg/tcacaggtgag-3′
(SEQ ID NO: 74)
(Ka3vg670):
5′-gac/ttc/gct/gtt/-
/tat/tat/tgc/caa/cag/<3>/<1>/<1>/<1>/cct/<1>/act/ttc/ggt/caa/-
/ggt/acc/aag/gtt/g-3′
(SEQ ID NO: 75)
(Ka3vg670-8):
5′-gac/ttc/gct/gtt/-
/tat/tat/tgc/caa/cag/<3>/<3>/<1>/<1>/<1>/cct/ttc/ggt/caa/-
/ggt/acc/aag/gtt/g-3′
(SEQ ID NO: 76)
(Ka3vg670-10):
5′-gac/ttc/gct/gtt/tat/-
/tat/tgc/caa/cag/<3>/<2>/<1>/<1>/cct/cct/<1>/act/ttc/ggt/caa/-
/ggt/acc/aag/gtt/g-3′
(SEQ ID NO: 77)
Lambda Chains:
CDR1 (“1”), CDR2 (“2”), CDR3 (“3”)
CDR1
(Lm1TPri75):
5′-gacgagtcctgg/tca/cct/ggt/-3′
(SEQ ID NO: 78)
(Lm1tlo715):
5′-gacgagtcctgg/tca/cct/ggt/caa/agt/atc/act/att/tct/tgt/aca/ggt-3′
(SEQ ID NO: 79)
(Lm1blo724) [rc]:
5′-gtt/tct/tgg/tat/caa/caa/cac/ccg/ggc/aag/gcg/agatcttcacaggtgag-3′
(SEQ ID NO: 80)
(Lm1bsh737) [rc]:
5′-gc/aag/gcg/agatcttcacaggtgag-3′
(SEQ ID NO: 81)
(Lm1vg710b):
5′-gt/atc/act/att/tct/tgt/aca/ggt/<2>/<4>/ctc/<4>/<4>/<4>/-
/<3>/<4>/<4>/tgg/tat/caa/caa/cac/cc-3′
(SEQ ID NO: 82)
(Lm1vg710):
5′-gt/atc/act/att/tct/tgt/aca/ggt/<1>/tct/tct/<2>/gtt/ggc/-
/<1>/<3>/<2>/<3>/gtt/tct/tgg/tat/caa/caa/cac/cc-3′
(SEQ ID NO: 83)
CDR2
(Lm2TSh757):
5′-gagcagaggac/ccg/ggc/aag/gc-3′
(SEQ ID NO: 84)
(Lm2TLo753):
5′-gagcagaggac/ccg/ggc/aag/gcg/ccg/aag/ttg/atg/atc/tac/-3′
(SEQ ID NO: 85)
(Lm2BLo762) [RC]:
5′-cgt/cct/tct/ggt/gtc/agc/aat/cgt/ttc/tcc/gga/tcacaggtgag-3′
(SEQ ID NO: 86)
(Lm2BSh765) [RC]:
5′-cgt/ttc/tcc/gga/tcacaggtgag-3′
(SEQ ID NO: 87)
(Lm2vg750):
5′-g/ccg/aag/ttg/atg/atc/tac/-
<4>/<4>/<4>/<2>/cgt/cct/tct/ggt/gtc/agc/aat/c-3′
(SEQ ID NO: 88)
CDR3
(Lm3TSh822):
5′-ctg/cag/gct/gaa/gac/gag/gct/gac-3′
(SEQ ID NO: 89)
(Lm3TLo819):
5′-ctg/cag/gct/gaa/gac/gag/gct/gac/tac/tat/tgt/-3′
(SEQ ID NO: 90)
(Lm3BLo825) [RC]:
5′-gtc/ttc/ggc/ggt/ggt/acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/g-
acacaggtgag-3′
(SEQ ID NO: 91)
(Lm3BSh832) [RC]:
5′-c/ggt/caa/cct/aag/gacacaggtgag-3′
(SEQ ID NO: 92)
(Lm3vg817):
5′-gac/gag/gct/gac/tac/tat/tgt/-
/<4>/<5>/<4>/<2>/<4>/tct/<4>/<4>/<4>/<4>/-
Gtc/ttc/ggc/ggt/ggt/acc/aaa/ctt/ac-3′
(SEQ ID NO: 93)
(Lm3vg817-10):
5′-gac/gag/gct/gac/tac/tat/tgt/-
/<5>/agc/tat/<1>/<5>/tct/<5>/<1>/<4>/gtc/ttc/ggc/ggt/ggt/-
/acc/aaa/ctt/ac-3′
(SEQ ID NO: 94)
TABLE 10
A27:JH1 Kappa light chain gene with stuffers in place of CDRs
Each stuffer contains at least one stop codon and a
restriction site that will be unique within the diversity vector.
gaggacc attgggcccc ctccgagact ctcgagcgca
Scab.....EcoO109I
ApaI.
XhoI..
acgcaattaa tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc
..-35.. Plac ..-10.
cggctcgtat gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatgac
catgatta cgccaagctt tggagccttt tttttggaga ttttcaac (SEQ ID NO: 95)
PflMI.......
Hind3.
M13 III signal sequence (AA seq)--------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
M K K L L F A I P L V V P F Y
gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac
--Signal--> FR1------------------------------------------->
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
S H S A Q S V L T Q S P G T L
/agc/cat/agt/gca/caa/tcc/gtc/ctt/act/caa/tct/cct/ggc/act/ctt/
ApaLI...
----- FR1 --------------------------------->/-------Stuffer->
31 32 33 34 35 36 37 38 39 40 41 42 43
S L S P G E R A T L S / / (SEQ ID NO: 96)
/tcg/cta/agc/ccg/ggt/gaa/cgt/gct/acc/tta/agt/tag/taa/gct/ccc/
(SEQ ID NO: 95; Cont'd)
EspI..... AflII...
XmaI....
- Stuffer for CDR1--> FR2 ------- FR2 ------>/-----------Stuffer for CDR2
59 60 61 62 63 64 65 66
K P G Q A P R
/agg/cct/ctt/tga/tct/g/aaa/cct/ggt/cag/gcg/ccg/cgt/taa/tga/aagcgctaatggccaacagtg
StuI... SexAI... KasI.... AfeI.. MscI..
Stuffer-->/--- FR3 ----------------------------------------------->
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T G I P D R F S G S G S G T D
(SEQ ID NO: 96; Cont'd)
/act/ggg/atc/ccg/gac/cgt/ttc/tct/ggc/tct/ggt/tca/ggt/act/gac/
(SEQ ID NO: 95; Cont'd)
BamHI...
RsrII.....
------ FR3 ----->----------------STUFFER for CDR3------------------>
91 92 93 94 95 96 97
F T L T I S R / /
/ttt/acc/ctt/act/att/tct/aga/taa/tga/ gttaac tag acc tacgta acc tag
XbaI... HpaI.. SnaBI.
-----------------CDR3 stuffer------------------>/-----FR4--->
118 119 120
F G Q
/ttc/ggt/caa/
-----FR4------------------->/ <------- Ckappa ------------
121 122 123 124 125 126 127 128 129 130 131 132 133 134
G T K V E I K R T V A A P S
(SEQ ID NO: 96; Cont'd)
/ggt/acc/aag/gtt/gaa/atc/aag/ /cgt/acg/gtt/gcc/gct/cct/agt/
(SEQ ID NO: 95; Cont'd)
StyI.... BsiWI..
135 136 137 138 139 140 141 142 143 144 145 146 147 148 149
V F I F P P S D E Q L K S G T
(SEQ ID NO: 96; Cont'd)
/gtg/ttt/atc/ttt/cct/cct/tct/gac/gaa/caa/ttg/aag/tca/ggt/act/
MfeI...
acgcatctctaa gcggccgc aacaggaggag
(SEQ ID NO: 95; Cont'd)
NotI....
EagI..
TABLE 11
2a2:JH2 Human lambda-chain gene with stuffers in place of CDRs
gaggaccatt gggcccc ttactccgtgac
Scab...... EcoO109I
ApaI..
-----------FR1-------------------------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
S A Q S A L T Q P A S V S G S P G
agt/gca/caa/tcc/gct/ctc/act/cag/cct/gct/agc/gtt/tcc/ggg/tca/cct/ggt/
ApaLI... NheI... BstEII...
SexAI....
------FR1------------------> /-----stuffer for CDR1---------
16 17 18 19 20 21 22 23
Q S I T I S C T
/caa/agt/atc/act/att/tct/tgt/aca/tct tag tga ctc
BsrGI..
-----Stuffer--------------------------->-------FR2---------->
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
R S / / P / H P G K A
aga tct taa tga ccg tag cac/ccg/ggc/aag/gcg/
BglII XmaI.... KasI.....
AvaI....
--/-------------Stuffer for CDR2 ----------------------------------------------->
P
/ccg/taa/tga/atc tcg tac g ct/ggt/gtt/
KasI.... BsiWI...
-------FR3----------------------------------------------------
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
S N R F S G S K S G N T A S L
(SEQ ID NO: 98; Cont'd)
/agc/aat/cgt/ttc/tcc/gga/tct/aaa/tcc/ggt/aat/acc/gca/agc/tta/
(SEQ ID NO: 97; Cont'd)
BspEI.. HindIII.
BsaBI........(blunt)
-------FR3------------->/--Stuffer for CDR3----------------->/
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T I S G L Q
/act/atc/tct/ggt/ctg/cag/gtt ctg tag ttc caattg ctt tag tga ccc
PstI... MfeI..
-----Stuffer------------------------------->/---FR4---------
103 104 105
G G G
/ggc/ggt/ggt/
KpnI...
-------FR4-------------->
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
T K L T V L G Q P K A A P S V
(SEQ ID NO: 98; Cont'd)
/acc/aaa/ctt/act/gtc/ctc/ggt/caa/cct/aag/gct/gct/cct/tcc/gtt/
(SEQ ID NO: 97; Cont'd)
KpnI... HincII..
Bsu36I...
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
T L F P P S S E E L Q A N K A
/act/ctc/ttc/cct/cct/agt/tct/gaa/gag/ctt/caa/gct/aac/aag/gct/
SapI.....
136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
T L V C L I S D F Y P G A V T
(SEQ ID NO: 98; Cont'd)
/act/ctt/gtt/tgc/ttg/atc/agt/gac/ttt/tat/cct/ggt/gct/gtt/act/
(SEQ ID NO: 97; Cont'd)
BclI....
The invention relates to generation of useful diversity in synthetic antibody (Ab) gene, especially to Ab genes having frameworks derived from human Abs.
BACKGROUND OF THE INVENTION
Antibodies are highly useful molecules because of their ability to bind almost any substance with high specificity and affinity and their ability to remain in circulation in blood for prolonged periods as therapeutic or diagnostic agents. For treatment of humans, Abs derived from human Abs are much preferred to avoid immune response to the Ab. For example, murine Abs very often cause Human Anti Mouse Antibodies (HAMA) which at a minimum prevent the therapeutic effects of the murine Ab. For many medical applications, monoclonal Abs are preferred. Nowadays the preferred method of obtaining a human Ab having a particular binding specificity is to select the Ab from a library of human-derived Abs displayed on a genetic package, such as filamentous phage.
Libraries of phage-displayed Fabs and scFvs have been produced in several ways. One method is to capture the diversity of donors, either naive or immunized. Another way is to generate libraries having synthetic diversity. The present invention relates to methods of generating useful diversity in human Ab scaffolds. As is well known, typical Abs consist of two heavy chains (HC) and two light chains (LC). There are several types of HCs: gamma, mu, epsilon, delta, etc. Each type has an N-terminal V domain followed by three or more constant domains. The LCs comprise an N-terminal V domain followed by a constant domain. LCs come in two types: kappa and lambda.
Within each V domain (LC or HC) there are seven canonical regions, named FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4, where “FR” stands for “Framework Region” and “CDR” stands for “Complementarity Determining Region”. For LC and HC, the FR and CDR GLGs have been selected over time to be secretable, stable, non-antigenic and these properties should be preserved as much as possible. Actual Ab genes contain mutations in the FR regions and some of these mutations contribute to binding, but such useful FR mutations are rare and are not necessary to obtain high-affinity binding. Thus, the present invention will concentrate diversity in the CDR regions.
In LC, FR1 up to FR3 and part of CDR3 comes from a genomic collection of genes called “V-genes”. The remainder of CDR3 and FR4 comes from a genomic collection of genes called “J-genes”. The joining may involve a certain degree of mutation, allowing diversity in CDR3 that is not present in the genomic sequences. After the LC gene is formed, somatic mutations can give rise to mature, rearranged LC genes that have higher affinity for an antigen (Ag) than does any LC encoded by genomic sequences. A large fraction of somatic mutations occur in CDRs.
The HC V region is more complicated. A V gene is joined to a J gene with the possible inclusion of a D segment. About half of HC Abs sequences contain a recognizable D segment in CDR3. The joining is achieved with an amazing degree of molecular sloppiness. Roughly, the end of the V gene may have zero to several bases deleted or changed, the D segment may have zero to many bases removed or changed at either end, a number of random bases may be inserted between V and D or between D and J, and the 5′ end of J may be edited to remove or change several bases. Withal, it is amazing that human heavy chains work, but they do. The upshot is that the CDR3 is highly diverse both in encoded amino-acid sequences and in length. In designing synthetic libraries, there is the temptation to just throw in a high degree of synthetic diversity and let the phage sort it out. Nevertheless, D regions serve a function. They cause the Ab repertoire to be rich in sequences that a) allow Abs to fold correctly, and b) are conducive to binding to biological molecules, i.e. antigens.
One purpose of the present invention is to show how a manageable collection of diversified sequences can confer these advantages on synthetic Ab libraries. Another purpose of the present invention is to disclose analysis of known mature Ab sequences that lead to improved designs for diversity in the CDR1 and CDR2 of HC and the three CDRs of lambda and kappa chains.
BRIEF STATEMENT OF THE INVENTION
The invention is directed to methods of preparing synthetically diverse populations of Ab genes suitable for display on genetic packages (such as phage or phagemids) or for other regimens that allow selection of specific binding. Said populations concentrate the diversity into regions of the Ab that are likely to be involved in determining affinity and specificity of the Ab for particular targets. In particular, a collection of actual Ab genes has been analyzed and the sites of actual diversity have been identified. In addition, structural considerations were used to determine whether the diversity is likely to greatly influence the binding activity of the Ab. Schemes of variegation are presented that encode populations in which the majority of members will fold correctly and in which there is likely to be a plurality of members that will bind to any given Ag. Specifically, a plan of variegation is presented for each CDR of the human heavy chain, kappa light chain, and lambda light chain. The variegated CDRs are presented in synthetic HC and LC frameworks.
In one embodiment, the invention involves variegation of human HC variable domains based on a synthetic 3-23 domain joined to a JH4 segment in which the variability in CDR1 and CDR2 comprises sequence variation of segments of fixed length while in CDR3 there are several components such that the population has lengths roughly corresponding to lengths seen in human Abs and having embedded D segments in a portion of the longer segments. In the light chains, the kappa chain is built in an A27 framework and a JK1 while lambda is built in a 2a2 framework with an L2 J region.
EXAMPLES
Choice of a Heavy-Chain V Domain
The HC Germ-Line Gene (GLG) 3-23 (also known as VP-47) accounts for about 12% of all human Abs and it suitable for the framework of the library. Certain types of Ags elicit Abs having particular types of VH genes; in some cases, the types elicited are otherwise rarely found. This apparent Ag/Ab type specificity has been ascribed to possible structural differences between the various families of V genes. It is also possible that the selection has to do with the availability of particular AA types in the GLG CDRs. Suppose, for example, that the sequence YR at positions 4 and 5 of CDR2 is particularly effective in binding a particular type of Ag. Only the V gene 6-1 provides this combination. Most Abs specific for the Ag will come from GLG 6-1. If Y4-R5 were provided in other frameworks, then other frameworks are likely to be as effective in binding the Ag.
Analysis of HC CDR1 and CDR2:
In CDR1 and CDR2 of HCs, the GLGs provide limited length diversity as shown in Table 15P. Note that GLGs provide CDR1s only of the lengths 5, 6, and 7. Mutations during the maturation of the V-domain gene leads to CDR1s having lengths as short as 2 and as long as 16. Nevertheless, length 5 predominates. The preferred length for the present invention is 5 AAs in CDR1 with a possible supplemental components having lengths of 7 and 14.
GLGs provide CDR2s only of the lengths 15-19, but mutations during maturation result in CDR2s of length from 16 to 28 AAs. The lengths 16 and 17 predominate in mature Ab genes and length 17 is the most preferred length for the present invention. Possible supplementary components of length 16 and 19 may also be incorporated.
Table 20P shows the AA sequences of human GLG CDR1s and CDR2. Table 21P shows the frequency of each amino-acid type at each position in the GLGs. The GLGs as shown in Table 20P have been aligned by inserting gaps near the middle of the segment so that the ends align.
The 1398 mature V-domain genes used in studying D segments (vide infra) were scanned for examples in which CDR1 and CDR2 could be readily identified. Of this sample 1095 had identifiable CDR1, 2, and 3. The CDRs were identified by finding subsequences of the GLGs in an open reading frame. There are 51 human HC V genes. At the end of FR1, there are 20 different 9-mers. At the start of FR2, there are 11 different 9-mers. At the end of FR2 there are 14 different 9-mers. At the start of FR3, there are 14 different 9-mers. At the end of FR3, there are 13 different 9-mers. At the start of JH, there are three different 9-mers. These motifs were compared to the reported gene in frame and a match, at the site of maximum similarity, of seven out of nine was deemed acceptable. Only when all three CDRs were identified were any of the CDRs included in the analysis. In addition, the type of the gene was determined by comparing the framework regions to the GLG frameworks; the results are shown in Table 22P.
Design of HC CDR1 and CDR2 Diversity.
Diversity in CDR1 and CDR2 was designed from: a) the diversity of the GLGs, b) observed diversity in mature HC genes, and c) structural considerations. In CDR1, examination of a 3D model of a humanized Ab showed that the side groups of residues 1, 3, and 5 were directed toward the combining pocket. Consequently, we allow each of these positions to be any amino-acid type except cysteine. Cysteine can form disulfide bonds. Disulfide bonds are an important component of the canonical Ig fold. Having free thiol groups could interfere with proper folding of the HC and could lead to problems in production or manipulation of selected Abs. Thus, I exclude cysteine from the menu. The side groups of residue 2 is directed away from the combining pocket. Although this position shows substantial diversity, both in GLG and mature genes, I fixed this residue as Tyr because it occurs in 681/820 mature genes (Table 21P). Position 4 is fixed as Met. There is some diversity here, but almost all mature genes have uncharged hydrophobic AA types: M, W, I, V, etc. (Table 21P). Inspection of a 3D model shows that the side group of residue 4 is packed into the innards of the HC. Since we are using a single framework (3-23), we retain the Met that 3-23 has because it is likely to fit very well into the framework of 3-23. Thus, the most preferred CDR1 library consists of XYXMX (SEQ ID NO:109) where X can be any one of [A,D,E,F,G,H,I,K,L,M,N,P,Q,R,S,T,V,W,Y] (no C). The DNA that encodes this is preferably synthesized using trinucleotide building blocks so that each AA type is present in essentially equimolar amounts. Specifically, the X codons are synthesized using a mixture of the codons [gct, gat, gag, ttt, ggt, cat, att, aag, atg, aat, cct, cag, cgt, tct, act, gtt, tgg, tat]. This diversity is shown in the context of a synthetic 3-23 gene in Table 18P. The diversity oligonucleotide (ON) is synthesized from BspEI to BstXI and can be incorporated either by PCR synthesis using overlapping ONs or introduced by ligation of BspEI/BstXI-cut fragments. Table 22P shows ONs that embody the specified variegation. PCR using ON-R1V1vg, ON-R1top, and ON-R1bot gives a dsDNA product of 73 base pairs, cleavage with BspEI and BstXI trims 11 and 13 bases from the ends and provides cohesive ends that can be ligated to similarly cut vector having the synthetic 3-23 domain shown in Table 18P. Replacement of ON-R1V1vg with either ONR1V2vg or ONR1V3vg allows synthesis of the two alternative diversity patterns given below.
Alternatively, one can include CDR1s of length 7 and/or 14. For length 7, a preferred diversity is (S/T) 1 (S/G/x) 2 (S/G/x) 3 Y 4 Y 5 W 6 (S/G/x) 7 (SEQ ID NO:107); where (S/T) indicates an equimolar mixture of Ser and Thr codons; (S/G/x) indicates a mixture of 0.2025 S, 0.2025 G, and 0.035 for each of A, D, E, F, H, I, K, L, M, N, P, Q, R, T, V, W, Y. Other proportions could be used. The design gives a predominance of Ser and Gly at positions 2, 3, and 7, as occurs in mature HC genes. For length 14, a preferred pattern of diversity is VSGGSISXXXYYWX (SEQ ID NO:1) where X can be any AA type except Cys. This pattern appears to arise by insertions into the GLG sequences (SGGYYWS; SEQ ID NO:110, (4-30.1 and 4-31) and similar sequences. There is a preference for a hydrophobic residue at position 1 (V or C) with a second insertion of SISXXX (SEQ ID NO:111) between GG and YY. Diversity ONs having CDR1s of length 7 or 14 are synthesized from BspEI to BstXI and introduced into the library in appropriate proportions to the CDR1 of length 5. The components should be incorporated in approximately the ratios in which they are observed in antibodies selected without reference to the length of the CDRs. For example, the sample of 1095 HC genes examined here have them in the ratios (L=5:L=7:L=14::820:175:23::0.80:0.17:0.02).
CDR2
Diversity at CDR2 was designed with the same considerations: GLG sequences, mature sequences and 3D structure. A preferred length for CDR2 is 17, as shown in Table 18P. Examination of a 3D model suggests that the residues shown as varied in Table 18P are the most likely to interact directly with Ag. Thus a preferred pattern of variegation is: <2>I<2><3>SGG<1>T<1>YADSVKG (SEQ ID NO:2), where <2> indicates a mixture of YRWVGS, <3> is a mixture of P and S, and <1> is a mixture of ADEFGHIKLMNPQRSTVWY (no C). ON-R2V1vg shown in Table 22P embodies this diversity pattern. PCR with ON-R2V1vg, ON-R2top, and ONR2bot gives a dsDNA product of 122 base pairs. Cleavage with BstXI and XbaI removes about 10 bases from each end and produces cohesive ends that can be ligated to similarly cut vector that contains the 3-23 gene shown in Table 18P.
An alternative pattern would include the variability seen in mature CDR2s as shown in Table 21P: <1>I<4><1><1>G<5><1><1><1>YADSVKG (SEQ ID NO:3), where <4>indicates a mixture of DINSWY, and <5> indicates a mixture of SGDN. This diversity pattern is embodied in ON-R2V2vg shown in Table 22P. For either case, the variegated ONs would be synthesized so that fragments of dsDNA containing the BstXI and XbaI site can be generated by PCR. ON-R2V2vg embodies this diversity pattern.
Alternatively, one can allow shorter or longer CDR2s. Table 22P shows ON-R2V3vg which embodies a CDR2 of length 16 and ON-R2V4vg which embodies a CDR2 of length 19. Table 22P shows ON-R2V3vg is PCR amplified with ON-R2top and ON-R2bo3 while ON-R2V4vg is amplified with ON-R2top and ONR2-bo4.
Analysis of HC CDR3:
CDR3s of HC vary in length and in sequence. About half of human HCs consist of the components: V::nz::D::ny::JHn where V is a V gene, nz is a series of bases (mean 12) that are essentially random, D is a D segment, often with heavy editing at both ends, ny is a series of bases (mean 6) that are essentially random, and JH is one of the six JH segments, often with heavy editing at the 5′ end. In HCs that have no identifiable D segment, the structure is V::nz::JHn where JH is usually edited at the 5′ end. Our goal is to mimic the diversity of CDR3, but not to duplicate it (which would be impossible). The D segments appear to provide spacer segments that allow folding of the IgG. The greatest diversity is at the junctions of V with D and of D with JH. The planned CDR3 library will consist of several components. Some of these will have only sequence diversity. Others will have sequence diversity with embedded D segments to extend the length while incorporating sequences known to allow Igs to fold.
There are many papers on D segments. Corbett et al. (1997) show which D segments are used in which reading frames. My analysis basically confirms their findings. They did not report, however, the level of editing of each D segment and this information is needed for design of an effective library.
The following diversified sequences would be incorporated in the indicated proportions: “1” stands for 0.095 [G, Y] and 0.048 [A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W]; double dose of Gly and Tyr plus all other AAs except Cys at equal level.
The amount of each component is assigned from the tabulation of lengths of the collection of natural VH genes. Component 1 represents all the genes having length 0 to 8 (counting from the YYCAR (SEQ ID NO:112) motif to the WG dipeptide motif). Component 2 corresponds the all the chains having length 9 or 10. Component 3 corresponds to the genes having length 11 or 12 plus half the genes having length 13. Component 4 corresponds to those having length 14 plus half those having length 13. Component 5 corresponds to the genes having length 15 and half of those having length 16. Component 6 corresponds to genes of length 17 plus half of those with length 16. Component 7 corresponds to those with length 18. Component 8 corresponds to those having length 19 and greater.
The composition has been adjusted because the first component is not complex enough to justify including it as 10% of the library. If the final library were to be 1. E 9, then 1. E 8 sequences would come from component 1, but it has only 2.6 E 5 CDR3 sequences so that each one would occur in ˜385 CDR1/2 contexts. I think it better to have this short CDR3 diversity occur in ˜77 CDR1/2 contexts and have the other, longer CDR3s occur more often.
The ONs would be PCR amplified with the primers CtprmA and CBprmB, cut with AflII and BstEII, and ligated to similarly cut V3-23.
This set of components was designed after studying the sequences of 1383 human HC sequences as described below. The proposed components are meant to fulfill the goals:
1) approximately the same distribution of lengths as seen in real Ab genes,
2) high level of sequence diversity at places having high diversity in real Ab genes, and
3) incorporation of constant sequences often seen in real Ab genes.
Note that the design uses JH4 (YFDYWGQGTLVTVSS; SEQ ID NO:20), which is found more often, instead of JH3 (AFDIWGQGTMVTVSS; SEQ ID NO:21). This involves three changes in AA sequence, shown as double underscored bold. An alternative JH segment is shown.
How the Library Components were Designed:
The processing of sequence data was accomplished by a series of custom-written FORTRAN programs, each of which carries out a fairly simple transformation on the data and writes its results as one or more ASCII files. The next program then uses these files as input.
A set of 2049 human heavy-chain genes was selected from the version of GenBank that was available at Dyax on the Sun server on 26 Jun. 2000. A program named “Reformat” changed the format of the files to that of GenBank from the GCG format, creating one file per sequence. A second program named “IDENT_CDR3” processed each of these files as follows. Files were tested for duplication by previous entries, duplicates were discarded. Each reading frame was tested. Most entries had a single open reading frame (ORF), none had two, and some had none. Entries with multiple stops in every reading frame were discarded because this indicates poor quality of sequencing. The sequence was written in triplets in the ORF or in all three reading frames if no ORF was found. The sequence was examined for three motifs: a) AA sequence=“YYCxx”, b) DNA sequence=“tgg ggc (=WG)”, and DNA sequence=“g gtc acc (=BstEII)”. FR3 ends with a conserved motif YYCAR or a close approximation. When writing the DNA sequence, IDENT_CDR3 prints the DNA mostly in lower case. Cysteine codons (TGT or TGC) are printed in uppercase. When the motif “tay tay tgy” is found, IDENT_CDR3 starts a new line that contains “< >xxx xxx xxx xxx xxx” where the xxx's stand for the actual five codons that encode YYC and the next two codons (most often AR or AK). The following DNA is printed in triplets on new lines. A typical processed entry appears as in Table 1P.
Following the YYC motif, IDENT_CDR3 seeks the sequence “TGG GGC” (the “WG” motif) in the correct reading frame, 5/6 bases is counted as a hit. If found, the DNA is made uppercase. Following the WG motif (if found) or the YYC motif (if no WG found), IDENT_CDR3 seeks the sequence “G GTC ACC” (the BstEII site) in the correct reading frame, 6/7 bases is counted as a hit. If found, the bases are made upper case. If either the WG or BstEII motif are not found, a note is inserted saying that the feature was not identified. The output of IDENT_CDR3 was processed by hand. In many cases, the lacking YYC motif could be seen as a closely related sequence, such as YFC, FYC, or HYC. When this was supported by an appropriately positioned WG and/or BstEII site, the effective YYC site was marked and the sequence retained for further analysis. If the YYC motif could not be identified or if the WG or BstEII sites could not be found, the entry was discarded. For example, the entry in Table 2P had no YYC motif.
The double underscored sequence encodes YHCAS and is taken as the end of FR3. Note that there is a WG motif at bases 403-408 (bold upper case) and a BstEII site at bases 420-426 (bold upper case). Using WordPerfect, I first made all occurrences of TGC and TGT bold. I then searched for “YYC not found”. If I could see the “YYC”-related sequence quickly, I edited the entry so that a YYC was shown. The entry above would be converted to that shown in Table 3P. This processing reduced the list of entries to 1669.
A third program named “New_DJ” processed the output of IDENT_CDR3. The end of the YYC motif (including the two codon following TGy=Cys) was taken as the end of FR3. The WG motif was taken as the end of the region that might contain a D segment. If WG was not observed and BstEII was, the WG site was assumed to be 17 bases upstream of BstEII. Using the WG motif for alignment, the sequence was compared to each human GLG JH segment (1-6) and the best one identified (New_DJ always assigned a JH segment). Starting from the WG motif of JH and moving toward the 5′ end, the program looked for the first codon having more than one mismatch. The region from YYCxx (SEQ ID NO:113) to this codon was taken as the region that might contain a D segment.
The region that might contain a D segment was tested against all the germ-line genes (GLGs) of human D segments and the best D segment was identified. The scoring involved matching the observed sequence to the GLG sequence in all possible ways. Starting at each base, multiply by 4 for a match and divide by 4 for a mismatch. Record the maximum value obtained for this function. The match was deemed significant if 7/7, 8/9, 9/11, etc. or more bases matched. Of the 1383 sequences examined for D segments,
“Assign_D” processes the output of New_DJ. For each sequence that had a significant match with a GLG D segment, a file was written containing the putative D segment, the DJ segment, the identified GLG D segment, the identified JH segment, the phase of the match between observed and GLG gene. For example, “D1 — 1-01_Phz0_hsa239356.txt” is a file recording the match of entry hsa239356 with D1-01 in phase 0. The file contains the information shown in Table 4P. The final DV of the second sequence immediately precedes the WG in JH and is ascribed to JH3. Other files that begin D1 — 1-01_Phz0 match the same GLG D segment and these can be aligned by sliding amino-acid sequences across each other.
Table 5P shows how sequence hs6d4xb7 is first assigned to JH4 and then to D3-22. Note that the DNA sequence TGGGGG is aligned to the TGG GGC of the GLG and that the sequence is truncated on the left to fit. The program finds that JH4 has the best fit (5 misses and 18 correct out of 23). From the right, the program sees that DYWGQ (underscored) come from JH, but then the match drops off and the rest of the sequence on the left comes either from added bases or a D segment.
The lower part of Table 5P shows that the possible D segment matches D#13 (3-23) is a very good match.
Of 1383 files accepted by Assign_D, 757 had identifiable D segments. The tally of JHs in Table 6P shows that JH4 is by far the most common.
JH4 is most common, JH6 next, followed by JH3 and JH5. JH1 and JH2 are seldom used. Table 7P shows the length distributions of each JH class; they do not differ significantly class to class. These lengths count only amino-acids that are not accounted for by JH and so are shorter that the lengths given in Table 8P which cover from YYCAR (SEQ ID NO:112) to WG.
Table 8P contains the distribution of lengths for a) all the CDR3 segments, b) the CDR3 segments with identified D segments, and c) the CDR3 segments having no identifiable D segment. The CDR3s with identifiable D segments (13.9) are systematically longer than are those that lack D segments (11.2).
The identified CDR3 segments can be collated in two ways: aligned to the left (looking for a pattern following YYCAR; SEQ ID NO:112) or aligned to the right (looking for a pattern preceding WG). Table 9P shows the collation of left-aligned sequences while Table 10P shows the right-aligned sequences. For each position, I have tabulated the frequency of each AA type (A-M in the first block and N-Y in the second). The column headed “#” shows how many sequences have some AA at that position. The final column shows all of the AA types seen at that position with the most frequent first and the least frequent last. In the left-aligned sequences, we see that Gly is highly over-represented in the first seven positions while Tyr is over-represented at positions 8-16.
In Table 11P, I have tabulated the AA frequencies for the sequences having between 7 and 15 AAs between YYCAR (SEQ ID NO:112) and WG. The last four positions can be viewed as coming from JH and so would be given lower levels of diversity than would earlier positions. From these tabulations, I conclude that most AA types are allowed at all the positions, but there is a fairly strong tendency to have Gly at the early positions and to end in Asp-Tyr (DY). We could use these tendencies in designing a pattern of variegation. I would not exclude any AA except Cys, but I might increase the frequency of Gly in the first several positions and Tyr in the last few.
There are 80 sequences (5.8%) having a pair of cysteines in CDR3. It is more surprising that 53 (3.8%) have a single Cys in CDR3.
MS-DOS was used to make a list of the files written by Assign_D. “Filter” converts the output of MS-DOS Dir into a form that can be read into WordPerfect and sorted to bring a files belonging to the same D region together.
“Filter2” collects the sequences and produces a draft table of sequences, grouped by the D-segment used, and written so that the sequences can be aligned. The output of Filter2 were edited by hand. For each group, the translation of the GLG was inserted and the collection of observed sequences was aligned to the conserved part of the GLG.
“Filter3” collated the aligned sequences. Table 12P shows an example of an alignment and the tabulation of AA types. The entries are as follows: “Entry” is the name used in the data base, “Seq1” is the sequence from the YYCAR (SEQ ID NO:112) motif to the first amino acid not assigned to JH and “L1” is the length of the segment. The segments are shown aligned to the identified D segment. Seq2 is the sequence from the YYCAR (SEQ ID NO:112) motif to the WG motif (i.e. including part of JH) and “L2” is the length of that sequence. JH is the identified JH segment for this sequence. “P” is the phase of the match. For positive values of P, P bases are found in the observed sequence that do not correspond to any from the GLG, i.e. the observed sequence has had that many bases inserted. For negative values of P, there are |P| bases in the GLG sequence for which there are no corresponding bases in the observed sequence. “Score” is approximately 1/(probability of accidental match). This is calculated by looking at all possible alignments. For each alignment, the score is first set to 1.0. Base by base, the score is multiplied by 4. if the bases match and divided by 4. if they do not. This is done for all starting points and ending points and the maximum value is recorded.
Table 13P is a summary of how often each D segment was identified and in which reading frame. I have not been consistent with Corbett et al. in assigning the phases of the GLG D segments. The MRC Web page that I took the GLGs from did not have D segments D1-14, D4-11, D5-18, or D6-25. None of these contribute to any great extent and this omission is unlikely to have any serious effect on the conclusions. The column headed “%” contains the percentage of the sequences examined here. The column headed “C %” contains the percentage reported by Corbett et al. I assume that the data used in Corbett et al. is mostly included in my collection. Nevertheless, the observed frequencies differ in detail. For example, my compilation shows that 10.7% of the collection contains a D segment encoding two cysteines while they have only 4.16% in this category. In D3 phase “0”, I see 19.4% of the collection while they report 11.8%.
The most common actual D segments were further analyzed. The GLGs are heavily edited at either end. The aligned sequences were aligned. For each D-segment having more than seven examples, Filter3 produced a table of the frequency of each amino-acid type at each position. From these tabulations, library components shown in Table 17P were designed. At each position where at least half the examples have an amino acid, I entered either the dominant AA type or “x”. An AA type was “dominant” if it occurred more than 50% of the time. L is the length and f is the number of sequences observed that have related sequences.
Table 14P shows possible library components for a library of CDR3's. “L” is the length of the insert and “f” is the frequency of the motif in the assayed collection. Table 17P shows vgDNA that embodies each of the components shown in Table 14P. In Table 17P, the oligonucleotides (ON) Ctop25, CtprmA, CBprmB, and CBot25 allow PCR amplification of each of the variegated ONs (vgDNA): C1t08, C2t10, C3t12, C4t14, C5t15, C6t17, C7t18, and c8t19. After amplification, the dsDNA can be cleaved with AflII and BstEII (or KpnI) and ligated to similarly cleaved vector that contains the remainder of the 3-23 synthetic domain. Preferably, this vector already contains diversity in CDR1 and CDR2 as disclosed herein. Preferably, the recipient vector contains a stuffer in place of CDR3 so that there will be no parental sequence that would then occur in the resulting library. Table 50P shows a version of the V3-23 gene segment with each CDR replaced by a short segment that contains both stop codons and restriction sites that will allow specific cleavage of any vector that does not have the stuffer removed. The stuffer can either be short and contain a restriction enzyme site that will not occur in the finish library, allowing removal of vectors that are not cleaved by both AflII and BstEII (or KpnI) and religated. Alternatively, the stuffer could be 200-400 bases long so that uncleaved or once cleaved vector can be readily separated from doubly cleaved vector.
In the vgDNA for HC CDR3, <1> means a mixture comprising 0.27 Y, 0.27 G, and 0.027 of each of the amino-acid codons {A, D, E, F, H, I, K, L, M, N, P, Q, R, S, T, V, W}; <2> means an equimolar mixture of K and R; and <3> means an equimolar mixture of S and G.
Analysis of Human Kappa Light Chains and Preferred Variegation Scheme:
A collection of 285 human kappa chains was assembled from the public data base. Table 27 shows the names of the entries used. The GLG sequences of nine bases at each end of the framework regions were used to find the FR/CDR junctions. Only in cases where all six junctions could be found was the sequences included. Table 25P shows the distribution of lengths in CDRs in human kappas. CDR1s with lengths of 11, 12, 13, 16, and 17 were observed with 11 being predominant and 12 well represented. CDR2 exhibits only length 7. CDR3 exhibits lengths of 1, 4, 6, 7, 8, 9, 10, 11, 12, 13, and 19. Essentially all examples are in the 8, 9, or 10 length groups. Table 26P shows the distribution of V and J genes seen in the sample. A27 is the most common V and JK1 is the most common J. Thus, a suitable synthetic kappa gene comprises A27 joined to JK1. Table 30P shows a suitable synthetic kappa chain gene, including a PlacZ promoter, ribosome-binding site, and signal sequence (M13 III signal). The DNA sequence encodes the GLG amino-acid sequence, but does not comprise the GLG DNA sequence. Restriction sites are designed to fall within each framework region so that diversity can be cloned into the CDRs. XmaI and Espl are in FR1, SexAI is in FR2, RsrII is in FR3, and KpnI (or Acc65I) are in FR4. Additional sites are provided in the constant kappa chain to facilitate construction of the gene.
Table 30P also shows a suitable scheme of variegation for kappa. In CDR1, a preferred length is 11 codons. The A27 GLG has a CDR1 of 12 codons, but the sample of mature kappa chains has length 11 predominating. One could also introduce a component of kappas having length 12 in CDR1 by introducing codon 52 as <2> (i.e. a Ser-biased mixture). CDR2 of kappa is always 7 codons. Table 31P shows a tally of 285 CDR2s and a preferred variegation scheme for CDR2. The predominant length of CDR3 in kappa chains is 9 codons. Table 32P shows a tally of 166 CDR3s from human kappas and a preferred variegation scheme (which is also shown in Table 30P).
Analysis of Lambda Chains and Preferred Variegation Scheme:
A collection of 158 lambda sequences was obtained from the public data base. Of these 93 contained sequences in which the FR/CDR boundaries could be identified automatically. Table 33P shows the distribution of lengths of CDRs.
Method of Construction:
The diversity of HC, kappa, and lambda are best constructed in separate vectors. First a synthetic gene is designed to embody each of the synthetic variable domains. The light chains are bounded by restriction sites for ApaLI (positioned at the very end of the signal sequence) and AscI (positioned after the stop codon). The heavy chain is bounded by SfiI (positioned within the Pe1B signal sequence) and NotI (positioned in the linker between CH1 and the anchor protein. The initial genes are made with “stuffer” sequences in place of the desired CDRs. A “Stuffer” is a sequence the is to be cut away and replaced by diverse DNA but which does not allow expression of a functional antibody gene. For example, the stuffer may contain several stop codons and restriction sites that will not occur in the correct finished library vector. In Table 40P, the stuffer for CDR1 of kappa A27 contains a StuI site. The vgDNA for CDR1 is introduced as a cassette from EspI, XmaI, or AflII to either SexAI or KasI. After the ligation, the DNA is cleaved with StuI; there should be no StuI sites in the desired vectors.
REFERENCES
Corbett, S J, Tomlinson, I M, Sonnhammer, E L L, Buck, D, Winter, G. “Sequences of the Human Immunoglobulin Diversity (D) Segment Locus: A Systematic Analysis Provides No Evidence for the Use of DIR Segments, Inverted D Segments, ‘Minor’ D Segments or D-D Recombination”. J Molec Biol (1997) 270:587-597.
TABLES
TABLE 1P
Typical entry in which YYC motif is found.
++++C:\tmp\haj10335.txt
LOCUS
HAJ10335 306 bp mRNA PRI Aug. 18, 1998
DEFINITION
Homo sapiens mRNA for immunoglobulin heavy chain variable region,
clone ELD16/6.
ACCESSION
AJ010335
VERSION
AJ010335.1 GI: 3445266
Ngene =
306
Stop codons in reading frame 1
49 115 124 253 277
No stops in reading frame 2
Stop codons in reading frame 3
12 60 81 147 204 213
(SEQ ID NO: 113)
1
t ttg ggg tcc ctg aga ctc tcc TGT gca gcc tct gga ttc acc
44
gtc agt agc aac tac atg acc tgg gtc cgc cag gct cta ggg aag
89
ggg ctg gag tgg gtc tca gtt att tat agc ggt ggt agc aca tac
134
tac gca gac tcc gtg aag ggc gga ttc acc atc tcc aga gac aat
179
tcc aag aac aca ctg tat ctt caa atg aac agc ctg aga ccc gag
224
gac acg gct gtg
<
> TAT TAC TGT gcg aca
251
ggt aat cgc ctg gaa atg gct gca att aac TGG GGC caa gga acc
263
ctG GTC ACC aa
TABLE 2P
entry in which YYC motif was not automatically identified
++C:\tmp\hs202g3.txt
!!NA_SEQUENCE 1.0
LOCUS
HS202G3 522 bp mRNA PRI Aug. 3, 1995
DEFINITION
H. sapiens mRNA for immunoglobulin variable region (clone 202-G3).
ACCESSION
Z47259
VERSION
Z47259.1 GI: 619470
Ngene =
522
No stops in reading frame 1
Stop codons in reading frame 2
89 110 305 314
Stop codons in reading frame 3
84 192 321 351 369
(SEQ ID NO: 114)
1
atg gac tgg acc tgg agg ttc ctc ttt gtg gtg gca gca gct aca
46
ggt gtc cag tcc cag gtg cag ctg gtg cag tct ggg gct gag gtg
91
aag aag cct ggg tcc tcg gtg aag gtc tcc TGC aag gct tct gga
136
ggc acc ttc agc agc tat gct atc agc tgg gtg cga cag gcc cct
181
gga caa ggg ctt gag tgg atg gga ggg atc atc cct atc ttt ggt
226
aca gca aac tac gca cag aag ttc cag ggc aga gtc acg att acc
271
gcg gac gaa tcc acg agc aca gcc tac atg gag ctg agc agc ctg
316
aga tct gag gac acg gcc gtg tat cac TGT gcg agt gag gga tgg
361
gag agt TGT agt ggt ggt ggc TGC tac gac ggt atg gac gtc TGG
406
GGC caa ggg acc ac G GTC ACC gtc tcc tca gct tcc acc aag ggc
451
cca tcg gtc ttc ccc ctg gcg ccc TGC tcc agg agc acc tct ggg
496
ggc aca gcg gcc ctg ggc TGC ctg
YYC
not found !!!
TABLE 3P
Entry of Table 2P after editting.
++C:\tmp\hs202g3.txt
!!NA_SEQUENCE 1.0
LOCUS
HS202G3 522 bp mRNA PRI Aug. 3, 1995
DEFINITION
H. sapiens mRNA for immunoglobulin variable region (clone 202-G3).
ACCESSION
Z47259
VERSION
Z47259.1 GI: 619470
Ngene =
522
No stops in reading frame 1
Stop codons in reading frame 2
89 110 305 314
Stop codons in reading frame 3
84 192 321 351 369
(SEQ ID NO: 116)
1
atg gac tgg acc tgg agg ttc ctc ttt gtg gtg gca gca gct aca
46
ggt gtc cag tcc cag gtg cag ctg gtg cag tct ggg gct gag gtg
91
aag aag cct ggg tcc tcg gtg aag gtc tcc TGC aag gct tct gga
136
ggc acc ttc agc agc tat gct atc agc tgg gtg cga cag gcc cct
181
gga caa ggg ctt gag tgg atg gga ggg atc atc cct atc ttt ggt
226
aca gca aac tac gca cag aag ttc cag ggc aga gtc acg att acc
271
gcg gac gaa tcc acg agc aca gcc tac atg gag ctg agc agc ctg
316
aga tct gag gac acg gcc gtg
<YHCAS> tat cac TGT gcg agt
(SEQ ID NO: 115)
gag gga tgg
361
gag agt TGT agt ggt ggt ggc TGC tac gac ggt atg gac gtc TGG
406
GGC caa ggg acc ac G GTC ACC gtc tcc tca gct tcc acc aag ggc
451
cca tcg gtc ttc ccc ctg gcg ccc TGC tcc agg agc acc tct ggg
496
ggc aca gcg gcc ctg ggc TGC ctg
YYC
not found !!!
TABLE 4P
contents of file D1_1-01_Phz0_hsa239356.txt
DRGGKYQLAPKGGM
(SEQ ID NO: 117)
DRGGKYQLAPKGGMDV
(SEQ ID NO: 118)
JH3 D# 1 Phase 15 Score 6.55D+04
-----------------------------------------------
TABLE 5P
alignment of a CDR3:: JH segment to GLG JHs and D-segments.
+C:\tmp\hs6d4xb7.txt
1 1 2 2 3 3 3
1234567890 5 0 5 0 5 9
Observed
tatgatagtagtgggtcatactccgactacTGGGGGcag
(SEQ ID NO: 119)
JH1
------------ g ctga atact t c c a gc ac tggggccagggcaccctggtcaccgtctcctcag
(SEQ ID NO: 120)
Miss = 9 Nt = 27
JH2
-----------ctac t gg tact t cga tct c tggggccgtggcaccctggtcactgtctcctcag
(SEQ ID NO: 121)
Miss = 13 Nt = 28
JH3
--------------tgatgct t tt ga tat c tggggccaagggacaatggtcaccgtctcttcag
(SEQ ID NO: 122)
Miss = 14 Nt = 25
JH4
----------------ac tact tt gactac tggggccagggaaccctggtcaccgtctcctcag
(SEQ ID NO: 123)
Miss = 5 Nt = 23
JH5
-------------acaac t gg t t cgac cc c tggggccagggaaccctggtcaccgtctcctcag
(SEQ ID NO: 124)
Miss = 11 Nt = 26
JH6
- at t a ctactactac t acggtatg gac gtctggggccaagggaccacggtcaccgtctcctcag
(SEQ ID NO: 125)
Miss = 23 Nt = 38
4
tat gat agt agt ggg tca TAC Tcc GAC TAC TGG GGg CAG
(SEQ ID NO: 126)
Y D S S G S Y S D Y W G Q
(SEQ ID NO: 127)
JH4
--- --- --- --- --- -ac tac ttt gac tac tgg ggc cag gga acc ctg
(SEQ ID NO: 128)
- - - - - - Y F D W W G Q G T L
(SEQ ID NO: 129)
gtc acc gtc tcc tca g--
V T V S S -
Fract = 0.783 = 18/23
D#13
--------gtattactatgatagtagtggttattactac GLG
(SEQ ID NO: 130)
gatcgccacaattactatgatagtagtgggtcatactcc Observed
(SEQ ID NO: 131)
--------gt...................t.at....a. . = match
D#13
Phase = 9 Score = 4.3980E+12
-----------------------------------------------------------------------------
TABLE 6P
Number of sequences
identified as having JH derived from GLG JHn
JH
1
2
3
4
5
6
# sequences
17
40
198
707
160
261
--------------------------------------------------
TABLE 7P
Distribution of CDR3 fragments that might contain D segments.
For JH1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
0
1
1
3
1
1
2
0
3
1
1
1
2
Total = 17 Median = 8.0
For JH2
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0
0
0
0
0
2
4
6
2
6
3
4
5
2
3
15
16
17
18
2
0
0
1
Total = 40 Median = 9.0
For JH3
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0
0
2
6
16
12
17
17
15
22
20
20
18
13
4
15
16
17
18
19
8
3
2
1
2
Total = 198 Median = 8.6
For JH4
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0
0
7
15
19
40
63
82
81
77
81
53
57
44
30
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
15
23
8
3
5
2
0
1
0
0
0
0
0
0
0
30
31
32
33
34
35
0
0
0
0
0
1
Total = 707 Median = 8.6
For JH5
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0
0
0
3
4
6
13
19
12
14
22
18
10
18
10
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
5
1
1
0
0
1
1
0
0
0
0
0
0
0
0
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
45
46
0
1
Total = 160 Median = 9.4
For JH6
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2
0
1
2
5
15
20
18
22
29
29
28
23
16
10
15
16
17
18
19
20
14
9
9
4
2
3
Total = 261 Median = 9.6
TABLE 8P
Lengths of CDR3 segments from YYCAR to WG.
Distribution of lengths from end of FR3 to WG motif all sequences.
L
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
N
6
0
0
4
2
9
13
38
61
88
101
118
154
150
118
Sum(N)
6
6
6
10
12
21
34
72
133
221
322
440
594
744
862
f
.004
.004
.004
.007
.009
.015
.025
.052
.096
.160
.233
.318
.430
.538
.623
L
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
N
125
105
84
61
46
42
16
17
7
9
2
1
0
2
1
SN
987
1092
1176
1237
1283
1325
1341
1358
1365
1374
1376
1377
1377
1379
1380
f
.714
.790
.850
.894
.928
.958
.970
.982
.987
.993
.995
.996
.996
.997
.998
L
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
N
0
0
0
0
0
0
0
1
0
0
0
0
1
0
0
SN
1380
1380
1380
1380
1380
1380
1380
1381
1381
1381
1381
1381
1382
1382
1382
f
.998
.998
.998
.998
.998
.998
.998
.999
.999
.999
.999
.999
.999
.999
.999
L
45
46
N
0
1
SN
1382
1383
f
.999
1.0
Median = 12.65
L is the length
N is the number of examples
Sum(N) = SN is the sum of the Ns
f is the cumulative fraction seen
Distribution of lengths from end of FR3 to WG motif with assigned D.
L
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
N
3
0
0
0
0
0
3
9
21
15
39
64
77
97
72
SN
3
3
3
3
3
3
6
15
36
51
90
154
231
328
400
f
.004
.004
.004
.004
.004
.004
.008
.019
.046
.065
.115
.196
.294
.418
.510
L
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
N
77
75
63
45
35
38
15
15
6
9
2
1
0
1
1
SN
477
552
615
660
695
733
748
763
769
778
780
781
781
782
783
f
.608
.703
.783
.841
.885
.934
.953
.972
.980
.991
.994
.995
.995
.996
.997
L
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
N
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
SN
783
783
783
783
783
783
783
784
784
784
784
784
784
784
784
f
.997
.997
.997
.997
.997
.997
.997
.999
.999
.999
.999
.999
.999
.999
.999
L
45
46
N
0
1
SN
784
785
f
.999
1.0
Median = 13.90
Distribution of lengths from end of FR3 to WG motif with no assigned D.
L
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
N
3
0
0
4
2
9
10
29
40
73
62
54
77
53
46
SN
3
3
3
7
9
18
28
57
97
170
232
286
363
416
462
f
.005
.005
.005
.012
.015
.030
.047
.095
.162
.284
.388
.478
.607
.696
.773
L
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
N
48
30
21
16
11
4
1
2
1
0
0
0
0
1
0
SN
510
540
561
577
588
592
593
595
596
596
596
596
596
597
597
f
.853
.903
.938
.965
.983
.990
.992
.995
.997
.997
.997
.997
.997
.998
.998
L
30
31
32
33
34
35
36
37
38
39
40
41
42
N
0
0
0
0
0
0
0
0
0
0
0
0
1
SN
597
597
597
597
597
597
597
597
597
597
597
597
598
f
.998
.998
.998
.998
.998
.998
.998
.998
.998
.998
.998
.998
1.0
Median = 11.17
TABLE 9P
Tally of left-aligned CDR3 sequences
A
C
D
E
F
G
H
I
K
L
M
#
1
74
6
278
109
11
319
50
18
11
60
8
1383
GDERVASLHTNQPIWYFKMCX
2
50
9
64
32
29
249
43
42
41
109
22
1377
GRPSLDVYTANHIQKEFMWCX
3
81
18
74
39
25
214
29
42
16
83
19
1377
GSYRTVLADPIWEQHNFMCK/
4
70
23
92
49
50
228
23
58
21
70
16
1373
GSYDRVALTIPFEWNCHQKMX
5
86
28
106
32
59
217
21
41
16
72
19
1371
GYSDAVTLRFIPWNECHMQK/X
6
88
17
104
28
94
171
17
48
12
50
17
1362
GYSDFATVRWPLINEQCHMK/
7
69
15
110
21
89
176
22
50
15
81
12
1349
GSYDFVLTAPRWINHEQCKM/X
8
53
19
141
17
90
150
18
47
17
68
11
1311
YSGDFLTVWAPIRNCHEKQM/
9
44
21
120
24
102
174
24
36
20
71
11
1250
YGSDFLNVRTAWPIEHCKQM/
10
39
31
129
23
124
116
23
42
9
58
32
1162
YDFGSLIARPTVWNMCEHQK
11
36
12
158
17
137
83
13
18
10
40
21
1061
YDFGSPLVANWMTRIEHCKQX
12
34
11
164
10
82
74
34
30
1
31
20
943
YDFGPSVAHLINMRTWCEQKX
13
32
2
121
6
84
56
10
26
7
43
32
789
YDFGLSPVAMIWRTHNKQEC
14
23
131
5
59
65
10
16
4
25
34
639
YDGFMVLAPISWNRHTQEKX
15
15
4
107
5
43
42
1
23
20
34
521
YDFGVMILWAPRSENCQTH/
16
4
2
80
3
33
26
4
5
1
10
29
396
YDVFMGPSLNTRIWAHECQ/K
17
3
1
63
19
19
9
13
12
21
291
DYVMFGILHPSTWAQRCNX
18
3
47
16
13
1
4
7
23
207
DYVMFGPSLTIAHN
19
5
1
39
1
4
13
3
3
1
14
146
DYVMGAFHINRSCELPQW
20
2
17
4
5
3
4
12
100
VYDMGFLIPSARWQ
21
17
3
8
1
1
4
58
DVGYMFHINTW
22
1
7
6
1
1
5
42
VDFMYSAGITW
23
9
1
1
1
1
25
DVYGILMPS
24
1
2
1
1
1
18
VYDAHLMPT
25
1
3
9
GVDPSY
26
2
2
7
GMSTV
27
2
1
1
6
DKMST
28
1
1
1
6
VADGS
29
1
4
DPSV
30
1
3
FST
31
1
1
3
KLV
32
1
1
3
FGP
33
1
3
PG
34
1
1
3
HLS
35
1
3
AVW
36
1
1
3
DFP
37
3
PSY
38
1
2
LS
39
1
1
2
AK
40
2
PS
41
2
ST
42
2
S
43
1
1
K
44
1
S
45
1
T
46
1
S
816
220
2186
421
1166
2428
358
568
205
920
421
N
P
Q
R
S
T
V
W
Y
/
X
#
1
35
23
31
108
63
50
94
16
13
6
1383
GDERVASLHTNQPIWYFKMCX
2
44
114
42
169
114
59
62
21
60
2
1377
GRPSLDVYTANHIQKEFMWCX
3
26
73
37
110
140
97
89
42
122
1
1377
GSYRTVLADPIWEQHNFMCK/
4
48
51
22
79
141
65
77
49
139
2
1373
GSYDRVALTIPFEWNCHQKMX
5
37
41
18
61
157
75
85
38
158
2
2
1371
GYSDAVTLRFIPWNECHMQK/X
6
32
54
23
67
152
80
78
64
165
1
1362
GYSDFATVRWPLINEQCHMK/
7
44
59
18
58
157
73
85
54
139
1
1
1349
GSYDFVLTAPRWINHEQCKM/X
8
38
48
14
41
167
68
59
59
185
1
1311
YSGDFLTVWAPIRNCHEKQM/
9
52
40
14
47
123
45
48
41
192
1
1250
YGSDFLNVRTAWPIEHCKQM/
10
33
37
12
39
73
36
36
35
235
1162
YDFGSLIARPTVWNMCEHQK
11
33
49
7
20
68
21
37
29
251
1
1061
YDFGSPLVANWMTRIEHCKQX
12
30
53
10
19
45
19
42
18
215
1
943
YDFGPSVAHLINMRTWCEQKX
13
10
34
7
22
40
15
33
25
184
789
YDFGLSPVAMIWRTHNKQEC
14
13
22
6
12
15
10
26
14
148
1
639
YDGFMVLAPISWNRHTQEKX
15
5
12
3
12
12
3
40
20
119
1
521
YDFGVMILWAPRSENCQTH/
16
10
24
2
6
12
7
49
5
82
2
396
YDVFMGPSLNTRIWAHECQ/K
17
1
8
2
2
8
5
42
4
58
1
291
DYVMFGILHPSTWAQRCNX
18
1
13
8
5
31
35
207
DYVMFGPSLTIAHN
19
2
1
1
2
2
24
1
29
146
DYVMGAFHINRSCELPQW
20
3
1
2
3
23
2
19
100
VYDMGFLIPSARWQ
21
1
1
14
1
7
58
DVGYMFHINTW
22
2
1
12
1
5
42
VDFMYSAGITW
23
1
1
5
5
25
DVYGILMPS
24
1
1
5
5
18
VYDAHLMPT
25
1
1
2
1
9
GVDPSY
26
1
1
1
7
GMSTV
27
1
1
6
DKMST
28
1
2
6
VADGS
29
1
1
1
4
DPSV
30
1
1
3
FST
31
1
3
KLV
32
1
3
FGP
33
2
3
PG
34
1
3
HLS
35
1
1
3
AVW
36
1
3
DFP
37
1
1
1
3
PSY
38
1
2
LS
39
2
AK
40
1
1
2
PS
41
1
1
2
ST
42
2
2
S
43
1
K
44
1
1
S
45
1
1
T
46
1
1
S
495
769
270
876
1518
741
1104
540
2572
10
17
18621
TABLE 10P
Tally of right-aligned sequences
A
C
D
E
F
G
H
I
K
L
M
#
5
1
1
G
6
1
S
7
1
1
G
8
1
1
G
9
2
RV
10
2
RV
11
1
1
2
GI
12
2
V
13
2
TY
14
1
1
3
DGN
15
1
3
ISY
16
1
3
DSY
17
1
3
APY
18
1
1
1
3
DFM
19
2
1
3
DG
20
1
1
3
ILV
21
3
WP
22
3
4
GS
23
2
1
6
GHQSV
24
1
3
1
6
GALR
25
1
2
1
7
DTAIS
26
1
1
1
1
1
1
1
9
ACDGKLMST
27
2
5
1
2
1
1
18
DAGVEILNQRS
28
2
2
3
1
2
25
TGQSDELPRIV
29
3
5
6
7
1
1
1
42
GEDVAPQRSKLMTY/
30
2
9
1
9
1
4
5
2
58
DGRLSIVPAMQTFHNY
31
4
2
19
9
2
18
1
2
1
3
100
DGSERVYALPTCFINHKW
32
10
5
18
5
3
16
3
3
2
14
1
146
DGLRVAPYSTCEQFHINWKM
33
20
18
10
7
34
7
8
2
6
1
207
GARDPSYTEVIFHLQWKM
34
13
4
31
18
9
37
8
16
4
14
4
291
GDRYPVEILASTFHQWCKMNX/
35
17
5
32
23
10
70
12
10
6
25
1
396
GRSDYLEVTPAHNFIWKCQM/
36
23
6
51
21
9
79
19
15
14
36
9
521
GDSYRLTVPAEHIKNFMWCQ/
37
35
12
56
23
15
110
14
17
5
24
4
639
GYDVRSTAPLEIFHNCWQKMX
38
28
19
68
27
29
133
26
31
12
43
7
789
GSYDVRLPTIFAEHCNWKQM
39
51
25
80
27
33
162
16
30
18
55
15
943
GSDRYVLATPFWIECKHMQNX
40
44
14
73
36
46
161
27
32
17
59
8
1061
GSRDYVTLPFAEIWHQNKCM
41
54
21
74
25
23
178
23
52
15
57
11
1162
GSYTDRVLPAIWNQEFHCKMX/
42
57
13
82
40
42
190
14
39
15
82
15
1250
GSYDLVRTANPFEIWQKMHC/
43
75
18
54
25
35
242
13
29
18
49
12
1311
GYSTARVPDLWNFIQECKHM/
44
63
17
79
15
43
197
20
38
14
76
8
1349
YGSTDLRAPVWNFIQHCEKM
45
59
16
69
35
55
165
26
23
23
75
9
1362
YGSLRTDNAFPVWEHIKCQM
46
41
19
125
26
27
208
31
14
16
38
8
1371
YGDSNRWATLPHFEVQCKIM
47
160
10
24
13
53
332
36
16
11
40
10
1373
GYAWPSFRLHTVNDIEKCMQX
48
21
4
8
5
680
27
4
44
5
145
288
1377
FMLISGVYPAWTDNQREKCHX
49
23
2
1181
29
1
30
15
4
2
8
1
1377
DGEAHNQSYVLPTIRCKW/FMX
50
7
7
15
42
3
41
135
3
59
4
1383
YVIPSLFHNDTACXMGKQRW/
816
220
2186
421
1166
2428
358
568
205
920
421
N
P
Q
R
S
T
V
W
Y
/
X
#
5
1
G
6
1
1
S
7
1
G
8
1
G
9
1
1
2
RV
10
1
1
2
RV
11
2
GI
12
2
2
V
13
1
1
2
TY
14
1
3
DGN
15
1
1
3
ISY
16
1
1
3
DSY
17
1
1
3
APY
18
3
DFM
19
3
DG
20
1
3
ILV
21
1
2
3
WP
22
1
4
GS
23
1
1
1
6
GHQSV
24
1
6
GALR
25
1
2
7
DTAIS
26
1
1
9
ACDGKLMST
27
1
1
1
1
2
18
DAGVEILNQRS
28
2
3
2
3
4
1
25
TGQSDELPRIV
29
3
3
2
2
1
5
1
1
42
GEDVAPQRSKLMTY/
30
1
3
2
7
5
2
4
1
58
DGRLSIVPAMQTFHNY
31
2
3
7
10
3
7
1
6
100
DGSERVYALPTCFINHKW
32
3
9
4
12
8
6
12
3
9
146
DGLRVAPYSTCEQFHINWKM
33
16
6
19
15
12
10
3
13
207
GARDPSYTEVIFHLQWKM
34
2
20
5
31
12
12
20
5
23
1
2
291
GDRYPVEILASTFHQWCKMNX/
35
12
18
5
39
35
19
23
7
26
1
396
GRSDYLEVTPAHNFIWKCQM/
36
11
24
6
42
47
29
28
7
44
1
521
GDSYRLTVPAEHIKNFMWCQ/
37
14
33
9
54
52
37
55
11
58
1
639
GYDVRSTAPLEIFHNCWQKMX
38
18
33
12
46
77
32
58
17
73
789
GSYDVRLPTIFAEHCNWKQM
39
11
38
12
70
94
42
61
33
68
2
943
GSDRYVLATPFWIECKHMQNX
40
24
52
27
74
140
61
66
29
71
1061
GSRDYVTLPFAEIWHQNKCM
41
31
55
29
70
156
76
61
51
97
1
2
1162
GSYTDRVLPAIWNQEFHCKMX/
42
48
47
24
68
171
68
70
39
125
1
1250
GSYDLVRTANPFEIWQKMHC/
43
38
58
28
73
164
76
66
43
194
1
1311
GYSTARVPDLWNFIQECKHM/
44
48
60
24
69
131
86
57
52
252
1349
YGSTDLRAPVWNFIQHCEKM
45
62
51
16
75
116
74
50
39
324
1362
YGSLRTDNAFPVWEHIKCQM
46
97
38
21
55
110
39
26
55
377
1371
YGDSNRWATLPHFEVQCKIM
47
25
54
9
44
54
34
32
122
292
2
1373
GYAWPSFRLHTVNDIEKCMQX
48
8
22
7
6
28
10
25
16
23
1
1377
FMLISGVYPAWTDNQREKCHX
49
15
6
13
4
13
5
9
2
11
2
1
1377
DGEAHNQSYVLPTIRCKW/FMX
50
23
122
3
3
67
9
350
3
480
1
6
1383
YVIPSLFHNDTACXMGKQRW/
50
495
769
270
876
1518
741
1104
540
2572
10
17
18621
TABLE 11P
Tallies of AA frequencies in all CDR3 by length
Tally of sequences of length 7 # = 38
A
C
D
E
F
G
H
I
K
L
M
#
1
1
8
1
1
14
1
1
5
38
GDLRWAEFHKS
2
1
1
2
6
3
2
1
1
38
RGNHVFKTYADLMW
3
1
4
1
5
1
2
2
38
GSDWYPVILTAFHN
4
3
1
1
12
1
1
1
38
GYSANRVDFHILPT
5
2
1
14
3
4
1
3
3
38
FIGLMARVYEKP
6
26
1
1
38
DVPTHISWY
7
1
2
2
3
1
38
YVINDHSALR
9
42
2
19
40
9
11
4
13
4
N
P
Q
R
S
T
V
W
Y
/
X
#
1
3
1
2
38
GDLRWAEFHKS
2
6
7
2
3
1
2
38
RGNHVFKTYADLMW
3
1
3
5
2
3
4
4
38
GSDWYPVILTAFHN
4
2
1
2
4
1
2
6
38
GYSANRVDFHILPT
5
1
2
2
2
38
FIGLMARVYEKP
6
2
1
2
3
1
1
38
DVPTHISWY
7
3
1
2
7
16
38
YVINDHSALR
12
7
15
13
7
20
8
31
266
Tally of sequences of length 8 # = 61
A
C
D
E
F
G
H
I
K
L
M
#
1
3
7
3
14
2
2
5
61
GDLTVRSAEHINWPQY
2
1
9
1
1
15
1
2
1
61
GDTNRSVKWYAEFILPQ
3
2
3
1
10
1
1
7
1
61
GLSTYVDPRAFHIMNQW
4
4
1
3
1
1
15
1
4
61
GYRALQDSWVCEFHNPT
5
10
2
1
9
5
1
5
1
61
AGYHLTPRVDSEKMW
6
5
1
24
2
7
5
2
61
FIALPSVYGMCQRW
7
5
37
2
4
1
2
61
DAHSELNVIP/
8
1
2
3
1
12
3
61
YISFLVDNAHPRT
31
2
63
8
30
65
14
24
3
32
4
N
P
Q
R
S
T
V
W
Y
/
X
#
1
2
1
1
4
4
5
5
2
1
61
GDLTVRSAEHINWPQY
2
6
1
1
4
3
8
3
2
2
61
GDTNRSVKWYAEFILPQ
3
1
3
1
3
7
7
5
1
7
61
GLSTYVDPRAFHIMNQW
4
1
1
4
5
3
1
2
3
11
61
GYRALQDSWVCEFHNPT
5
4
4
2
5
4
1
7
61
AGYHLTPRVDSEKMW
6
3
1
1
3
3
1
3
61
FIALPSVYGMCQRW
7
2
1
4
2
1
61
DAHSELNVIP/
8
2
1
1
7
1
3
24
61
YISFLVDNAHPRT
14
15
8
22
33
27
27
10
55
1
488
Tally of sequences of length 9 # = 88
A
C
D
E
F
G
H
I
K
L
M
#
1
9
12
4
21
1
1
2
5
88
GDARNVLEQTKWHIPSY
2
2
2
3
3
13
4
3
7
2
88
GPSRLNTHEFKYADMQW
3
4
2
3
3
3
15
1
1
88
GTPSQNRVWYADEFCLM
4
5
1
6
3
6
22
2
4
1
6
1
88
GSDFLARITYENPWHVCKM
5
7
1
4
3
4
14
2
7
2
88
GSYALNDFVERWHMQTCP
6
13
2
1
3
13
6
2
1
4
1
88
YAGHNLPSVFTWDIEKMQR
7
4
2
41
2
3
1
14
5
88
FLMAPWIDGSVKNQTY
8
1
1
73
2
2
1
2
88
DEGLSACHNQRV
9
1
1
4
1
3
8
2
88
YVISFHPLNTCDGR
45
6
105
19
64
103
19
18
8
48
12
N
P
Q
R
S
T
V
W
Y
/
X
#
1
7
1
3
8
1
3
7
2
1
88
GDARNVLEQTKWHIPSY
2
5
11
2
10
11
5
2
3
88
GPSRLNTHEFKYADMQW
3
5
7
6
5
7
11
5
5
5
88
GTPSQNRVWYADEFCLM
4
3
3
5
7
4
2
3
4
88
GSDFLARITYENPWHVCKM
5
6
1
2
3
12
2
4
3
11
88
GSYALNDFVERWHMQTCP
6
5
4
1
1
4
3
4
3
17
88
YAGHNLPSVFTWDIEKMQR
7
1
4
1
2
1
2
4
1
88
FLMAPWIDGSVKNQTY
8
1
1
1
2
1
88
DEGLSACHNQRV
9
2
3
1
8
2
9
43
88
YVISFHPLNTCDGR
35
34
16
34
54
31
34
22
85
792
Tally of sequences of length 10 # = 101
A
C
D
E
F
G
H
I
K
L
M
#
1
8
1
19
7
1
16
3
2
3
2
101
DGNAERTSQVHLWKMYCF
2
3
8
3
5
13
5
15
2
101
LGRDSPVFINTAEQYMW
3
6
9
1
26
1
3
1
4
1
101
GSYDAVTLNRIPWFHKMQ
4
7
6
1
25
1
5
4
1
101
GSYARDINPLTVWQFHM
5
6
5
9
4
16
1
3
4
101
GYTESANDPRFLVKQWH
6
6
1
6
5
4
23
2
4
3
3
1
101
GYRSWADEFINKLTHCMQV
7
13
3
1
5
9
3
1
4
1
101
YASGPRWFTVLDHNEIMQ
8
2
1
1
57
3
4
15
4
101
FLIMSGWANPVCEY
9
3
78
2
6
1
1
1
101
DGAQENIKLPRSW
10
3
4
4
13
1
101
YIPSVFHNDL
54
3
137
28
82
137
15
36
10
54
12
N
P
Q
R
S
T
V
W
Y
/
X
#
1
9
4
6
5
6
4
3
2
101
DGNAERTSQVHLWKMYCF
2
5
6
3
11
8
4
6
1
3
101
LGRDSPVFINTAEQYMW
3
4
3
1
4
14
5
6
2
10
101
GSYDAVTLNRIPWFHKMQ
4
5
5
3
7
11
4
4
4
8
101
GSYARDINPLTVWQFHM
5
6
5
2
5
8
10
4
2
11
101
GYTESANDPRFLVKQWH
6
4
1
8
7
3
1
7
12
101
GYRSWADEFINKLTHCMQV
7
2
7
1
7
11
5
5
6
17
101
YASGPRWFTVLDHNEIMQ
8
2
2
4
2
3
1
101
FLIMSGWANPVCEY
9
2
1
3
1
1
1
101
DGAQENIKLPRSW
10
4
8
7
5
52
101
YIPSVFHNDL
43
37
18
49
76
37
37
29
116
1010
Tally of sequences of length 11 # = 118
A
C
D
E
F
G
H
I
K
L
M
#
1
7
1
21
11
23
5
2
7
118
GDEVRALQHSPTINCWY
2
1
2
9
1
1
24
5
6
2
7
3
118
GSRDYLPIVHQTMNCKWAEFX
3
4
4
2
4
13
2
3
1
7
2
118
SGTVRLYWADFNQIEHMKP
4
10
3
3
2
25
1
2
4
3
118
SGARTWYLVDEMQFINPH
5
5
2
10
1
4
24
2
1
5
1
118
GSVYDTNALRFWCHQEKM
6
6
4
2
7
19
2
3
1
5
1
118
GSYWTFAVLRDINEHQKMP
7
4
1
8
5
2
20
4
1
2
1
118
GYSNRDWTEPAHFLQVCIM
8
13
2
6
1
8
12
4
2
7
118
YAGWFLDPRSTHCKVE
9
2
2
68
2
5
14
7
118
FLMYVITADGP
10
2
1
100
5
3
2
1
1
118
DEGAHCLMNPQ
11
2
6
1
7
1
6
1
118
YPVISFLNDHKM
54
9
169
31
102
165
28
29
8
65
20
N
P
Q
R
S
T
V
W
Y
/
X
#
1
2
4
7
8
5
3
10
1
1
118
GDEVRALQHSPTINCWY
2
3
7
4
10
11
4
6
2
9
1
118
GSRDYLPIVHQTMNCKWAEFX
3
4
1
4
8
25
12
9
6
7
118
SGTVRLYWADFNQIEHMKP
4
2
2
3
9
26
8
4
6
5
118
SGARTWYLVDEMQFINPH
5
6
2
5
15
9
11
4
11
118
GSVYDTNALRFWCHQEKM
6
3
1
2
5
16
9
6
11
15
118
GSYWTFAVLRDINEHQKMP
7
9
5
2
9
11
6
2
7
19
118
GYSNRDWTEPAHFLQVCIM
8
6
5
5
5
2
11
29
118
YAGWFLDPRSTHCKVE
9
1
4
6
7
118
FLMYVITADGP
10
1
1
1
118
DEGAHCLMNPQ
11
3
13
7
11
60
118
YPVISFLNDHKM
33
41
25
59
121
60
67
48
163
1
1298
Tally of sequences of length 12 # = 154
A
C
D
E
F
G
H
I
K
L
M
#
1
5
31
12
37
6
1
1
7
3
154
GDRESVLHAPMNQTWYIK
2
5
1
7
6
1
25
3
7
3
13
2
154
GSRLPDIQEAVYHKNTMWCF
3
10
2
7
5
1
19
5
4
12
2
154
GRSYLATVPDQEIKWCMNF
4
8
9
6
8
27
6
5
6
1
154
GVSDNAFRTYEILKWPQM
5
18
1
8
5
6
42
1
9
1
7
3
154
GSAIDYLFPTEQVMNWCHK
6
13
12
4
10
23
1
7
8
1
154
GAVDSFYTLPRWINEQHM
7
11
2
4
3
10
15
1
4
12
154
YGSPLRAFWTNVDIECQH
8
3
2
18
3
3
25
4
2
5
6
154
YGDSNLTKRWHPAEFCIQV
9
15
1
2
8
33
4
7
1
5
1
154
GYWARFISPLHTDQCKMN
10
1
1
2
1
79
1
2
5
1
19
26
154
FMLIPYDHVWACEGKNQRST
11
2
135
2
4
2
154
DGYAEHSVNR
12
1
1
6
1
9
16
4
154
YVPIHFSLNCDGW
91
11
236
47
132
252
33
69
21
99
39
N
P
Q
R
S
T
V
W
Y
/
X
#
1
3
4
3
14
10
3
10
2
2
154
GDRESVLHAPMNQTWYIK
2
3
11
7
22
24
3
5
2
4
154
GSRLPDIQEAVYHKNTMWCF
3
2
8
6
17
17
9
9
4
15
154
GRSYLATVPDQEIKWCMNF
4
9
4
4
7
17
7
18
5
7
154
GVSDNAFRTYEILKWPQM
5
3
6
4
20
6
4
2
8
154
GSAIDYLFPTEQVMNWCHK
6
5
8
3
8
11
9
13
8
10
154
GAVDSFYTLPRWINEQHM
7
5
14
2
12
15
6
5
9
24
154
YGSPLRAFWTNVDIECQH
8
10
4
2
5
15
6
2
5
34
154
YGDSNLTKRWHPAEFCIQV
9
1
6
2
10
7
3
18
30
154
GYWARFISPLHTDQCKMN
10
1
4
1
1
1
1
2
2
3
154
FMLIPYDHVWACEGKNQRST
11
1
1
2
2
3
154
DGYAEHSVNR
12
2
18
5
32
1
58
154
YVPIHFSLNCDGW
45
87
34
97
144
53
102
58
198
1848
Tally of sequences of length 13 # = 150
A
C
D
E
F
G
H
I
K
L
M
#
1
4
2
28
9
3
37
8
3
3
5
150
GDTESHRVLPAQFIKCNW
2
11
4
4
1
2
32
3
1
5
11
3
150
GRSPALTKVCDYHMQWFEIN
3
7
2
8
4
4
23
11
1
4
6
2
150
GSYHQTDPRAVLEFKNCMWI
4
6
2
6
4
6
30
1
8
6
1
150
GSWYTIADFLPVEQRCHMNX
5
8
10
4
2
28
1
2
22
3
150
GLSYDATWPREQMNVFIH
6
10
2
11
1
6
21
2
2
5
1
150
GYSPTDAQVFRLNWCIKEM
7
5
1
8
1
4
19
1
6
5
21
2
150
LGYSTDPIRVAKFNWMQCEH
8
7
5
22
5
3
12
3
3
3
8
1
150
YDSGLARTCEQVNPFHIKWM
9
1
2
12
3
1
26
7
2
4
7
2
150
NGYDSWHLPRKETVCIMAFQ
10
19
1
2
2
17
24
5
2
5
1
150
YGAFWHLPTNSVDEIQRCM
11
1
1
105
2
2
1
13
14
150
FMLYGIVAEKPQRSWX
12
130
3
5
1
150
DGYEQNHT
13
1
2
5
5
14
18
1
150
YVLIPSFHTDAMN
80
21
243
38
158
259
46
46
27
127
31
N
P
Q
R
S
T
V
W
Y
/
X
#
1
2
5
4
8
9
11
8
1
150
GDTESHRVLPAQFIKCNW
2
1
13
3
20
17
7
5
3
4
150
GRSPALTKVCDYHMQWFEIN
3
3
8
11
8
16
11
7
2
12
150
GSYHQTDPRAVLEFKNCMWI
4
1
6
4
4
18
10
6
16
14
1
150
GSWYTIADFLPVEQRCHMNX
5
3
6
4
5
19
8
3
7
15
150
GLSYDATWPREQMNVFIH
6
3
15
8
6
16
13
8
3
17
150
GYSPTDAQVFRLNWCIKEM
7
4
7
2
6
15
14
6
4
19
150
LGYSTDPIRVAKFNWMQCEH
8
4
4
5
7
15
7
5
2
29
150
YDSGLARTCEQVNPFHIKWM
9
31
5
1
5
10
3
3
9
16
150
NGYDSWHLPRKETVCIMAFQ
10
3
5
2
2
3
4
3
15
35
150
YGAFWHLPTNSVDEIQRCM
11
1
1
1
1
2
1
3
1
150
FMLYGIVAEKPQRSWX
12
2
3
1
5
150
DGYEQNHT
13
1
14
13
4
21
51
150
YVLIPSFHTDAMN
58
89
48
72
152
93
77
63
220
2
1950
Tally of sequences of length 14 # = 118
A
C
D
E
F
G
H
I
K
L
M
#
1
6
29
7
2
32
8
1
1
2
118
GDVHERTAFLPSIKNQ
2
4
10
1
5
22
7
3
4
7
118
GPDRYSVHLFAKIQTENW
3
11
2
7
2
3
25
5
1
9
2
118
GVARYLSDITFWCEMPK
4
5
2
7
7
3
12
4
4
3
6
118
SGVYPDELRTANHIFKWC
5
6
5
12
2
18
2
2
2
4
1
118
GYSDTVARCLPFHIKNWMQ
6
6
10
5
4
16
5
3
2
1
118
YGSTDRAEIFVKWLPQMN
7
4
4
1
4
32
2
2
2
1
118
GSVTYNADFHIKPQRWEM
8
6
1
5
1
4
18
2
5
3
2
118
GSYTWAPRDIFNVLHMCE
9
5
2
4
1
2
11
2
1
5
9
1
118
YSGTLVAKNRDWCFHPEIM
10
2
5
9
2
3
21
2
2
4
118
YGSDNTCQLRFWAEIKPV
11
12
1
3
5
25
2
2
1
118
YGWAPVFNEHLTDMQR
12
1
64
5
1
5
12
16
118
FMLGIPSVAHQTY
13
3
97
4
5
1
1
1
1
118
DGEANQHIKLV
14
2
3
4
12
6
118
YVPILHFANS
73
17
195
34
104
242
35
48
24
67
25
N
P
Q
R
S
T
V
W
Y
/
X
#
1
1
2
1
7
2
7
10
118
GDVHERTAFLPSIKNQ
2
1
13
2
10
8
2
8
1
10
118
GPDRYSVHLFAKIQTENW
3
2
11
8
4
13
3
10
118
GVARYLSDITFWCEMPK
4
5
8
6
13
6
12
3
12
118
SGVYPDELRTANHIFKWC
5
2
3
1
6
15
10
7
2
18
118
GYSDTVARCLPFHIKNWMQ
6
1
2
2
7
16
12
4
3
19
118
YGSTDRAEIFVKWLPQMN
7
5
2
2
2
18
12
13
2
10
118
GSVTYNADFHIKPQRWEM
8
4
6
6
16
12
4
9
14
118
GSYTWAPRDIFNVLHMCE
9
5
2
5
14
10
8
4
27
118
YSGTLVAKNRDWCFHPEIM
10
6
2
5
4
13
6
2
3
27
118
YGSDNTCQLRFWAEIKPV
11
4
7
1
1
2
6
14
32
118
YGWAPVFNEHLTDMQR
12
4
1
4
1
3
1
118
FMLGIPSVAHQTY
13
2
2
1
118
DGEANQHIKLV
14
2
14
2
20
53
118
YVPILHFANS
38
67
17
65
129
84
111
44
233
1652
Tally of sequences of length 15 # = 125
A
C
D
E
F
G
H
I
K
L
M
#
1
7
26
8
3
29
1
3
10
125
GDLREASTVNFIPYH
2
6
2
3
22
3
4
1
9
125
RGPLNSTYAVIQEHWDK
3
4
4
5
7
2
19
2
6
2
9
2
125
GRYLSVEPIDTACQWFHKMN
4
7
4
14
6
6
15
2
7
5
7
4
125
GDYAILVEFRKSTCMNPWHQ
5
6
3
10
2
5
18
4
2
3
2
125
GSYVDRWAFTICLNEKMP
6
6
2
7
2
5
10
1
5
7
1
125
SRYGTDLWAPFIVNCEQHM
7
8
4
14
2
2
22
3
3
1
9
1
125
GSDLAVRPYCTHIWEFNKM
8
6
2
4
22
2
2
3
125
GYSVWRATDNPLCIKQ
9
4
3
8
4
20
4
3
1
6
125
YGSDLPTRVAFHQCINKW
10
3
4
5
8
8
17
1
3
7
125
YGEFNTLSRDVCPAIWH
11
4
2
15
3
3
17
1
1
1
125
YGDSNPAWEFRTCQHIKV
12
22
3
2
31
3
1
3
3
125
GYAWPSNCHLMFQRVITX
13
71
1
4
6
30
125
FMLISQTVGPRY
14
115
2
1
1
1
125
DNEFGHPQ
15
3
5
1
1
20
7
1
125
YVILPFSCNGHMQ
83
34
225
43
117
245
23
66
15
86
44
N
P
Q
R
S
T
V
W
Y
/
X
#
1
4
3
10
7
6
6
2
125
GDLREASTVNFIPYH
2
8
11
4
23
7
7
5
3
7
125
RGPLNSTYAVIQEHWDK
3
2
7
3
13
9
5
8
3
13
125
GRYLSVEPIDTACQWFHKMN
4
4
4
1
6
5
5
7
3
13
125
GDYAILVEFRKSTCMNPWHQ
5
3
2
8
18
5
11
8
15
125
GSYVDRWAFTICLNEKMP
6
3
6
2
12
24
9
4
7
12
125
SRYGTDLWAPFIVNCEQHM
7
2
6
7
21
4
8
3
5
125
GSDLAVRPYCTHIWEFNKM
8
4
4
2
7
19
5
12
10
21
125
GYSVWRATDNPLCIKQ
9
3
6
4
5
19
6
5
1
23
125
YGSDLPTRVAFHQCINKW
10
8
4
6
7
8
5
2
29
125
YGEFNTLSRDVCPAIWH
11
7
5
2
3
14
3
1
4
39
125
YGDSNPAWEFRTCQHIKV
12
4
7
2
2
6
1
2
8
24
1
125
GYAWPSNCHLMFQRVITX
13
1
2
1
4
2
2
1
125
FMLISQTVGPRY
14
3
1
1
125
DNEFGHPQ
15
2
7
1
5
33
39
125
YVILPFSCNGHMQ
57
74
24
103
165
66
109
52
243
1
1875
Distribution of D-JH with number of cys's
0
1
2
3
4
1248
53
80
1
1
Tally of AAs in the YYCar motif
A
C
D
E
F
G
H
I
K
L
M
#
1
1
1
14
1
1383
YFDEH
2
4
1
92
11
4
1383
YFHCLSWDR
3
1379
1383
CRS
4
1207
3
2
12
2
2
1383
AVTSGNDFILRQX
5
14
1
4
18
17
9
187
4
1
1383
RKTSGHAIVNFLQYPEM/
1221
1383
5
2
112
30
29
11
187
10
1
N
P
Q
R
S
T
V
W
Y
/
X
#
1
1366
1383
YFDEH
2
1
3
2
1265
1383
YFHCLSWDR
3
2
2
1383
CRS
4
4
1
2
17
51
79
1
1383
AVTSGNDFILRQX
5
7
2
3
992
55
56
9
3
1
1383
RKTSGHAIVNFLQYPEM/
11
2
4
997
77
107
88
2
2634
1
1
6915
TABLE 12P
Alignment and tabulation of sequences having 3-22 D segments
D3:3-22_Phz0 YYYDSSGYYY (SEQ ID NO: 448) = GLG
Entry
Seq1
L1
Seq2
L2
JH
P
Score
1
hs3d6hcv
GRDYYDSGGYFT
12
GRDYYDSGGYFTVAFDI
17
3
6
1.76D+13
(SEQ ID NO: 334)
(SEQ ID NO: 335)
2
hs6d4xb7
DRHNYYDSSGSYS
13
DRHNYYDSSGSYSDY
15
4
9
4.40D+12
(SEQ ID NO: 336)
(SEQ ID NO: 337)
3
hs6d4xg3
DCPAPAKMYYYGSGICT
17
DCPAPAKMYYYGSGICTFDY
20
4
3
6.55D+04
(SEQ ID NO: 338)
(SEQ ID NO: 339)
4
hs83x6f2
AFYDSAD
7
AFYDSADDY
9
4
−4
2.62D+05
(SEQ ID NO: 340)
(SEQ ID NO: 341)
5
hsa230644
RDYYDSSGPEAG
12
RDYYDSSGPEAGFDI
15
3
3
6.87D+10
(SEQ ID NO: 342)
(SEQ ID NO: 343)
6
hsa239386
DGTLIDTSAYYYL
13
DGTLIDTSAYYYLY
14
4
6
6.87D+10
(SEQ ID NO: 344)
(SEQ ID NO: 345)
7
hsa234232
NSSDSS
6
NSSDSSVLDV
10
6
−4
6.55D+04
(SEQ ID NO: 346)
(SEQ ID NO: 347)
8
hsa239378
DQVFDSGGYNHR
12
DQVFDSGGYNHRFDS
15
4
3
1.07D+09
(SEQ ID NO: 348)
(SEQ ID NO: 349)
9
hsa239367
DLEYYYDSGGHYSP
14
DLEYYYDSGGHYSPFHY
17
4
9
1.10D+12
(SEQ ID NO: 350)
(SEQ ID NO: 351)
10
hsa239339
DDSSGY
6
DDSSGYYYIDY
11
4
−10
1.72D+10
(SEQ ID NO: 352)
(SEQ ID NO: 353)
11
hsa245311
GHYYDSPGQYSYS
13
GHYYDSPGQYSYSEY
15
4
3
1.07D+09
(SEQ ID NO: 354)
(SEQ ID NO: 355)
12
hsa240578
GGFRPPPYDYESSAYRTYR
19
GGFRPPPYDYESSAYRTYRLDF
22
4
21
2.75D+11
(SEQ ID NO: 356)
(SEQ ID NO: 357)
13
hsa245359
DSDTRAY
7
DSDTRAYYWYFDL
13
2
−7
1.68D+07
(SEQ ID NO: 358)
(SEQ ID NO: 359)
14
hsa245028
GRHYYDSSGYYSTPE
15
GRHYYDSSGYYSTPENYFDY
20
4
6
1.80D+16
(SEQ ID NO: 360)
(SEQ ID NO: 361)
15
hsa245019
DPSYYYDSSGLPL
13
DPSYYYDSSGLPLHGMDV
18
6
9
4.40D+12
(SEQ ID NO: 362)
(SEQ ID NO: 363)
16
hsa244991
TYYYDSSGYLLTR
13
TYYYDSSGYLLTRYFQH
17
1
3
4.50D+15
(SEQ ID NO: 364)
(SEQ ID NO: 365)
17
hsa244945
NAPHYDSSGYYQT
13
NAPHYDSSGYYQTFDY
16
4
6
7.04D+13
(SEQ ID NO: 366)
(SEQ ID NO: 367)
18
hsa244943
GYHSSSYA
8
GYHSSSYADAFDI
13
3
−7
6.71D+07
(SEQ ID NO: 368)
(SEQ ID NO: 369)
19
hsa245289
PIGYCSGGSC
10
PIGYCSGGSCYSFDY
15
4
−4
2.62D+05
(SEQ ID NO: 370)
(SEQ ID NO: 371)
20
hsa240554
THGTYVTSGYYPKI
14
THGTYVTSGYYPKI
14
4
6
2.68D+08
(SEQ ID NO: 372)
(SEQ ID NO: 373)
21
hsa279533
GATYYYESSGNYP
13
GATYYYESSGNYPDY
15
4
9
7.04D+13
(SEQ ID NO: 374)
(SEQ ID NO: 375)
22
hsa389177
AFYHYDSTGYPNRRY
15
AFYHYDSTGYPNRRYYFDY
19
4
6
4.29D+09
(SEQ ID NO: 376)
(SEQ ID NO: 377)
23
hsa7321
SYSYYYDSSGYWGG
14
SYSYYYDSSGYWGGYFDY
18
4
9
4.50D+15
(SEQ ID NO: 378)
(SEQ ID NO: 379)
24
hsaj2772
LSPYYYDSSSYH
12
LSPYYYDSSSYHDAFDI
17
3
6
2.62D+05
(SEQ ID NO: 380)
(SEQ ID NO: 381)
25
hsb7g4f08
EEDYYDSSGQAS
12
EEDYYDSSGQASYNWFXP
18
5
6
2.75D+11
(SEQ ID NO: 382)
(SEQ ID NO: 383)
26
hsb7g3b02
ETNYYDSGGYPG
12
ETNYYDSGGYPGFDF
15
4
6
4.40D+12
(SEQ ID NO: 384)
(SEQ ID NO: 385)
27
hsb7g3c12
GDHYYDRSGYRH
12
GDHYYDRSGYRHSYYYYAMDV
21
6
6
2.75D+11
(SEQ ID NO: 386)
(SEQ ID NO: 387)
28
hsb8g3b07
DRSSGN
6
DRSSGNYFDGMDV
13
6
−10
6.55D+04
(SEQ ID NO: 388)
(SEQ ID NO: 389)
29
hsfog1h
GRSRYSGYG
9
GRSRYSGYGFYSGMDV
16
6
−4
2.62D+05
(SEQ ID NO: 390)
(SEQ ID NO: 391)
30
hsgvh0209
DDTSGYGP
8
DDTSGYGPYYFYYGMDV
17
6
−10
2.68D+08
(SEQ ID NO: 392)
(SEQ ID NO: 393)
31
hsgvh55
RAYYDTSFYFEY
12
RAYYDTSFYFEYY
13
4
3
1.72D+10
(SEQ ID NO: 394)
(SEQ ID NO: 395)
32
hsgvh0304
DRIDYYKSGYYLGSA
15
DRIDYYKSGYYLGSADS
17
4
6
1.68D+07
(SEQ ID NO: 396)
(SEQ ID NO: 397)
33
hsgvh0332
DTDSSSHYG
9
DTDSSSHYGRFDP
13
5
−7
1.68D+07
(SEQ ID NO: 398)
(SEQ ID NO: 399)
34
hsgvh0328
VSISHYDSSGRPQRVF
16
VSISHYDSSGRPQRVFYGMDV
21
6
9
1.07D+09
(SEQ ID NO: 400)
(SEQ ID NO: 401)
35
hsgvh536
QARENVFYDSSGPTAP
16
QARENVFYDSSGPTAPFDH
19
4
15
1.72D+10
(SEQ ID NO: 402)
(SEQ ID NO: 403)
36
hshcmg42
VPAGNYYDTSGPDN
14
VPAGNYYDTSGPDNAD
16
4
12
1.72D+10
(SEQ ID NO: 404)
(SEQ ID NO: 405)
37
hsig001vh
WYYFDTSGYYPRNFYYMDV
19
WYYFDTSGYYPRNFYYMDV
19
4
3
2.81D+14
(SEQ ID NO: 406)
(SEQ ID NO: 407)
38
hsig13g10
GYYYDSGGNYNG
12
GYYYDSGGNYNGDY
14
4
3
1.10D+12
(SEQ ID NO: 408)
(SEQ ID NO: 409)
39
hsighpat3
DLRSYDPSGYYN
12
DLRSYDPSGYYNDGFDI
17
3
6
2.75D+11
(SEQ ID NO: 410)
(SEQ ID NO: 411)
40
hsigh13g7
GYYYDRGGNCNG
12
GYYYDRGGNCNGDY
14
4
3
6.87D+10
(SEQ ID NO: 412)
(SEQ ID NO: 413)
41
hsigh13g1
GYYYDRGGNYNG
12
GYYYDRGGNYNGDY
14
4
3
1.10D+12
(SEQ ID NO: 414)
(SEQ ID NO: 415)
42
hsighxx20
THYDSSGL
8
THYDSSGLDAFDI
13
3
−4
1.72D+10
(SEQ ID NO: 416)
(SEQ ID NO: 417)
43
hsihr9
DDSSGS
6
DDSSGSYYFDY
11
4
−10
1.07D+09
(SEQ ID NO: 418)
(SEQ ID NO: 419)
44
hsihv11
LSGGYYS
7
LSGGYYSDFDY
11
4
−13
2.68D+08
(SEQ ID NO: 420)
(SEQ ID NO: 421)
45
hs ej1f
GDYSDSSDSYI
11
GDYSDSSDSYIDAFDV
16
3
3
1.10D+12
(SEQ ID NO: 422)
(SEQ ID NO: 423)
46
hsmvh51
GETYYYDSRGYA
12
GETYYYDSRGYAFDH
15
4
6
2.62D+05
(SEQ ID NO: 424)
(SEQ ID NO: 425)
47
hsmvh517
PTRDSSGY
8
PTRDSSGYYVGY
12
4
−4
1.07D+09
(SEQ ID NO: 426)
(SEQ ID NO: 427)
48
hsmvh0406
GSFYYDSSGYPP
12
GSFYYDSSGYPPFDC
15
4
6
6.87D+10
(SEQ ID NO: 428)
(SEQ ID NO: 429)
49
hst14x14
GPYYYDSSGYYL
12
GPYYYDSSGYYLLDY
15
4
6
1.80D+16
(SEQ ID NO: 430)
(SEQ ID NO: 431)
50
hsvhig2
EEGYYDSSGYYSLGA
15
EEGYYDSSGYYSLGASDY
18
4
6
4.50D+15
(SEQ ID NO: 432)
(SEQ ID NO: 433)
51
hsvhia2
RPDSSGSRW
9
RPDSSGSRWYFDY
13
4
−7
6.71D+07
(SEQ ID NO: 434)
(SEQ ID NO: 435)
52
hsy14936
GYYDISGYYF
10
GYYDISGYYFDAFNI
15
3
−4
2.81D+14
(SEQ ID NO: 436)
(SEQ ID NO: 437)
53
hsy14934
DRGYDSSGYYGN
12
DRGYDSSGYYGNLDC
15
4
3
1.76D+13
(SEQ ID NO: 438)
(SEQ ID NO: 439)
54
hsy14935
DRGYDSIGYYGN
12
DRGYDSIGYYGNLDC
15
4
3
1.10D+12
(SEQ ID NO: 440)
(SEQ ID NO: 441)
55
hsz80519
AEDLTYYYDRSGWGVHGLL
19
AEDLTYYYDRSGWGVHGLLYYFDY
24
4
15
4.40D+12
(SEQ ID NO: 442)
(SEQ ID NO: 443)
56
hsz80429
LYPHYDSSGYYYV
13
LYPHYDSSGYYYVLDY
16
4
6
4.50D+15
(SEQ ID NO: 444)
(SEQ ID NO: 445)
57
hsz80461
DRVGYYDSSGYPPGSP
16
DRVGYYDSSGYPPGSPLDY
19
4
9
1.76D+13
(SEQ ID NO: 446)
(SEQ ID NO: 447)
Frequency of each AA type at each position in 57 Sequences
having D3-22 segments
Pos
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
|
X
#
1
1
1
2
1
1
3
1
1
1
3
4
1
1
1
1
4
5
5
1
1
2
1
1
1
12
6
3
3
4
6
3
1
2
2
2
1
1
28
x
7
1
5
4
1
7
2
1
1
1
3
5
3
4
1
1
1
41
x
8
2
1
4
1
5
3
1
4
4
1
3
1
3
1
14
48
x
9
4
2
3
5
1
1
1
2
2
2
1
28
52
Y
10
1
4
2
1
1
1
1
4
1
40
56
Y
11
46
2
1
1
1
2
1
3
57
D
12
1
1
1
1
1
1
4
39
7
1
57
S
13
1
8
1
1
1
1
43
1
57
S
14
3
2
1
45
1
1
3
56
G
15
2
2
2
5
3
2
1
4
1
33
55
Y
16
2
1
1
1
2
3
1
1
1
6
3
1
1
1
24
49
x
17
3
1
1
1
5
2
1
4
6
6
2
7
2
1
1
3
46
x
18
8
1
1
2
2
2
4
3
1
3
27
19
2
1
1
1
3
4
1
13
20
2
1
2
1
1
1
1
9
21
1
1
1
3
22
1
1
2
23
1
1
2
24
1
1
25
1
1
Average Dseg = 11.9 Average DJ = 15.7
Median D = 12 12 Shortest 6 Longest 19
Median DJ = 15 15 Shortest 9 Longest 24
TABLE 13P
Frequency of D-segments.
D seg
“0”
%
C %
GLG
“1”
%
C %
GLG
“2”
%
C %
GLG
1-01
1
0.13
0
VQLERX
4
0.53
0.22
GTTGTX
5
0.66
0.34
YNWND
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
132)
133)
134)
1-07
0
0
0
V|LELX
3
0.4
0.11
GITGTX
9
1.19
0.34
YNWNY
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
135)
136)
137)
1-20
0
0
0
V|LERX
1
0.13
0.22
GITGTX
4
0.53
0.45
YNWND
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
138)
139)
140)
1-26
4
0.53
0
V|WELLX
13
1.72
0.90
GIVGATX
36
4.76
0.78
YSGSYY
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
141)
142)
143)
2-02
31
4.1
2.47
GYCSSTSCYT
4
0.53
0.22
RIL||YQLLYX
9
1.19
2.47
DIVVVPAAIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
144)
145)
146)
2-08
5
0.66
0.56
GYCTNGVCYT
0
0
0
RILY|WCMLYX
3
0.4
0.56
DIVLMVYAIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
147)
148)
149)
2-15
29
3.83
1.57
GYCSGGSCYS
2
0.26
0.11
RIL|WW|LLLX
7
0.92
1.57
DIVVVVAATX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
150)
151)
152)
2-21
16
2.11
0.67
AYCGGDCYS
0
0
0
SILWW|LLFX
7
0.92
0.67
HIVVVTAIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
153)
154)
155)
3-03
32
4.23
2.80
YYDFWSGYYT
7
0.92
0.90
VLRFLEWLLYX
27
3.57
1.12
ITIFGVVIIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
156)
157)
158)
3-09
13
1.72
1.35
YYDILTGYYN
5
0.66
0.78
VLRYFDWLL|X
0
0
0
ITIF|LVIIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
159)
160)
161)
3-10
42
5.55
4.26
YYYGSGSYYN
13
1.72
0.89
VLLWFGELL|X
11
1.45
2.91
ITMVRGVIIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
162)
163)
164)
3-16
18
2.38
0.67
YYDYVWGSYRYT
8
1.06
0
VL|LRLGELSLYX
5
0.66
0.34
IMITFGGVIVIX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
165)
166)
167)
3-22
57
7.53
3.36
YYYDSSGYYY
1
0.13
0.11
VLL|||WLLLX
6
0.79
0.34
ITMIVVVITX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
168)
169)
170)
4-04
5
0.66
0.28
DYSNY
2
0.26
0
|LQ|LX
2
0.26
0.06
TTVTX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
171)
172)
173)
4-17
29
3.83
1.45
DYGDY
0
0
0
|LR|LX
20
2.64
0.90
TTVTX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
174)
175)
176)
4-23
10
1.32
0.56
DYGGNS
1
0.13
0
|LRW|LX
4
0.53
0.56
TTVVTX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
177)
178)
179)
5-05
3
0.4
0.06
WIQLWLX
10
1.32
0.39
VDTAMVX
31
4.1
0.73
GYSYGY
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
180)
181)
182)
5-12
0
0
0
WI|WLRLX
8
1.06
0.45
VDIVATIX
14
1.85
1.12
GYSGYDY
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
183)
184)
185)
5-24
11
1.45
0
|RWLQLX
5
0.66
0.34
VEMATIX
13
1.72
0.44
RDGYNY
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
186)
187)
188)
6-06
11
1.45
0.78
SIAARX
9
1.19
0.48
EYSSSS
1
0.13
0.11
V|QLVX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
189)
190)
191)
6-13
19
2.51
1.01
GIAAAGX
35
4.62
2.13
GYSSSWY
2
0.26
0.31
V|QQLVX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
192)
193)
194)
6-19
14
1.85
2.12
GIAVAGX
48
6.34
2.02
GYSSGWY
4
0.53
0.56
V|QWLVX
(SEQ ID NO:
(SEQ ID NO:
(SEQ ID NO:
195)
196)
197)
D7: 7-27
1
0.13
0
|LGX
2
0.26
0.68
LTGX
2
0.26
0.22
NWG
(SEQ ID NO:
198)
Total = 757
“|” stands for a stop codon.
TABLE 14P
Possible library components.
Component
L
f
D2_2-02_Phz0
xxxY C SSTS C xxx
13,
31,
(SEQ ID NO: 199)
D3_3-16_Phz0
xxxxYVWGSYxxx
13,
18,
(SEQ ID NO: 200)
D5_5-12_Phz2
xxxxxxxSGYxxx
13,
14,
(SEQ ID NO: 201)
D3_3-09_Phz0
xxxYDILTGYYxx
13,
13,
(SEQ ID NO: 202)
D2_2-02_Phz2
xxxVVVPAAxxxx
13,
9,
(SEQ ID NO: 203)
D3_3-22_Phz0
xxxYYDSSGYxx
12,
57,
(SEQ ID NO: 204)
D3_3-03_Phz0
xxxDFWSGxxxx
12,
32,
(SEQ ID NO: 205)
D3_3-03_Phz2
xxxTIFGVxxxx
12,
27,
(SEQ ID NO: 206)
D5_5-12_Phz1
xxxxIVATxxxx
12,
8,
(SEQ ID NO: 207)
D3_3-10_Phz0
xxxYGSGSYYx
11,
42,
! could add one
x at either end
(SEQ ID NO: 208)
D5_5-05_Phz2
xxxxYSYGxxx
11,
31,
(SEQ ID NO: 209)
D2_2-15_Phz0
xxx C SGxx C Yx
11,
29,
(SEQ ID NO: 210)
D6_6-13_Phz0
xxxxAAAGxxx
11,
19,
(SEQ ID NO: 211)
D4_4-23_Phz0
xGxxxGGNxxx
11,
10,
(SEQ ID NO: 212)
D1_1-26_Phz2
xxxSGSYxxx
10,
35,
(SEQ ID NO: 213)
D6_6-13_Phz1
xxxSSSWxxx
10,
35,
(SEQ ID NO: 214)
D4_4-17_Phz2
xxxxTTVTTx
10,
20,
(SEQ ID NO: 215)
D2_2-21_Phz0
xxx C (SG)GDx C x
10,
16,
(SEQ ID NO: 216)
D6_6-19_Phz0
xxx(IV)AVAGxx
10,
14,
(SEQ ID NO: 217)
D3_3-10_Phz1
xxLWFGELxx
10,
13,
(SEQ ID NO: 218)
D5_5-24_Phz0
GxxWLxxxxF
10,
11,
(SEQ ID NO: 219)
D5_5-05_Phz1
xxxDTxMVxx
10,
10,
(SEQ ID NO: 220)
D3_3-16_Phz1
xxxxxGExxx
10,
8,
(SEQ ID NO: 221)
D6_6-19_Phz1
xxxxSGWxx
9,
48,
(SEQ ID NO: 222)
D5_5-24_Phz2
xxxxGYNxx
9,
13,
(SEQ ID NO: 223)
D3_3-10_Phz2
xxxVRGVxx
9,
11,
(SEQ ID NO: 224)
D6_6-06_Phz0
xxxIAAxxx
9,
11,
(SEQ ID NO: 225)
D1_1-07_Phz2
xxYxWNxxx
9,
9,
(SEQ ID NO: 226)
D4_4-17_Phz0
xxxYGDxx
8,
29,
(SEQ ID NO: 227)
D1_1-26_Phz1
xxVGATxx
8,
13,
(SEQ ID NO: 228)
D6_6-06_Phz1
xxxYSSSx
8,
9,
(SEQ ID NO: 229)
TABLE 15P
Lengths of CDRs: 1095 actual VH domains and 51 VH GLGs.
Length
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CDR1
0
0
10
0
1
820
38
175
1
1
5
1
11
0
23
1
7
0
GLG
0
0
0
0
0
38
3
10
0
0 . . .
CDR2
0
0
0
0
0
2
0
0
0
0
0
0
0
0
0
0
464
579
GLG
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
17
28
CDR3
0
0
0
4
2
8
6
28
40
65
77
90
117
117
88
105
86
81
Length
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
(33 or more)
CDR2
9
31
1
3
3
1
0
0
0
0
2
0
0 . . .
GLG
1
4
0
0 . . .
CDR3
45
36
36
16
16
8
8
2
3
0
2
1
0
0
1
5
TABLE 16P
Library of HC CDR3
Component
Fraction of
Length
#X
Complexity
library
Adjusted
1:
YYCA21111YFDYWG.
8
4
2.6E 5
.10 (0-8)
.02
(2 = KR; SEQ ID NO: 6)
2:
YYCA2111111YFDYWG.
10
6
9.4E 7
.14 (9-10)
.14
(2 = KR; SEQ ID NO: 7)
3:
YYCA211111111YFDYTG.
12
8
3.4E 10
.25 (11 + 12 + 13/2)
.25
(2 = KR; SEQ ID NO: 8)
4:
YYCAR111S2S3111YFDYWG.
14
6
1.9e 8
.13 (14 + 13/2)
.14
(2 = SG 3 = YW;
SEQ ID NO: 9)
5:
YYCA2111 C SG11 C Y1YFDYWG.
15
6
9.4E 7
.13 (15 + 16/2)
.14
(2 = KR; SEQ ID NO: 10)
6:
YYCA211S1TIFG11111YFDYWG.
17
8
1.7E 10
.11 (17 + 16/2)
.12
(2 = KR; SEQ ID NO: 11)
7:
YYCAR111YY2S33YY111YFDYWG.
18
6
3.8E 8
.04 (18)
.08
(2 = D|G; 3 = S|G;
SEQ ID NO: 12)
8:
YYCAR1111Y C 2231 C Y111YFDYWG.
19
8
2.0E 11
.10 (19 on)
.11
(2 = S|G; 3 = T|D|G;
SEQ ID NO: 13)
Allowed lengths: 8, 10, 12, 14, 15, 17, 18, & 19
TABLE 17P
vgDNA encoding the CDR3 elements of the library
CDR3 library components
(Ctop25)
5′-gctctggtcaa C| TTA|A Gg|gct|gag|g-3′ (SEQ ID NO: 40)
(CtprmA)
5′-gctctggtcaa C| TTA|A Gg|gct|gag|gac-
AflII...
|acc|gct|gtc|tac|tac|tgc|gcc-3′ (SEQ ID NO: 41)
(CBprmB)
[RC] 5′- |tac|ttc|gat|tac|ttg|ggc|caa| GGT|ACC|ct G|GTC|ACC| tcgctccacc-3′
(SEQ ID NO: 42)
BstEII...
(CBot25)
[RC] 5′-| GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′
(SEQ ID NO: 43)
N.B. [RC] means the the actual oligonucleotide is the reverse complement
of the one shown.
N.B. The 20 bases at 3′ end of CtprmA are identical to the most 5′ 20 bases
of each of the vgDNA molecules.
N.B. Ctop25 is identical to the most 5′ 25 bases of CtprmA.
N.B. The 23 most 3′ bases of CBprmB are the reverse complement of the
most 3′ 23 bases of each of the vgDNA molecules.
N.B. CBot25 is identical to the 25 bases at the 5′ end of CBprmB.
(C1t08)
5′- cc|gct|gtc|tac|tac|tgc|gcc|-
<2>|<1>|<1>|<1>|<1>-
|tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 44)
2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C
(C2t10)
5′-cc|gct|gtc|tac|tac|tgc|gcc|-
<2>|<1>|<1>|<1>|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 45)
2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C
(C3t12)
5′-cc|gct|gtc|tac|tac|tgc|gcc|-
<2>|<1>|<1>|<1>|<1>|<1>|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 46)
2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C
(C4t14)
5′-cc|gct|gtc|tac|tac|tgc|gcc|cgt|-
|<1>|<1>|<1>|tct|<2>|tct|<3>|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 47)
2 = SG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = YW
(C5t15)
5′-cc|gct|gtc|tac|tac|tgc|gcc|-
<2>|<1>|<1>|<1>|tgc|tct|ggt|<1>|<1>|tgc|tat|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG -3′ (SEQ ID NO: 48)
2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C
(C6t17)
5′-cc|gct|gtc|tac|tac|tgc|gcc|-
<2>|<1>|<1>|tct|<1>|act|atc|ttc|ggt|<1>|<1>|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 49)
2 = KR, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C
(C7t18)
5′-cc|gct|gtc|tac|tac|tgc|gcc|cgt|-
|<1>|<1>|<1>|tat|tac|<2>|tct|<3>|<3>|tac|tat|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 50)
2 = DG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = SG
(c8t19)
5′-cc|gct|gtc|tac|tac|tgc|gcc|cgt|-
|<1>|<1>|<1>|<1>|tat|tgc|<2>|<2>|<3>|<1>|tgc|tat|<1>|<1>|<1>|-
tac|ttc|gat|tac|ttg|ggc|caa|GG-3′ (SEQ ID NO: 51)
2 = SG, 1 = 0.27Y + 0.27G + 0.027{ADEFHIKLMNPQRSTVW} no C, 3 = TDG
TABLE 19
Names of 1398 GeneBank entries examined
haj10335
hsa006165
hsa234190
hsa234288
hsa239366
hsa240594
hsa244963
hs201e3
hsa006167
hsa234191
hsa234290
hsa239367
hsa240595
hsa244965
hs201g1
hsa006169
hsa234193
hsa234291
hsa239368
hsa240599
hsa244966
hs201m2
hsa006171
hsa234194
hsa234294
hsa239369
hsa240604
hsa244967
hs202e2
hsa006173
hsa234196
hsa234296
hsa239370
hsa241344
hsa244968
hs202g3
hsa131921
hsa234197
hsa234298
hsa239371
hsa241345
hsa244969
hs202g9
hsa132847
hsa234199
hsa235649
hsa239372
hsa241346
hsa244970
hs202m3
hsa132849
hsa234202
hsa235658
hsa239373
hsa241347
hsa244971
hs203e1
hsa132850
hsa234203
hsa235662
hsa239375
hsa241348
hsa244972
hs203g1
hsa132851
hsa234205
hsa235664
hsa239376
hsa241349
hsa244973
hs203m5
hsa132852
hsa234206
hsa235665
hsa239377
hsa241350
hsa244974
hs204e1
hsa224746
hsa234207
hsa235667
hsa239378
hsa241351
hsa244975
hs204g1
hsa225092
hsa234208
hsa235671
hsa239379
hsa241353
hsa244976
hs3d6hcv
hsa225093
hsa234209
hsa235675
hsa239380
hsa241354
hsa244977
hs6d4xa7
hsa230634
hsa234211
hsa235677
hsa239381
hsa241355
hsa244978
hs6d4xb7
hsa230635
hsa234212
hsa238036
hsa239382
hsa241356
hsa244979
hs6d4xf1
hsa230636
hsa234214
hsa238037
hsa239383
hsa241357
hsa244980
hs6d4xf2
hsa230637
hsa234217
hsa238038
hsa239384
hsa241420
hsa244981
hs6d4xg3
hsa230638
hsa234221
hsa238039
hsa239385
hsa241421
hsa244982
hs6d4xh5
hsa230639
hsa234224
hsa238040
hsa239386
hsa242555
hsa244983
hs83x6b2
hsa230640
hsa234227
hsa238326
hsa239387
hsa242556
hsa244984
hs83x6b5
hsa230641
hsa234229
hsa238327
hsa239388
hsa243108
hsa244985
hs83x6c3
hsa230643
hsa234230
hsa238328
hsa239390
hsa243110
hsa244986
hs83x6c4
hsa230644
hsa234232
hsa239330
hsa239391
hsa244928
hsa244987
hs83x6c5
hsa230645
hsa234235
hsa239331
hsa240553
hsa244929
hsa244988
hs83x6d4
hsa230646
hsa234238
hsa239332
hsa240554
hsa244930
hsa244989
hs83x6f1
hsa230647
hsa234239
hsa239333
hsa240555
hsa244931
hsa244990
hs83x6f2
hsa230648
hsa234242
hsa239334
hsa240556
hsa244932
hsa244991
hs83x6f3
hsa230649
hsa234245
hsa239335
hsa240557
hsa244933
hsa244992
hs83x6f5
hsa230650
hsa234248
hsa239336
hsa240558
hsa244934
hsa244993
hs83x6h3
hsa230651
hsa234249
hsa239337
hsa240559
hsa244935
hsa244994
hs83x9a6
hsa230652
hsa234251
hsa239338
hsa240560
hsa244936
hsa244995
hs83x9b6
hsa230653
hsa234252
hsa239339
hsa240561
hsa244937
hsa244996
hs83x9b9
hsa230654
hsa234255
hsa239340
hsa240562
hsa244938
hsa244997
hs83x9c8
hsa230655
hsa234256
hsa239341
hsa240563
hsa244939
hsa244998
hs83x9d6
hsa230656
hsa234257
hsa239342
hsa240564
hsa244940
hsa244999
hs83x9d7
hsa230657
hsa234258
hsa239343
hsa240565
hsa244941
hsa245000
hs83x9e6
hsa230658
hsa234259
hsa239344
hsa240566
hsa244942
hsa245001
hs83x9e8
hsa234156
hsa234260
hsa239345
hsa240567
hsa244943
hsa245002
hs83x9e9
hsa234158
hsa234262
hsa239346
hsa240568
hsa244944
hsa245003
hs83x9f6
hsa234160
hsa234263
hsa239347
hsa240569
hsa244945
hsa245004
hs83x9g6
hsa234161
hsa234264
hsa239348
hsa240570
hsa244946
hsa245005
hs9d4x10
hsa234163
hsa234266
hsa239349
hsa240571
hsa244947
hsa245006
hs9d4x7
hsa234164
hsa234268
hsa239350
hsa240572
hsa244948
hsa245007
hs9d4x8
hsa234166
hsa234269
hsa239351
hsa240573
hsa244949
hsa245008
hs9d4x9
hsa234168
hsa234270
hsa239353
hsa240575
hsa244950
hsa245009
hs9d4xa6
hsa234169
hsa234272
hsa239354
hsa240576
hsa244951
hsa245010
hs9d4xa7
hsa234171
hsa234273
hsa239355
hsa240578
hsa244952
hsa245011
hs9d4xb6
hsa234172
hsa234274
hsa239356
hsa240580
hsa244953
hsa245012
hs9d4xc2
hsa234175
hsa234276
hsa239357
hsa240581
hsa244954
hsa245013
hs9d4xd6
hsa234178
hsa234277
hsa239358
hsa240582
hsa244955
hsa245014
hs9d4xe6
hsa234180
hsa234279
hsa239359
hsa240585
hsa244956
hsa245015
hs9d4xf3
hsa234181
hsa234281
hsa239360
hsa240586
hsa244957
hsa245016
hs9d4xh4
hsa234183
hsa234282
hsa239361
hsa240588
hsa244958
hsa245017
hs9d4xh5
hsa234184
hsa234283
hsa239362
hsa240589
hsa244959
hsa245018
hsa005975
hsa234186
hsa234284
hsa239363
hsa240590
hsa244960
hsa245019
hsa005977
hsa234187
hsa234286
hsa239364
hsa240592
hsa244961
hsa245020
hsa006161
hsa234189
hsa234287
hsa239365
hsa240593
hsa244962
hsa245021
hsa245022
hsa245217
hsa245305
hsa279524
hsabhiv8
hsb8g2g08
hsevh52a1
hsa245023
hsa245218
hsa245307
hsa279526
hsadeigvh
hsb8g3b07
hsevh52a2
hsa245024
hsa245219
hsa245309
hsa279527
hsaj2768
hsb8g3c07
hsevh52a3
hsa245025
hsa245220
hsa245311
hsa279528
hsaj2769
hsb8g3c08
hsevh52a4
hsa245026
hsa245221
hsa245312
hsa279529
hsaj2771
hsb8g3c12
hsevh52a5
hsa245027
hsa245222
hsa245313
hsa279530
hsaj2772
hsb8g3d03
hsevh52b1
hsa245028
hsa245223
hsa245315
hsa279531
hsaj2773
hsb8g3d04
hsevh53a1
hsa245029
hsa245224
hsa245317
hsa279532
hsaj2776
hsb8g3d07
hsevh53a2
hsa245030
hsa245225
hsa245318
hsa279533
hsaj2777
hsb8g3d08
hsfog1h
hsa245031
hsa245226
hsa245319
hsa279535
hsaj4083
hsb8g3e02
hsfog3h
hsa245032
hsa245228
hsa245320
hsa279536
hsaj4899
hsb8g3e03
hsfogbh
hsa245033
hsa245229
hsa245321
hsa279537
hsasighc
hsb8g3f03
hsfom1h
hsa245034
hsa245230
hsa245322
hsa279543
hsavh510
hsb8g3g01
hsfs10hc
hsa245035
hsa245231
hsa245323
hsa279544
hsavh512
hsb8g3g03
hsfs11hc
hsa245036
hsa245232
hsa245325
hsa279545
hsavh513
hsb8g3g05
hsfs9whc
hsa245037
hsa245233
hsa245326
hsa279552
hsavh514
hsb8g3g10
hsgad2h
hsa245039
hsa245234
hsa245338
hsa389169
hsavh515
hsb8g3h01
hsgvh0117
hsa245040
hsa245235
hsa245342
hsa389170
hsavh516
hsb8g4c02
hsgvh0118
hsa245041
hsa245236
hsa245343
hsa389171
hsavh517
hsb8g4e01
hsgvh0119
hsa245042
hsa245237
hsa245345
hsa389172
hsavh519
hsb8g4e05
hsgvh0120
hsa245043
hsa245238
hsa245346
hsa389173
hsavh520
hsb8g4f11
hsgvh0121
hsa245044
hsa245239
hsa245347
hsa389174
hsavh523
hsb8g4h09
hsgvh0122
hsa245045
hsa245240
hsa245348
hsa389175
hsavh524
hsb8g4h10
hsgvh0123
hsa245046
hsa245241
hsa245349
hsa389176
hsavh526
hsb8g5d10
hsgvh0124
hsa245047
hsa245246
hsa245350
hsa389177
hsavh529
hsb8g5h08
hsgvh0201
hsa245048
hsa245251
hsa245352
hsa389178
hsavh53
hsbel1
hsgvh0202
hsa245049
hsa245255
hsa245353
hsa389179
hsavh56
hsbel14
hsgvh0203
hsa245050
hsa245258
hsa245355
hsa389180
hsb3g4a07
hsbel28
hsgvh0204
hsa245051
hsa245260
hsa245356
hsa389181
hsb73g04n
hsbel29
hsgvh0205
hsa245052
hsa245261
hsa245357
hsa389182
hsb74a08n
hsbel3
hsgvh0206
hsa245053
hsa245262
hsa245358
hsa389183
hsb7g1a11
hsbel34
hsgvh0207
hsa245054
hsa245263
hsa245359
hsa389184
hsb7g2b01
hsbel43
hsgvh0208
hsa245055
hsa245265
hsa249378
hsa389185
hsb7g3a01
hsbel45
hsgvh0209
hsa245056
hsa245266
hsa249628
hsa389186
hsb7g3a05
hsbel5
hsgvh0210
hsa245057
hsa245268
hsa249629
hsa389187
hsb7g3a10
hsbel54
hsgvh0211
hsa245058
hsa245272
hsa249630
hsa389188
hsb7g3b02
hsbel69
hsgvh0213
hsa245059
hsa245273
hsa249631
hsa389190
hsb7g3b03
hsbo1vhig
hsgvh0214
hsa245060
hsa245275
hsa249632
hsa389191
hsb7g3b05
hsbo3vhig
hsgvh0215
hsa245061
hsa245277
hsa249633
hsa389192
hsb7g3c03
hsbr1vhig
hsgvh0216
hsa245062
hsa245278
hsa249634
hsa389193
hsb7g3c12
hsbradh3
hsgvh0217
hsa245063
hsa245279
hsa249635
hsa389194
hsb7g3d07
hscal4ghc
hsgvh0218
hsa245064
hsa245280
hsa249636
hsa389195
hsb7g3e01
hsd4xd10
hsgvh0219
hsa245065
hsa245281
hsa249637
hsa389927
hsb7g3f02
hsd4xf21
hsgvh0220
hsa245066
hsa245282
hsa271600
hsa389929
hsb7g3f10
hsd4xg2
hsgvh0221
hsa245067
hsa245283
hsa271601
hsa6351
hsb7g3g02
hsd4xi10
hsgvh0222
hsa245068
hsa245284
hsa271602
hsa7321
hsb7g3g04
hsd4xi4
hsgvh0223
hsa245069
hsa245285
hsa271603
hsa7322
hsb7g4a08
hsd4xk9
hsgvh0224
hsa245071
hsa245286
hsa271604
hsa7323
hsb7g4c05
hsd4x13
hsgvh0302
hsa245072
hsa245287
hsa279513
hsa7325
hsb7g4d09
hsd5hc
hsgvh0304
hsa245073
hsa245288
hsa279514
hsa7326
hsb7g4f08
hsdolvhig
hsgvh0306
hsa245201
hsa245289
hsa279515
hsa7328
hsb7g4g07
hseliepa1
hsgvh0307
hsa245203
hsa245290
hsa279516
hsa7438
hsb7g5g03
hseliepa3
hsgvh0308
hsa245204
hsa245291
hsa279517
hsa7440
hsb8g1c04
hseliepa4
hsgvh0309
hsa245208
hsa245292
hsa279519
hsa7441
hsb8g1e04
hseliepb2
hsgvh0310
hsa245209
hsa245294
hsa279520
hsa7442
hsb8g1f03
hseliepd2
hsgvh0311
hsa245210
hsa245298
hsa279521
hsa7443
hsb8g1g04
hselilpb1
hsgvh0312
hsa245214
hsa245299
hsa279522
hsa7444
hsb8g1h02
hsevh51a1
hsgvh0314
hsa245215
hsa245301
hsa279523
hsaarma1
hsb8g2f09
hsevh51b1
hsgvh0315
hsgvh0318
hsig001vh
hsighpat5
hsigvhc07
hsimghc1
hsmvh0401
hsrou233
hsgvh0320
hsig030vh
hsighpat6
hsigvhc08
hsimghc2
hsmvh0403
hsrt792hc
hsgvh0321
hsig033vh
hsighpat7
hsigvhc09
hsimghc3
hsmvh0404
hsrt79hc
hsgvh0322
hsig039vh
hsighpat8
hsigvhc10
hsimghc4
hsmvh0405
hssm1vhig
hsgvh0323
hsig040vh
hsighpat9
hsigvhc11
hsimghc5
hsmvh0406
hssp46a
hsgvh0324
hsig055vh
hsighpt11
hsigvhc12
hsin42p5
hsmvh0501
hst14vh
hsgvh0325
hsig057vh
hsighpt12
hsigvhc14
hsin51p7
hsmvh0502
hst14x1
hsgvh0326
hsig1059
hsighpta1
hsigvhc16
hsin51p8
hsmvh0503
hst14x10
hsgvh0327
hsig10610
hsighvb5
hsigvhc17
hsin78
hsmvh0504
hst14x11
hsgvh0328
hsig13g10
hsighvca
hsigvhc18
hsin87
hsmvh0505
hst14x12
hsgvh0329
hsig473
hsighvcb
hsigvhc19
hsin89p2
hsmvh0506
hst14x13
hsgvh0330
hsig7sa11
hsighvcc
hsigvhc20
hsin92
hsmvh0507
hst14x14
hsgvh0331
hsigaehc
hsighvcd
hsigvhc21
hsin98p1
hsmvh0508
hst14x15
hsgvh0332
hsigaf2h2
hsighvce
hsigvhc22
hsjac10h
hsmvh0509
hst14x16
hsgvh0333
hsigashc
hsighvm
hsigvhc23
hsjhba1f
hsmvh0510
hst14x17
hsgvh0334
hsigathc
hsighxx1
hsigvhc24
hsjhbr2f
hsmvh0511
hst14x18
hsgvh0335
hsigdvrhc
hsighxx10
hsigvhc25
hsjhej1f
hsmvh0513
hst14x19
hsgvh0336
hsigg1kh
hsighxx11
hsigvhc26
hsld1110
hsmvh0515
hst14x20
hsgvh0419
hsigg1kl
hsighxx12
hsigvhc27
hsld1117
hsmvh0529
hst14x21
hsgvh0420
hsigg11h
hsighxx14
hsigvhc28
hsld152
hsmvh51
hst14x22
hsgvh0421
hsigghc85
hsighxx16
hsigvhc29
hsld21
hsmvh510
hst14x23
hsgvh0422
hsigghcv3
hsighxx18
hsigvhc30
hsld217
hsmvh511
hst14x24
hsgvh0423
hsigghevr
hsighxx2
hsigvhc31
hsld218
hsmvh512
hst14x25
hsgvh0424
hsiggvdj1
hsighxx20
hsigvhc32
hsld25
hsmvh515
hst14x3
hsgvh0428
hsiggvdj2
hsighxx21
hsigvhc33
hsmad2h
hsmvh516
hst14x6
hsgvh0429
hsiggvhb
hsighxx22
hsigvhc35
hsmbcl5h4
hsmvh517
hst14x7
hsgvh0430
hsiggvhc
hsighxx23
hsigvhc36
hsmica1h
hsmvh53
hst14x8
hsgvh0517
hsigh10g1
hsighxx25
hsigvhc37
hsmica3h
hsmvh54
hst14x9
hsgvh0519
hsigh10g2
hsighxx26
hsigvhc38
hsmica4h
hsmvh55
hst22x1
hsgvh0522
hsigh10g3
hsighxx28
hsigvhc39
hsmica5h
hsmvh56
hst22x11
hsgvh0523
hsigh10g4
hsighxx29
hsigvhc40
hsmica6h
hsmvh57
hst22x12
hsgvh0526
hsigh10g5
hsighxx3
hsigvhc41
hsmica7h
hsmvh58
hst22x13
hsgvh0527
hsigh10g7
hsighxx30
hsigvhc42
hsmt11ige
hsmvh59
hst22x14
hsgvh0531
hsigh10g8
hsighxx31
hsigvhc43
hsmt12ige
hsnamembo
hst22x15
hsgvh511
hsigh10g9
hsighxx32
hsigvhls
hsmt13ige
hsnpb346e
hst22x18
hsgvh512
hsigh13g1
hsighxx34
hsigvhttd
hsmt14ige
hsoak3h
hst22x20
hsgvh513
hsigh13g7
hsighxx36
hsigvp151
hsmt15ige
hsog31h
hst22x21
hsgvh515
hsigh14g1
hsighxx37
hsigvp152
hsmt16ige
hspag1h
hst22x22
hsgvh519
hsigh14g2
hsighxx38
hsigvp153
hsmt17ige
hsrael
hst22x23
hsgvh521
hsigh2f2
hsighxx5
hsigvp154
hsmt21ige
hsregah
hst22x25
hsgvh526
hsigh3135
hsighxx6
hsigvp155
hsmt22ige
hsrfabh37
hst22x26
hsgvh530
hsigh35
hsighxx7
hsigvp156
hsmt23ige
hsrighvja
hst22x27
hsgvh533
hsigh44
hsighxx8
hsigvp157
hsmt24ige
hsrighvjb
hst22x28
hsgvh534
hsigh4c2
hsighxx9
hsigvp158
hsmt25ige
hsrou10
hst22x30
hsgvh535
hsigh9e1
hsigkrf
hsigvp251
hsmt26ige
hsrou11
hst22x9
hsgvh536
hsighadi2
hsigmhavh
hsigvp255
hsmt27ige
hsrou111
hsu24687
hsgvh55
hsighadi3
hsigrhe15
hsigvp256
hsmutuiem
hsrou112
hsu24688
hsh217e
hsighcvr
hsigtgk1h
hsigvp257
hsmvh0001
hsrou119
hsu24690
hsh241e
hsighcza
hsigtgk4h
hsigvp360
hsmvh0002
hsrou122
hsu24691
hsh28e
hsighczb
hsigtgl9h
hsigvp363
hsmvh0003
hsrou126
hsv52a512
hsha3d1ig
hsighczc
hsigvarh1
hsigvp369
hsmvh0004
hsrou127
hsvdj10h
hshambh
hsighczd
hsigvhc
hsigvp39
hsmvh0005
hsrou129
hsvdj12h
hshcmg42
hsighczf
hsigvhc01
hsihr8
hsmvh0006
hsrou13
hsvgcg1
hshcmg43
hsighczg
hsigvhc02
hsihr9
hsmvh0007
hsrou131
hsvgcm1
hshcmg44
hsigheavy
hsigvhc03
hsihv1
hsmvh0009
hsrou18
hsvgcm2
hshcmg46
hsighpat2
hsigvhc04
hsihv11
hsmvh0010
hsrou219
hsvh1djh6
hshcmt42
hsighpat3
hsigvhc05
hsihv18
hsmvh0011
hsrou221
hsvh3djh4
hshcmt47
hsighpat4
hsigvhc06
hsim9vch
hsmvh0012
hsrou222
hsvh4dj
hsvh4djh6
hsvhic11
hsww1p10e
hsy14935
hsz80377
hsz80424
hsz80482
hsvh4r
hsvhic2
hsx98932
hsy14936
hsz80378
hsz80426
hsz80483
hsvh52a43
hsvhic3
hsx98933
hsy14937
hsz80383
hsz80427
hsz80487
hsvh52a55
hsvhid1
hsx98934
hsy14938
hsz80385
hsz80429
hsz80489
hsvh5dj
hsvhid5
hsx98935
hsy14939
hsz80386
hsz80433
hsz80492
hsvh5djh5
hsvhid7
hsx98936
hsy14940
hsz80388
hsz80436
hsz80495
hsvh710p1
hsvhid9
hsx98938
hsy14943
hsz80390
hsz80438
hsz80496
hsvheg7
hsvhie4
hsx98939
hsy14945
hsz80391
hsz80439
hsz80499
hsvhfa2
hsvhif10
hsx98940
hsy18120
hsz80392
hsz80441
hsz80500
hsvhfa7
hsvhif3
hsx98941
hsz74663
hsz80393
hsz80442
hsz80502
hsvhfb5
hsvhif7
hsx98943
hsz74665
hsz80394
hsz80443
hsz80504
hsvhfc2
hsvhig2
hsx98944
hsz74668
hsz80397
hsz80445
hsz80507
hsvhfd7
hsvhp2
hsx98945
hsz74671
hsz80400
hsz80458
hsz80509
hsvhfe5
hsvhp29
hsx98946
hsz74672
hsz80403
hsz80459
hsz80512
hsvhfg9
hsvhp30
hsx98947
hsz74682
hsz80406
hsz80460
hsz80513
hsvhgd8
hsvhp32
hsx98948
hsz74688
hsz80407
hsz80461
hsz80517
hsvhgd9
hsvhp34
hsx98950
hsz74690
hsz80409
hsz80462
hsz80519
hsvhgh7
hsvhp4
hsx98951
hsz74693
hsz80411
hsz80463
hsz80520
hsvhha10
hsvhp46
hsx98952
hsz74695
hsz80412
hsz80465
hsz80527
hsvhia2
hsvhp48
hsx98953
hsz80363
hsz80414
hsz80466
hsz80534
hsvhia5
hsvhp53
hsx98954
hsz80364
hsz80415
hsz80473
hsz80538
hsvhib12
hsvhp7
hsx98955
hsz80365
hsz80416
hsz80474
hsz80544
hsvhib6
hsvigd9
hsx98956
hsz80367
hsz80417
hsz80475
hsz80545
hsvhib8
hswad35vh
hsx98958
hsz80368
hsz80418
hsz80476
hsvhic1
hswanembo
hsx98963
hsz80372
hsz80421
hsz80477
hsvhic10
hswo1vhig
hsy14934
hsz80375
hsz80422
hsz80480
TABLE 20P
Human GLG CDR1 & CDR2 AA seqs
CDR2
CDR1
1 1 1
Name
1234567
1234567890123456789
1-02
GYY--MH
WINPNSGG--TNYAQKFQG
(SEQ ID NO: 230)
(SEQ ID NO: 231)
1-03
SYA--MH
WINAGNGN--TKYSQKFQG
(SEQ ID NO: 232)
(SEQ ID NO: 233)
1-08
SYD--IN
WMNPNSGN--TGYAQKFQG
(SEQ ID NO: 234)
(SEQ ID NO: 235)
1-18
SYG--IS
WISAYNGN--TNYAQKLQG
(SEQ ID NO: 236)
(SEQ ID NO: 237)
1-24
ELS--MH
GFDPEDGE--TIYAQKFQG
(SEQ ID NO: 238)
(SEQ ID NO: 239)
1-45
YRY--LH
WITPFNGN--TNYAQKFQD
(SEQ ID NO: 240)
(SEQ ID NO: 241)
1-46
SYY--MH
IINPSGGS--TSYAQKFQG
(SEQ ID NO: 242)
(SEQ ID NO: 243)
1-58
SSA--VQ
WIVVGSGN--TNYAQKFQE
(SEQ ID NO: 244)
(SEQ ID NO: 245)
1-69
SYA--IS
GIIPIFGT--ANYAQKFQG
(SEQ ID NO: 246)
(SEQ ID NO: 247)
1-e
SYA--IS
GIIPIFGT--ANYAQKFQG
(SEQ ID NO: 248)
(SEQ ID NO: 249)
1-f
DYY--MH
LVDPEDGE--TIYAEKFQG
(SEQ ID NO: 250)
(SEQ ID NO: 251)
2-05
TSGVGVG
LIYWNDDK---RYSPSLKS
(SEQ ID NO: 252)
(SEQ ID NO: 253)
2-26
NARMGVS
HIFSNDEK---SYSTSLKS
(SEQ ID NO: 254)
(SEQ ID NO: 255)
2-70
TSGMRVS
RIDWDDDK---FYSTSLKT
(SEQ ID NO: 256)
(SEQ ID NO: 257)
3-07
SYW--MS
NIKQDGSE--KYYVDSVKG
(SEQ ID NO: 258)
(SEQ ID NO: 259)
3-09
DYA--MH
GISWNSGS--IGYADSVKG
(SEQ ID NO: 260)
(SEQ ID NO: 261)
3-11
DYY--MS
YISSSGST--IYYADSVKG
(SEQ ID NO: 262)
(SEQ ID NO: 263)
3-13
SYD--MH
AIGTAGD---TYYPGSVKG
(SEQ ID NO: 264)
(SEQ ID NO: 265)
3-15
NAW--MS
RIKSKIDGGTIDYAAPVKG
(SEQ ID NO: 266)
(SEQ ID NO: 267)
3-20
DYG--MS
GINWNGGS--TGYADSVKG
(SEQ ID NO: 268)
(SEQ ID NO: 269)
3-21
SYS--MN
SISSSSSY--IYYADSVKG
(SEQ ID NO: 270)
(SEQ ID NO: 271)
3-23
SYA--MS
AISGSGGS--TYYADSVKG
(SEQ ID NO: 272)
(SEQ ID NO: 273)
3-30
SYG--MH
VISYDGSN--KYYADSVKG
(SEQ ID NO: 274)
(SEQ ID NO: 275)
3303
SYA--MH
VISYDGSN--KYYADSVKG
(SEQ ID NO: 276)
(SEQ ID NO: 277)
3305
SYG--MH
VISYDGSN--KYYADSVKG
(SEQ ID NO: 278)
(SEQ ID NO: 279)
3-33
SYG--MH
VIWYDGSN--KYYADSVKG
(SEQ ID NO: 280)
(SEQ ID NO: 281)
3-43
DYT--MH
LISWDGGS--TYYADSVKG
(SEQ ID NO: 282)
(SEQ ID NO: 283)
3-48
SYS--MN
YISSSSST--IYYADSVKG
(SEQ ID NO: 284)
(SEQ ID NO: 285)
3-49
DYA--MS
FIRSKAYGGTTEYTASVKG
(SEQ ID NO: 286)
(SEQ ID NO: 287)
3-53
SNY--MS
VIYSGGS---TYYADSVKG
(SEQ ID NO: 288)
(SEQ ID NO: 289)
3-64
SYA--MH
AISSNGGS--TYYANSVKG
(SEQ ID NO: 290)
(SEQ ID NO: 291)
3-66
SNY--MS
VIYSGGS---TYYADSVKG
(SEQ ID NO: 292)
(SEQ ID NO: 293)
3-72
DHY--MD
RTRNKANSYTTEYAASVKG
(SEQ ID NO: 294)
(SEQ ID NO: 295)
3-73
GSA--MH
RIRSKANSYATAYAASVKG
(SEQ ID NO: 296)
(SEQ ID NO: 297)
3-74
SYW--MH
RINSDGSS--TSYADSVKG
(SEQ ID NO: 298)
(SEQ ID NO: 299)
3-d
SNE--MS
SISGGS----TYYADSRKG
(SEQ ID NO: 300)
(SEQ ID NO: 301)
4-04
SSNW-WS
EIYHSGS---TNYNPSLKS
(SEQ ID NO: 302)
(SEQ ID NO: 303)
4-28
SSNW-WG
YIYYSGS---TYYNPSLKS
(SEQ ID NO: 304)
(SEQ ID NO: 305)
4301
SGGYYWS
YIYYSGS---TYYNPSLKS
(SEQ ID NO: 306)
(SEQ ID NO: 307)
4302
SGGYSWS
YIYHSGS---TYYNPSLKS
(SEQ ID NO: 308)
(SEQ ID NO: 309)
4304
SGDYYWS
YIYYSGS---TYYNPSLKS
(SEQ ID NO: 310)
(SEQ ID NO: 311)
4-31
SGGYYWS
YIYYSGS---TYYNPSLKS
(SEQ ID NO: 312)
(SEQ ID NO: 313)
4-34
GYY--WS
EINHSGS---TNYNPSLKS
(SEQ ID NO: 314)
(SEQ ID NO: 315)
4-39
SSSYYWG
SIYYSGS---TYYNPSLKS
(SEQ ID NO: 316)
(SEQ ID NO: 317)
4-59
SYY--WS
YIYYSGS---TNYNPSLKS
(SEQ ID NO: 318)
(SEQ ID NO: 319)
4-61
SGSYYWS
YIYYSGS---TNYNPSLKS
(SEQ ID NO: 320)
(SEQ ID NO: 321)
4-b
SGYY-WG
SIYHSGS---TYYNPSLKS
(SEQ ID NO: 322)
(SEQ ID NO: 323)
5-51
SYW--IG
IIYPGDSD--TRYSPSFQG
(SEQ ID NO: 324)
(SEQ ID NO: 325)
5-a
SYW--IS
RIDPSDSY--TNYSPSFQG
(SEQ ID NO: 326)
(SEQ ID NO: 327)
6-1
SNSAAWN
RTYYRSKWY-NDYAVSVKS
(SEQ ID NO: 328)
(SEQ ID NO: 329)
74.1
SYA--MN
WINTNTGN--PTYAQGFTG
(SEQ ID NO: 330)
(SEQ ID NO: 331)
CDR1 of human GLGs
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
-
Consens.
1
7
1
3
2
35
2
1
Sd x
2
2
6
1
1
4
1
7
29
Ysg x
3
11
3
1
10
2
1
6
1
5
11
YAGS x
4
1
2
1
3
7
38
-
5
1
2
1
1
5
41
-
6
6
1
28
4
12
Mwi
7
1
5
16
5
1
23
SHng
CDR2 of human GLGs
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
-
Consens.
1
3
2
1
5
1
2
3
1
7
4
6
7
8
X
2
1
46
1
2
1
I
3
4
1
1
2
2
8
3
12
1
1
1
15
ysn x
4
2
2
4
1
10
1
11
2
1
5
12
ysp x
5
1
8
2
1
6
2
4
8
1
17
1
sd x
6
3
7
2
26
3
8
2
Gsd x
7
4
1
17
1
2
24
1
1
SG x
8
1
3
3
3
10
9
4
1
1
2
15
-ns
9
2
3
46
-
10
1
3
47
-
11
2
4
5
1
1
35
3
T
12
1
2
2
1
3
2
1
11
2
3
1
22
Yn x
13
51
Y
14
31
11
1
6
1
1
An x
15
4
16
1
1
1
14
11
2
1
dpq x
16
1
11
1
38
Sk
17
13
15
1
22
Vlf
18
37
13
1
Kq
19
1
1
34
14
1
GS
TABLE 21P
Tallies of Amino-acid frequencies in mature CDR1 and CDR2
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
|
X
Tally of 23 examples with length 14
1
8
2
13
2
3
15
3
2
3
2
1
14
1
5
4
2
2
11
5
3
5
7
1
1
13
1
6
1
4
3
12
2
1
7
3
1
1
2
1
5
10
8
6
1
1
2
1
6
4
2
9
1
5
1
3
1
4
7
1
10
1
8
3
1
2
1
4
1
2
11
1
1
1
1
2
1
16
12
1
2
1
1
1
1
1
1
14
13
4
2
17
14
4
1
5
5
4
Tally of 11 examples with length 12
1
4
7
2
1
4
4
2
3
7
4
4
1
1
1
5
2
1
5
1
9
1
6
2
1
3
2
3
7
3
1
3
1
3
8
1
3
2
1
2
2
9
1
1
9
10
1
10
11
11
12
2
1
7
1
Tally of 175 examples with length 7
1
2
1
1
2
1
3
2
153
10
2
3
2
1
87
1
10
1
5
61
2
2
3
3
26
1
54
1
5
1
2
76
3
1
2
4
6
1
1
6
1
2
1
11
1
145
5
5
2
13
2
2
3
6
2
140
6
1
1
1
13
159
7
2
1
67
1
10
88
5
1
Tally of 38 examples with length 6
1
2
34
2
2
1
2
1
8
4
22
3
3
26
9
4
1
1
29
7
5
38
6
10
3
22
3
Tally of 820 examples with length 5
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
Seen
1
8
81
10
151
4
8
5
3
100
4
15
364
55
8
4
SGNDT
15
x
2
7
5
12
24
1
30
1
1
5
26
1
1
23
2
681
Y
15
3
202
4
24
13
13
133
10
2
7
5
2
3
32
14
13
112
231
YAGW
17
x
4
6
172
2
7
409
3
16
205
MWI
8
5
8
6
1
1
49
241
2
79
1
3
367
56
2
4
SHNT
14
x
CDR2
A
C
D
E
F
G
H
I
K
L
M
N
Tally of 31 examples with CDR2 of length 19
1
11
1
1
2
1
28
3
9
1
4
1
2
6
5
1
1
1
22
1
6
16
1
1
1
1
7
1
9
7
8
23
1
9
2
18
10
4
1
1
1
1
11
1
3
1
12
2
11
9
1
1
1
1
13
1
1
14
29
15
25
3
1
16
1
17
1
1
18
1
27
19
1
30
Tally of 579 (n > 50, bold; over 400, underscored) examples with length 17
1
44
1
1
2
11
81
5
69
1
14
6
41
2
7
522
1
10
17
1
3
3
1
22
5
7
6
51
25
1
76
4
39
2
8
6
16
64
9
3
2
3
15
5
3
194
6
1
70
6
44
6
4
1
55
6
3
1
75
4
45
326
1
6
43
7
8
24
5
226
3
3
3
4
24
8
4
2
57
37
5
22
4
18
18
2
2
161
9
56
11
2
63
157
1
3
3
10
1
14
2
13
30
23
6
29
2
3
110
11
1
2
7
5
1
4
3
12
405
2
18
1
6
2
13
7
323
22
7
4
1
4
14
2
5
6
3
123
1
4
15
1
1
188
2
1
22
3
16
1
13
1
1
332
3
2
1
17
11
1
565
Tally of 464 (over 50, bold; over 400, underscored)
1
5
13
184
8
1
7
1
2
15
6
2
6
429
3
4
3
1
13
13
4
10
5
154
4
1
12
2
6
199
2
1
3
5
5
20
1
1
18
4
9
6
13
8
439
1
7
20
2
14
2
4
2
26
8
13
2
4
8
1
2
9
10
4
1
10
1
8
1
245
10
6
2
2
2
11
14
3
1
1
8
408
12
4
13
4
2
1
13
2
2
14
2
2
441
15
18
413
3
5
16
1
1
31
2
2
P
Q
R
S
T
V
W
Y
X
Tally of 31 examples with CDR2 of length 19
1
1
15
1
1
RF x
2
2
I
3
18
1
1
1
Rk
4
21
1
S
5
1
1
1
1
1
K x
6
3
1
6
1
A x
7
3
1
10
y x
8
1
5
1
G
9
1
1
1
7
1
G
10
1
21
1
T
11
26
T
12
2
1
2
x
13
29
Y
14
1
1
A
15
1
1
A
16
10
20
Sp
17
29
V
18
1
2
K
19
G
Tally of 579 (n > 50, bold; over 400, underscored)
examples with length 17
1
1
4
34
30
19
118
66
31
VGIW x
2
3
8
10
I
3
8
262
19
1
46
46
SNI x
4
178
23
6
50
11
8
16
120
PYG x
5
4
8
133
9
7
1
27
DSGN x
6
1
63
8
1
2
GDS x
7
2
11
245
14
6
1
SG x
8
1
4
11
106
90
2
1
32
NST X
9
11
5
13
4
242
8
TKIA x
10
3
52
20
10
1
1
259
YNR x
11
5
551
Y
12
3
1
89
8
44
A
13
66
138
3
1
3
DQP x
14
2
7
421
1
2
2
SK x
15
1
357
2
1
VF
16
1
199
21
4
KQ x
17
1
1
G
Tally of 464 (over 50, bold; over 400, underscored)
1
3
26
65
9
14
105
EYSL x
2
1
2
19
I
3
1
12
1
250
YN x
4
4
5
2
19
28
15
165
YH x
5
1
22
365
16
1
1
S x
6
1
1
1
G
7
1
12
357
20
1
2
1
S x
8
4
3
6
420
1
T
9
13
9
3
1
1
157
NY x
10
1
7
444
Y
11
4
21
2
2
N
12
418
14
7
1
P
13
6
452
1
1
S
14
1
18
L
15
11
10
1
2
1
K
16
3
419
5
S
TABLE 22P
Tally of VH types
1-02
16
1-03
16
1-08
13
1-18
27
1-24
5
1-45
0
1-46
14
1-58
1
1-69
37
1-e
16
1-f
1
2-05
13
2-26
1
2-70
2
3-07
33
3-09
13
3-11
15
3-13
4
3-15
10
3-20
4
3-21
25
3 - 23
85
3-30
55
3303
59
3305
0
3-33
42
3-43
1
3-48
24
3-49
11
3-53
12
3-64
4
3-66
4
3-72
3
3-73
3
3-74
12
3-d
0
4-04
29
4-28
3
4301
46
4302
7
4304
37
4-31
0
4 - 34
184
4-39
65
4-59
45
4-61
9
4-b
11
5-51
55
5-a
13
6-1
7
74.1
3
TABLE 23P
Oligonucleotides used to variegate CDR1 and CDR2 of human HC
(name) 5′-....DNA sequence....-3′
everything to right of an exclamation point is commentary
[RC] means “reverse complement” of sequence shown
If last non-comment and non-blank character is “-”, then continue
on next line.
Ignore case, “a” = “A”, “c” = “C”, etc.
Ignore “|” and blanks.
<number> means incorporate trinucleotide mixtue of given number.
CDR1
(ON-R1V1vg)
5′-ct|TCC|GGA|ttc|act|ttc|tct|-
<1>|tac|<1>|atg|<1>|-! CDR1 of length 5, ON = 55 bases
tgg|gtt|cgC|CAa|gct|ccT|GG-3′ (SEQ ID NO: 27)
<1> =
ADEFGHIKLMNPQRSTVWY no C
(ON-R1top)
5′-cctactgtct |TCC|GGA|ttc|act|ttc|tct-3′ (SEQ ID NO: 28)
(ON-R1bot)
[RC] 5′-tgg|gtt|cgC|CAa|gct|ccT|GG ttgctcactc-3′ (SEQ ID NO: 29)
(ON-R1V2vg)
5′-ct|TCC|GGA|ttc|act|ttc|tct|-
<6>|<7>|<7>|tac|tac|tgg|<7>|-! CDR1 of length 7, ON = 61 bases
tgg|gtt|cgC|CAa|gct|ccT|GG-3′ (SEQ ID NO: 30)
<6> =
ST, 1:1
<7> =
0.2025(SG) + 0.035(ADEFHIKLMNPQRTVWY) no C
(ON-R1V3vg)
5′-ct|TCC|GGA|ttc|act|ttc|tct|-
|atc|agc|ggt|ggt|tct|atc|tcc|<1>|<1>|<1>|tac|tac|tgg|<1>|-! CDR1, L = 14
tgg|gtt|cgC|CAa|gct|ccT|GG-3′ (SEQ ID NO: 31) ! ON = 82 bases
CDR2
(ON-R2V1vg)
5′-ggt|ttg|gag|tgg|gtt|tct|-
<2>|atc|<2>|<3>|tct|ggt|ggc|<1>|act|<1>|-
tat|gct|gac|tcc|gtt|aaa|gg-3′ (SEQ ID NO: 32)
! ON = 68 bases, CDR2 = 17 AA
(ON-R2top)
5′-ct|tgg|gtt|cgC|CAa|gct|ccT|GGt|aaa| ggt|ttg|gag|tgg|gtt|tct -3′
(SEQ ID NO: 33)
(ON-R2bot)
[RC] 5′-tat|gct|gac|tcc|gtt|aaa|ggt|-
cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 34)
! XbaI plus 10 bases of scab
(ON-R2V2vg)
5′-ggt|ttg|gag|tgg|gtt|tct|-
<1>|atc|<4>|<1>|<1>|ggt|<5>|<1>|<1>|<1>|-
tat|gct|gac|tcc|gtt|aaa|gg-3′ (SEQ ID NO: 35)
! ON = 68 bases, CDR2 = 17 AA
<4> =
DINSWY, equimolar
<5> =
SGDN, equimolar
(ON-R2V3vg)
5′-ggt|ttg|gag|tgg|gtt|tct|-
<1>|atc|<4>|<1>|<1>|ggt|<5>|<1>|<1>|-
tat|aac|cct|tcc|ctt|aag|gg-3′ (SEQ ID NO: 36)
! ON = 65 bases, CDR2 = 16 AA
(ON-R2bo3)
[RC] 5′-tat|aac|cct|tcc|ctt|aag|ggt|-
cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 37)
! XbaI plus 10 bases of scab
(ON-R2V4vg)
5′-ggt|ttg|gag|tgg|gtt|tct|-
<1>|atc|<8>|agt|<1>|<1>|<1>|ggt|ggt|act|act|<1>
tat|gcc|gct|tcc|gtt|aag|gg-3′ (SEQ ID NO: 38)
! ON = 74 bases, CDR2 = 19 AA
(ON-R2bo4)
[RC] 5′-tat|gcc|gct|tcc|gtt|aag|ggt|-
cgc|ttc|act|atc|TCT|AGA|ttcctgtcac-3′ (SEQ ID NO: 39)
! XbaI plus 10 bases of scab
TABLE 25P
Lengths of CDRs in 285 human kappa chains
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CDR1
0
0
0
0
0
0
0
0
0
0
0
154
73
3
0
0
28
27
0
0
CDR2
0
0
0
0
0
0
0
285
0
0
0
0
0
0
0
0
0
0
0
0
CDR3
0
5
0
0
1
0
3
2
28
166
63
12
1
1
0
0
0
0
0
1
TABLE 26P
Tally of kappa types: V and J
V genes:
O12
59
O2
0
O18
0
O8
0
A20
0
A30
0
L14
0
L1
2
L15
0
L4
2
L18
0
L5
4
L19
0
L8
4
L23
0
L9
1
L24
0
L11
4
L12
8
O11
10
O1
0
A17
5
A1
0
A18
3
A2
0
A19
13
A3
0
A23
4
A27
79
A11
26
L2
28
L16
0
L6
11
L20
0
L25
0
B3
22
B2
0
A26
0
A10
0
A14
0
JH#
1
2
3
4
5
tally
105
64
29
78
9
TABLE 27P
Names of Kappa chains analyzed
AB022651
HSA388657
hsigklv37
hsikcvjp1
humigkx
AB022653
hsew1vk
hsigklv38
hsikcvjp2
humigky1
AB022654
hsew3vk
hsigklv39
hsikcvjp3
humigky2
AB022656
hsew4vk
hsigklv40
hsikcvjp6
humigky4
AF007572
hsigdpk13
hsigklv41
hsikcvjp7
humigky5
AF021036
hsigg1kl
hsigklv42
hsld110vl
humigky6
AF103499
HSIGGVKA
hsigklv43
hsld117vl
humigl3ac
AF103500
hsigk123
hsigklv44
hsld128vl
humikc
AF103527
hsigk3l9
hsigklv45
hsld140vl
humikca
AF103873
hsigklc14
hsigklv46
hsld152vl
humikcad
AF107244
hsigklc28
hsigklv49
hsld184vl
humikcaf
AF107245
hsigklc5
hsigklv50
hsld198vl
humikcag
AF107246
hsigklg31
hsigklv51
hsld24vl
humikcah
AF107247
hsigklv01
hsigklv52
hsmbcl1k1
humikcai
AF115361
hsigklv02
hsigklv53
hsmbcl1k2
humikcaj
AF165099
hsigklv03
hsigklv54a
hsmbcl2k2
humikcal
AF165101
hsigklv04
hsigklv56
hsmbcl5k4
humikcam
AF165103
hsigklv05
hsigklv57
hss10avl
humikcan
AF165108
hsigklv06
hsigklv58
hss17bvl
humikcas
AF165110
hsigklv07
hsigklv59
hss1a15vl
humikcau
AF165111
hsigklv09
hsigklv60
HSU44792
humikcav
AF184763
hsigklv10
hsigklv61
HSU44794
humikcaw
AF184767
hsigklv12
hsigklv62
HSU94422
humikcax
hsa004955
hsigklv13
hsigklv63
hsz84852
humikcay
hsa004956
hsigklv14
hsigklv65
hsz84853
humikcaz
hsa011133
hsigklv15
hsigklv66
humigk1dm
humikcb
HSA241367
hsigklv16
hsigklv68
humigk3am
humikcba
HSA241375
hsigklv17
hsigklv69
humigk3bm
humikcbb
HSA388639
hsigklv18
hsigklv71
humigk3cm
humikcbc
HSA388640
hsigklv19
hsigkvba
humigkacoa
humikcbd
HSA388641
hsigklv20
hsigkvbb
humigkacob
humikcbe
HSA388642
hsigklv21
hsigkvbc
humigkacoc
humikcbf
HSA388643
hsigklv22
hsigkvbd
humigkacoe
humikcbg
HSA388644
hsigklv23
hsigkvbe
humigkacof
humikcbh
HSA388645
hsigklv24
hsigkvbf
humigkb1aa
humikcbi
HSA388646
hsigklv25
hsigkvc01
humigkb1ab
humikcbj
HSA388647
hsigklv27
hsigkvc03
humigkb1ac
humikcbl
HSA388648
hsigklv28
hsigkvc06
humigkvra
humikcbm
HSA388650
hsigklv29
hsigkvc11
humigkvrb
humikcbn
HSA388651
hsigklv31
hsigkvc12
humigkvrc
humikcbo
HSA388652
hsigklv32
hsigkvc20
humigkvrd
humikcbp
HSA388653
hsigklv33
hsigkvc23
humigkvre
humikcbq
HSA388654
hsigklv34
hsigkvc27
humigkvrg
humikcbs
HSA388655
hsigklv35
hsigkvc29
humigkvrh
humikcbt
HSA388656
hsigklv36
hsigrklc
humigkvri
humikcbu
humikcbv
humikcvg
humikcbw
humikcvh
humikcbx
humikcvi
humikcbz
humikcvj
humikcc
humikcw
humikcca
humikcx
humikccb
humikcy
humikccc
humikcz
humikccd
S46248
humikcce
S82746
humikccf
S82747
humikccg
SU96396
humikcch
SU96397
humikcci
humikccj
humikcck
humikcco
humikccp
humikccq
humikccr
humikccs
humikcct
humikccu
humikccv
humikccw
humikcd
humikcf
humikcg
humikch
humikci
humikck
humikcm
humikcn
humikco
humikcp
humikcq
humikcr
humikcs
humikct
humikcu
humikcv
humikcva
humikcvb
humikcvc
humikcvd
humikcve
humikcvf
TABLE 28P
AA types seen in 154 kappa sequences having CDR1 of length 11
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
11
143
R
2
148
1
2
2
1
A
3
152
2
S
4
1
3
3
147
Q
5
12
1
27
7
3
99
4
1
S
6
1
81
1
71
V
7
2
4
18
5
1
2
9
12
97
3
1
S
8
3
5
1
2
1
31
1
10
87
12
1
S
9
2
7
10
1
6
29
1
8
13
77
Y
10
2
150
1
1
L
11
96
4
2
46
2
1
3
A
TABLE 30P
Synthetic Kappa light chain gene
!
!
! A27::JH1 with all CDRs replaced by stuffers.
! Each stuffer contains at least one stop codon and a
! restriction site that will be unique within the diversity vector.
!
1 GAGGACCATt GGGCCCC ctccgagact
! Scab...... Eco0109I
! ApaI.
!----------------------------------
!
28 CTCGAG cgca
! XhoI..
!----------------------------------
!
38 acgcaatTAA TGTgagttag ctcactcatt aggcacccca ggcTTTACAc tttatgcttc
..−35.. Plac ..-10.
!----------------------------------
!
98 cggctcgtat gttgtgtgga attgtgagcg gataacaatt tc
!----------------------------------
!
140 acacagga aacagctatgac
!----------------------------------
!
160 catgatta cgCCAAGCTT TGGagccttt tttttggaga ttttcaac (SEQ ID NO: 54)
! Pf1MI.......
! Hind3.
!----------------------------------
!
! M13 III signal sequence (AA seq)--------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
M K K L L F A I P L V V P F Y
206 gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac
!----------------------------------
!
! --Signal--> FR1------------------------------------------>
! 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
! S H S A Q S V L T Q S P G T L
251 |agc|cat|aGT|GCA|Caa|tcc|gtc|ctt|act|caa|tct|cct|ggc|act|ctt|
! ApaLI...
!----------------------------------
!
! ----- FR1 ------------------------------------->| CDR1------->
! 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
! S L S P G E R A T L S C R A S (SEQ ID NO:55)
|tcG|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|tgc|cgt|gct|tcc| (SEQ ID NO:54; Cont'd))
! EspI..... AflII...
! XmaI....
!
!----------------------------------
! For CDR1:
! <1> ADEFGHIKLMNPQRSTVWY equimolar
! <2> S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each)
! <3> Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each)
! In a preferred embodiment, we omit codon 52 in vgDNA for CDR1.
!
! ------- CDR1 --------------------->|--- FR2 -------------->
! <1> <2> <2> xxx <3>
! 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
! Q S V S S S Y L A W Y Q Q K P
|cag|tct|gtt|tcc|tct|tct|tat|ctt|gct|tgg|tat|caa|cag|aaA|CCT|
! SexAI...
!----------------------------------
! For CDR2:
! <1> ADEFGHIKLMNPQRSTVWY equimolar
! <2> S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each)
! <4> A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each)
! ----- FR2 ------------------------>|------- CDR2 -------->
! <1> <2> <4>
! 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
! G Q A P R L L I Y G A S S R A
|GGT|caG|GCG|CCg|cgt|tta|ctt|att|tat|ggt|gct|tct|tcc|cgc|gct|
! SexAI.... KasI.... (CDR1 installed as AflII-(SexAI or KasI) cassette.)
!
!----------------------------------
!
! CDR2-->|--- FR3 -------------------------------------------->
! <1>
! 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
! T G I P D R F S G S G S G T D
|act|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggc|tct|ggt|tca|ggt|act|gac|
! BamHI...
! RsrII.....
! (CDR2 installed as (SexAI or KasI) to (BamHI or RsrII) cassette.)
!----------------------------------
!
! ------ FR3 ------------------------------------------------>
! 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
! F T L T I S R L E P E D F A V
477 |ttt|acc|ctt|act|att|TCT|AGA|ttg|gaa|cct|gaa|gac|ttc|gct|gtt|
! XbaI...
!
!----------------------------------
!
! ----------->|----CDR3--------------------------->|-----FR4--->
! <3> <1> <1> <1> <1>
! 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
! Y Y C Q Q Y G S S P E T F G Q
|tat|tat|tgC|CAa|cag|taT|GGt|tct|tct|cct|gaa|act|ttc|ggt|caa|
! BstXI...........
!
!----------------------------------
!
! -----FR4------------------->| <------- Ckappa ------------
! 121 122 123 124 125 126 127 128 129 130 131 132 133 134
! G T K V E I K R T V A A P S
510 |ggt|aCC|AAG|Gtt|gaa|atc|aag| |CGT|ACG|gtt|gcc|gct|cct|agt|
! StyI.... BsiWI..
!
! (CDR3 installed as XbaI to (Styl or BsiWI) cassette.)
!
! 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149
! V F I F P P S D E Q L K S G T
552 |gtg|ttt|atc|ttt|cct|cct|tct|gac|gaa|CAA|TTG|aag|tca|ggt|act|
! MfeI...
!
! 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164
! A S V V C L L N N F Y P R E A
597 |gct|tct|gtc|gta|tgt|ttg|ctc|aac|aat|ttc|tac|cCT|CGT|Gaa|gct|
! BssSI...
!
! 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179
! K V Q W K V D N A L Q S G N S
642 |aaa|gtt|cag|tgg|aaa|gtc|gat|aAC|GCG|Ttg|cag|tcg|ggt|aac|agt|
! MluI....
!
! 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194
! Q E S V T E Q D S K D S T Y S
687 |caa|gaa|tcc|gtc|act|gaa|cag|gat|agt|aag|gac|tct|acc|tac|tct|
!
! 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209
! L S S T L T L S K A D Y E K H
732 |ttg|tcc|tct|act|ctt|act|tta|tca|aag|gct|gat|tat|gag|aag|cat|
!
! 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224
! K V Y A C E V T H Q G L S S P
777 |aag|gtc|tat|GCt|TGC|gaa|gtt|acc|cac|cag|ggt|ctG|AGC|TCc|cct|
! SacI....
!
! 225 226 227 228 229 230 231 232 233 234
! V T K S F N R G E C . . (SEQ ID NO: 332)
822 |gtt|acc|aaa|agt|ttc|aaC|CGT|GGt|gaa|tgc|taa|tag GGCGCGCC
! DsaI.... AscI....
! BssHII
!
866 acgcatctctaa GCGGCCGC aacaggaggag (SEQ ID NO: 333)
! NotI....
! EagI..
TABLE 31P
Tally of 285 CDR2s of length 7 in human kappa
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
51
62
7
95
1
11
15
2
1
2
6
6
3
22
1
x
2
225
18
5
5
2
1
1
3
16
9
A
3
2
9
1
2
267
2
1
1
S
4
2
1
5
4
9
1
77
4
93
80
2
7
Sx
5
1
2
80
200
2
R
6
162
7
36
4
4
1
3
3
63
2
Ax
7
5
1
3
1
1
2
2
1
125
144
x
TABLE 32P
Tally of 166 CDR3s of length 9 from human kappa.
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
4
8
21
131
1
1
Q
2
1
9
2
1
153
Q
3
14
4
4
3
6
4
1
1
3
21
16
3
4
82
Yx
4
1
9
1
2
37
4
2
2
15
1
33
2
20
7
1
29
x
5
2
2
6
3
4
5
3
28
17
7
65
19
1
1
3
x
6
7
1
11
2
3
8
1
4
3
41
33
5
28
19
x
7
1
2
6
146
2
2
5
2
P
8
2
4
1
2
21
7
3
5
1
38
7
4
25
1
3
1
16
25
x
9
3
2
1
1
2
157
T
TABLE 33P
lengths of CDRs in 93 human lambda chains
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18+
CDR1
0
0
0
0
0
0
0
0
0
0
0
23
7
15
46
0
0
0
2
CDR2
5
0
0
1
0
0
0
80
2
0
0
1
4
0
0
0
0
0
1
CDR3
0
0
0
0
0
0
0
0
1
16
28
27
6
1
0
4
6
4
0
TABLE 34P
Tally of 46 CDR1s of length 14 from human lambda chains
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
2
2
1
41
T
2
43
3
G
3
2
1
1
6
36
TGx
4
1
45
S
5
5
1
40
S
6
39
1
4
2
DNx
7
8
1
37
V
8
1
42
2
1
G
9
4
1
35
1
2
3
TGx
10
1
1
3
1
2
38
Yx
11
4
1
35
6
DNx
12
3
1
2
1
1
2
36
Yx
13
1
2
43
V
14
1
4
41
S
TABLE 35P
Synthtic human lambda-chain gene
1
GAGGACCATt GGGCCCC ttactccgtgac
Scab...... EcoO109I
ApaI..
-----------FR1-------------------------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
S A Q S A L T Q P A S V S G S P G
30
aGT|GCA|Caa|tcc|gct|ctc|act|cag|cct|GCT|AGC|gtt|tcc|gGG|TcA|CCt|GGT|
ApaLI... NheI... BstEII...
SexAI....
For CDR1,
<1> = 0.27 T, 0.27 G, 0.027 {ADEFHIKLMNPQRSVWY} no C
<2> = 0.27 D, 0.27 N, 0.027 {AEFGHIKLMPQRSTVWY} no C
<3> = 0.36 Y, 0.0355{ADEFGHIKLMNPQRSTVW} no C
T G <1> S S <2> V G
------FR1------------------> |-----CDR1---------------------
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Q S I T I S C T G T S S D V G
|caa|agt|atc|act|att|tct|TGT|ACA|ggt|act|tct|tct|gat|gtt|ggc|
BsrGI..
a second vg scheme for CDR1 gives segments of length 11:
G 23 <2><4>L<4><4><4><3><4><4> where
<4> = equimolar {ADEFGHIKLMNPQRSTVWY} no C
<1> <3> <2> <3> V S = vg Scheme #1, length = 14
-----CDR1------------->|--------FR2-------------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
G Y N Y V S W Y Q Q H P G K A
|ggt|tac|aat|tac|gtt|tct|tgg|tat|caa|caa|caC|CCG|GGc|aaG|GCG|
XmaI.... KasI.....
AvaI....
<4> <4> <4> <2> R P S
--FR2-----------------> |------CDR2--------------->|-----FR3--
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
P K L M I Y E V S N R P S G V
|CCg|aag|ttg|atg|atc|tac|gaa|gtt|tcc|aat|cgt|cct|tct|ggt|gtt|
KasI....
-------FR3----------------------------------------------------
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
S N R F S G S K S G N T A S L
|agc|aat|cgt|ttc|TCC|GGA|tct|aaa|tcc|ggt|aat|acc|gcA|AGC|TTa|
BspEI.. | HindIII.
BsaBI........(blunt)
-------FR3--------------------------------------------------->|
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T I S G L Q A E D E A D Y Y C
|act|atc|tct|ggt|CTG|CAG|gct|gaa|gac|gag|gct|gac|tac|tat|tgt|
PstI...
<5> = 0.36 S, 0.0355{ADEFGHIKLMNPQRTVWY} no C
<4> <5> <4> <2> <4> S <4> <4> <4> <4> V
-----CDR3---------------------------------->|---FR4---------
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
S S Y T S S S T L V V F G G G
|tct|tct|tac|act|tct|tct|agt|acc|ctt|gtt|gtc|ttc|ggc|ggt|GGT|
KpnI...
-------FR4-------------->
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
T K L T V L G Q P K A A P S V
279
|ACC|aaa|ctt|act|gtc|ctc|gGT|CAA|CCT|aAG|Gct|gct|cct|tcc|gtt|
KpnI... HincII..
Bsu36I...
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
T L F P P S S E E L Q A N K A
324
|act|ctc|ttc|cct|cct|agt|tct|GAA|GAG|Ctt|caa|gct|aac|aag|gct|
SapI.....
136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
T L V C L I S D F Y P G A V T
369
|act|ctt|gtt|tgc|tTG|ATC|Agt|gac|ttt|tat|cct|ggt|gct|gtt|act|
BclI....
151 152 153 154 155 156 157 158 159 160 161 162 163 164 165
V A W K A D S S P V K A G V E
414
|gtc|gct|tgg|aaa|gcc|gat|tct|tct|cct|gtt|aaa|gct|ggt|gtt|GAG|
BsmBI...
166 167 168 169 170 171 172 173 174 175 176 177 178 179 180
T T T P S K Q S N N K Y A A S
459
|ACG|acc|act|cct|tct|aaa|caa|tct|aac|aat|aag|tac|gct|gcG|AGC|
BsmBI.... SacI....
181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
S Y L S L T P E Q W K S H K S
504
|TCt|tat|ctt|tct|ctc|acc|cct|gaa|caa|tgg|aag|tct|cat|aaa|tcc|
SacI...
196 197 198 199 200 201 202 203 204 205 206 207 208 209 210
Y S C Q V T H E G S T V E K T
549
|tat|tcc|tgt|caa|gtt|acT|CAT|GAa|ggt|tct|acc|gtt|gaa|aag|act|
BspHI...
211 212 213 214 215 216 217 218 219
V A P T E C S . . (SEQ ID NO: 57)
594
|gtt|gcc|cct|act|gag|tgt|tct|tag|tga|GGCGCGCC
AscI....
BssHII
629
aacgatgttc aag GCGGCCGC aacaggaggag (SEQ ID NO: 56)
NotI.... Scab.......
Lambda 14-7(A) 2a2 ::JH2::Clambda
AA sequence tested
TABLE 36P
Tally of 23 CDR1s of length 11 from human lambda chains
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
1
6
10
6
x
2
1
1
21
G
3
15
1
7
DNx
4
2
1
1
3
7
1
8
X
5
7
16
L
6
11
1
2
8
1
X
7
1
1
1
2
2
1
14
1
X
8
1
10
1
1
1
2
7
X
9
2
6
15
Yx
10
11
1
11
X
11
3
7
9
2
2
X
TABLE 37P
Tally of 80 CDR2s of length 7 from human lambda chains
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
1
14
32
1
13
3
1
4
5
1
2
3
X
2
18
2
8
16
2
34
X
3
1
2
1
31
39
4
2
X
4
6
4
1
14
1
41
8
1
1
2
1
DNx
5
1
1
78
R
6
1
77
2
P
7
2
78
S
TABLE 38P
Tally of 27 CDR3s of length 11 from human lambda chains
Tally
A
C
D
E
F
G
H
I
K
L
M
N
P
Q
R
S
T
V
W
Y
1
4
5
6
5
4
3
X
2
3
1
2
14
5
2
Sx
3
1
7
13
6
X
4
19
2
1
1
4
DNx
5
1
4
2
2
2
1
13
2
X
6
1
3
1
21
1
S
7
1
7
12
1
4
2
X
8
2
1
10
1
6
6
1
X
9
3
1
8
10
3
1
1
X
10
1
4
1
1
1
3
1
1
6
5
3
X
11
2
25
V
TABLE 40P
Synthetic Kappa light chain gene with stuffers
1
GAGGACCATt GGGCCCC ctccgagact
Scab...... EcoO109I
ApaI.
28
CTCGAG cgca
XhoI..
38
acgcaatTAA TGTgagttag ctcactcatt aggcacccca ggcTTTACAc tttatgcttc
..-35.. Plac ..-10.
98
cggctcgtat gttgtgtgga attgtgagcg gataacaatt tc
140
acacagga aacagctatgac
160
catgatta cgCCAAGCTT TGGagccttt tttttggaga ttttcaac
PflMI.......
Hind3.
M13 III signal sequence (AA seq)--------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
M K K L L F A I P L V V P F Y
206
gtg aag aag ctc cta ttt gct atc ccg ctt gtc gtt ccg ttt tac
--Signal--> FR1------------------------------------------->
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
S H S A Q S V L T Q S P G T L
251
|agc|cat|aGT|GCA|Caa|tcc|gtc|ctt|act|caa|tct|cct|ggc|act|ctt|
ApaLI...
----- FR1 --------------------------------->|-------Stuffer->
31 32 33 34 35 36 37 38 39 40 41 42 43
S L S P G E R A T L S | |
296
|tcG|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|TAG|TAA|gct|ccc|
EspI..... AflII ...
XmaI....
------- Stuffer for CDR1------------------------->|- FR2 -->
59 60
K P
341
|AGG|CCT|ctt|TGA|tct| g|aaA|CCT|
StuI... SexAI ...
----- FR2 ------|-----------Stuffer for CDR2---------------->
61 62 63 64 65 66
G Q A P R | |
363
|GGT|caG|GCG|CCg|cgt|TAA|TGA|a AGCGCT aa TGGCCA aca gtg
SexAI.... KasI.... AfeI.. MscI..
Stuffer-->|--- FR3 ----------------------------------------------->
<1>
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T G I P D R F S G S G S G T D
405
|act|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggc|tct|ggt|tca|ggt|act|gac|
BamHI...
RsrII.....
------ FR3 ---------------------STUFFER for CDR3------------------>
91 92 93 94 95 96 97
F T L T I S R | |
450
|ttt|acc|ctt|act|att|TCT|AGA|TAA|TGA| GTTAAC TAG acc TACGTA acc tag
XbaI... HpaI.. SnaBI.
-----------------CDR3 stuffer------------------>|-----FR4--->
118 119 120
F G Q
501
|ttc|ggt|caa|
-----FR4------------------->| <------- Ckappa ------------
121 122 123 124 125 126 127 128 129 130 131 132 133 134
G T K V E I K R T V A A P S
510
|ggt|aCC|AAG|Gtt|gaa|atc|aag| |CGT|ACG|gtt|gcc|gct|cct|agt|
StyI.... BsiWI..
(CDR3 installed as XbaI to (StyI or BsiWI) cassette.)
(SEQ ID NO: 96)
135 136 137 138 139 140 141 142 143 144 145 146 147 148 149
V F I F P P S D E Q L K S G T
552
|gtg|ttt|atc|ttt|cct|cct|tct|gac|gaa|CAA|TTG|aag|tca|ggt|act|
MfeI...
866
acgcatctctaa GCGGCCGC aacaggaggag (SEQ ID NO: 95)
NotI....
EagI..
A27::JH1 with all CDRs replaced by stuffers.
Each stuffer contains at least one stop codon and a restriction site that will be unique within the diversity vector.
TABLE 41P
Variegated DNA for kappa chains
Kappa chains
For CDR1:
<1>
ADEFGHIKLMNPQRSTVWY equimolar
<2>
S(0.2) ADEFGHIKLMNPQRTVWY (0.044 each)
<3>
Y(0.2) ADEFGHIKLMNPQRSTVW (0.044 each)
<4>
A(0.2) DEFGHIKLMNPQRSTVWY (0.044 each)
(Ka1vg600)
5′-gct|acC|TTA|AGt|tgc|cgt|gct|tcc|cag-
|<1>|gtt|<2>|<2>| <3>|ctt|gct|tgg|tat|caa|cag|aaA|CC-3′
(SEQ ID NO: 66)
(Ka2vg650)
5′-caG|GCG|CCg|cgt|tta|ctt|att|tat|<1>|gct|tct|<2>|cgc|<4>|-
|<1>|gGG|ATC|CCG|GAC|CGt|ttc|tct|ggt|tctcacc-3′
(SEQ ID NO: 71)
(Ka3vg670)
5′-gac|ttc|gct|gtt|-
|tat|tat|tgC|CAa|cag|<3>|<1>|<1>|<1>|cct|<1>|act|ttc|ggt|caa|-
|ggt|aCC|AAG|Gtt|g-3′
(SEQ DI NO: 77)
TABLE 42P
Variegated DNA for lambda chains
For CDR1,
<1> =
0.27 T, 0.27 G, 0.027 {ADEFHIKLMNPQRSVWY} no C
<2> =
0.27 D, 0.27 N, 0.027 {AEFGHIKLMPQRSTVWY} no C
<3> =
0.36 Y, 0.0355{ADEFGHIKLMNPQRSTVW} no C
<4> =
equimolar {ADEFGHIKLMNPQRSTVWY} no C
<5> =
0.36 S, 0.0355{ADEFGHIKLMNPQRTVWY} no C
(Lm1vg710)
5′-gt|atc|act|att|tct|TGT|ACA|ggt|<1>|tct|tct|<2>|gtt|ggc|-
|<1>|<3>|<2>|<3>|gtt|tct|tgg|tat|caa|caa|caC|CC-3′
(SEQ ID NO: 83)
(Lm2vg750)
5′-G|CCg|aag|ttg|atg|atc|tac|-
<4>|<4>|<4>|<2>|cgt|cct|tct|ggt|gtc|agc|aat|c-3′
(SEQ ID NO: 88)
(Lm3vg817)
5′-gac|gag|gct|gac|tac|tat|tgt|-
|<4>|<5>|<4>|<2>|<4>|tct|<4>|<4>|<4>|<4>|gtc|ttc|ggc|ggt|GGT|-
|ACC|aaa|ctt|ac-3′
(SEQ ID NO: 93)
TABLE 43P
Constant DNA for Synthetic Library
CDR3 library components
(Ctop25)
5′-gctctggtcaa C|TTA|AG g|gct|gag|g-3′ (SEQ ID NO: 58)
(CtprmA)
5′-gctctggtcaa C|TTA|AG g|gct|gag|gac-
AflII...
|acc|gct |gtc|tac|tac|tgc|gcc -3′ (SEQ ID NO: 59)
(CBprmB) [RC]
5′- |tac|ttc|gat|tac|ttg|ggc|caa|GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′
(SEQ ID NO: 60)
BstEII...
(CBot25) [RC]
5′- |GG T|ACC|ct G|GTC|ACC| tcgctccacc-3′ (SEQ ID NO: 61)
Kappa chains
(Ka1Top610)
5′-ggtctcagtt-
G|CTA|AGC|CCG|GGt|gaa|cgt|gct|acC|TTA|AGt|tgc|cgt|gct|tcc|cag-3′
(SEQ ID NO: 62)
(Ka1STp615)
5′-ggtctcagtt-
G|CTA|AGC|CCG|GGt|g-3′
(SEQ ID NO: 63)
(Ka1Bot620) [RC]
5′-ctt|gct|tgg|tat|caa|cag|aaA|-
CCt|GGT|caG|GCG|CC aagtcgtgtc-3′
(SEQ ID NO: 64)
(Ka1SB625) [RC]
5′-cct|GGT|caG|GCG|CC aagtcgtgtc-3′ (SEQ ID NO: 65)
(Ka2Tshort657)
5′-cacgagtcctA|CCT|GGT|-
caG|GC-3′
(SEQ ID NO: 68)
(Ka2Tlong655)
5′-cacgagtcctA|CCT|GGT|-
caG|GCG|CCg|cgt|tta|ctt|att|tat-3′
(SEQ ID NO: 69)
(Ka2Bshort660) [RC]
5′-|GAC|CGt|ttc|tct|ggt|tctcacc-3′ (SEQ ID NO: 70)
(Ka3Tlon672)
5′-gacgagtcct TCT|AGA|ttg|gaa|cct|gaa|gac|ttc|gct|gtt|-
|tat|tat|tgC|CAa|c-3′
(SEQ ID NO: 72)
(Ka3BotL682) [RC]
5′-act|ttc|ggt|caa|-
|ggt|aCC|AAG|Gtt|gaa|atc|aag| |CGT|ACG| tcacaggtgag-3′
(SEQ ID NO: 73)
(Ka3Bsho694) [RC]
5′-gaa|atc|aag| |CGT|ACG| tcacaggtgag-3′ (SEQ ID NO: 74)
(Lm1TPri75)
5′-gacgagtcct GG|TcA|CCt|GGT|-3′ (SEQ ID NO: 78)
(Lm1TLo715)
5′-gacgagtcct GG|TcA|CCt|GGT|-
caa|agt|atc|act|att|tct|TGT|ACA|ggt-3′
(SEQ ID NO: 79)
(Lm1BLo724) [RC]
5′-gtt|tct|tgg|tat|caa|caa|caC|CCG|GGc|aaG|GCG|-
AGA TCT tcacaggtgag-3′
(SEQ ID NO: 80)
(Lm1BSh737) [RC]
5′-Gc|aaG|GCG|-
AGA TCT tcacaggtgag-3′
(SEQ ID NO: 81)
(Lm2TSh757)
5′-gagcagagga C|CCG|GGc|aaG|GC-3′ (SEQ ID NO: 84)
(Lm2TLo753)
5′-gagcagagga C|CCG|GGc|aaG|GCG|CCg|aag|ttg|atg|atc|tac|-3′
(SEQ ID NO: 85)
(Lm2BLo762) [RC]
5′-cgt|cct|tct|ggt|gtc|agc|aat|cgt|ttc|TCC|GGA|tcacaggtgag-3′
(SEQ ID NO: 86)
(Lm2BSh765) [RC]
5′-cgt|ttc|TCC|GGA|tcacaggtgag-3′ (SEQ ID NO: 87)
(Lm3TSh822)
5′-CTG|CAG|gct|gaa|gac|gag|gct|gac-3′ (SEQ ID NO: 89)
(Lm3TLo819)
5′-CTG|CAG|gct|gaa|gac|gag|gct|gac|tac|tat|tgt|-3′
(SEQ ID NO: 90)
(Lm3BLo825) [RC]
5′-gtc|ttc|ggc|ggt|GGT|-
|ACC|aaa|ctt|act|gtc|ctc|gGT|CAA| CCT | aAG | G acacaggtgag-3′
(SEQ ID NO: 91)
(Lm3BSh832) [RC]
5′-c|gGT|CAA| CCT | aAG | G acacaggtgag-3′ (SEQ ID NO: 92)
TABLE 48P
Synthtic human lambda-chain gene with stuffers in place of CDRs
1
GAGGACCATt GGGCCCC ttactccgtgac
Scab...... EcoO109I
ApaI..
-----------FR1-------------------------------------------->
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
S A Q S A L T Q P A S V S G S P G
30
aGT|GCA|Caa|tcc|gct|ctc|act|cag|cct|GCT|AGC|gtt|tcc|gGG|TcA|CCt|GGT|
ApaLI... NheI... BstEII...
SexAI....
------FR1------------------> |-----stuffer for CDR1---------
16 17 18 19 20 21 22 23
Q S I T I S C T
81
|caa|agt|atc|act|att|tct|TGT|ACA|tct TAG TGA ctc
BsrGI..
-----Stuffer--------------------------->--------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
R S | | P | H P G K A
117
AGA TCT TAA TGA ccg tag caC|CCG|GGc|aaG|GCG|
BglII XmaI.... KasI.....
AvaI....
--|-------------Stuffer ------------------------------------->
P
150
|CCg|TAA|TGA|atc tCG TAC G ct|ggt|gtt|
KasI.... BsiWI...
-------FR3----------------------------------------------------
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
S N R F S G S K S G N T A S L
177
|agc|aat|cgt|ttc|TCC|GGA|tct|aaa|tcc|ggt|aat|acc|gcA|AGC|TTa|
BspEI.. | HindIII.
BsaBI........(blunt)
-------FR3------------->|--Stuffer-------------------------->|
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
T I S G L Q
222
|act|atc|tct|ggt|CTG|CAG|gtt ctg tag ttc CAATTG ctt tag tga ccc
PstI... MfeI..
-----Stuffer------------------------------->|---FR4---------
103 104 105
G G G
270
|ggc|ggt|GGT|
KpnI...
-------FR4-------------->
106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
T K L T V L G Q P K A A P S V
279
|ACC|aaa|ctt|act|gtc|ctc|gGT|CAA|CCT|aAG|Gct|gct|cct|tcc|gtt|
KpnI... HincII..
Bsu36I...
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
T L F P P S S E E L Q A N K A
324
|act|ctc|ttc|cct|cct|agt|tct|GAA|GAG|Ctt|caa|gct|aac|aag|gct|
SapI.....
136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
T L V C L I S D F Y P G A V T
(SEQ ID NO: 98)
369
|act|ctt|gtt|tgc|tTG|ATC|Agt|gac|ttt|tat|cct|ggt|gct|gtt|act|
(SEQ ID NO: 97)
BclI....
Lambda 14-7(A) 2a2 ::JH2::Clambda
AA sequence tested
TABLE 50P
3-23::CDR3::JH4 Stuffers in place of CDRs
FR1(DP47/V3-23)---------------
20 21 22 23 24 25 26 27 28 29 30
A M A E V Q L L E S G
ctgtctgaac CC atg gcc gaa|gtt|CAA|TTG|tta|gag|tct|ggt|
Scab...... NcoI.... | MfeI |
--------------FR1--------------------------------------------
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
G G L V Q P G G S L R L S C A
|ggc|ggt|ctt|gtt|cag|cct|ggt|ggt|tct|tta|cgt|ctt|tct|tgc|gct|
----FR1-------------------->|...CDR1 stuffer....|---FR2------
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
A S G F T F S S Y A | | W V R
|gct|TCC|GGA|ttc|act|ttc|tct|tCG|TAC|Gct| TAG|TAA |tgg|gtt|cgC|
| BspEI | | BsiWI| |BstXI.
-------FR2-------------------------------->|...CDR2 stuffer.
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
Q A P G K G L E W V S | p r |
|CAa|gct|ccT|GGt|aaa|ggt|ttg|gag|tgg|gtt|tct|TAA|CCT|AGG|TAG|
...BstXI | AvrII..
.....CDR2 stuffer....................................|---FR3---
--------FR3-------------------------------------------------
91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
T I S R D N S K N T L Y L Q M
|act|atc|TCT|AGA|gac|aac|tct|aag|aat|act|ctc|tac|ttg|cag|atg|
| XbaI |
---FR3-----------..> Stuffer------------->|
106 107 108 109 110
N S L R A (SEQ ID NO: 53)
|aac|agC|TTA|AGg|gct|TAG TAA AGG cct TAA (SEQ ID NO: 52)
|AflII | StuI...
|----- FR4 ---(JH4)-----------------------------------------
Y F D Y W G Q G T L V T V S S
(SEQ ID NO: 26)
|tat|ttc|gat|tat|tgg|ggt|caa|GGT|ACC|ctG|GTC|ACC|gtc|tct|agt|...
(SEQ ID NO: 25)
| KpnI | | BstEII | | Focused libraries of vectors or genetic packages that display, display and express, or comprise a member of a diverse family of antibody peptides, polypeptides or proteins and collectively display, display and express, or comprise at least a portion of the focused diversity of the family. The libraries have length and sequence diversities that mimic that found in native human antibodies. | 2 |
This is a continuation of application Ser. No. 206,557, filed Nov. 13, 1980, now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to laminar separation methods and apparatus and, more particularly, to new and improved methods and apparatus of this character embodying simple yet highly effective means for supplying and distributing a composite liquid such as a suspension or emulsion uniformly to the respective separation channels in the apparatus.
In conventional laminar separation apparatus, separation of sediment from a suspension or of liquids in an emulsion is accompanied by supplying the suspension or emulsion to a plurality of separation passages formed between a plurality of parallel, spaced apart plates, all inclined with respect to a horizontal plane. In operation, the sediment in the suspension or the heavier liquid in the emulsion sinks downwardly in the separation passages, flows past the lower edges of the plates, and is removed at the bottom of the separation apparatus, while the remaining liquid flows upwardly and is eventually discharged through outlets at the upper ends of the plate passages.
The influent suspension or emulsion is usually supplied to the separation passages via a distributor positioned close to the plates so that the influent supplied therefrom is allowed to flow into the passages between the plates. Preferably, the distributor is positioned laterally of a plate array or between two plate arrays and is provided with side walls, so that the influent is forced downwardly and enters the passages between the plates some distance below the top edges of the latter. The influent enters the distributor via an inlet form above, or preferably laterally.
For a complete utilization of the capacity of the laminar separation apparatus, it is of the utmost importance to obtain an even and uniform distribution of the influent composite liquid to the separation passages. In prior apparatuses, however, it has been difficult to accomplish this result. To begin with, the influent entering the distributor is highly concentrated and also undirected. This tends to overload certain separation passages positioned some distance from the inlet pipe, while other closer as well as more remote separation passages receive too low a load. Load in this respect relates to the amount of suspension or emulsion per unit time flowing into a separation passage. In some cases, certain separation passages do not receive any influent from the distributor; instead only clarified liquid enters the separation passage from the outlet of the distributor. Optimum operation obtains when the influent flow is evenly and uniformly distributed over all of the separation passages.
SUMMARY OF THE INVENTION
According to the invention, an even distribution of the flow of an influent composite liquid to the separation passages of a laminar separation apparatus is secured by decelerating the movement of the influent in the distributing space and deflecting its direction of motion several times before it flows into passages between the plates. This is accomplished by interposing in the flow path a plurality of obstacles or baffles suitably positioned and shaped to decelerate the flow of the influent and change its direction several times, and to divide it into a plurality of smaller flows resulting in dissipation of the kinetic energy of the influent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
For a better understanding of the invention, reference is made to the following detailed description taken with reference to the accompanying drawings, in which:
FIG. 1 is a side view, with the side wall partially broken away, showing a portion of a laminar separation apparatus embodying the invention;
FIG. 2 is an end view, partially broken away, of the laminar separation apparatus of FIG. 1, as viewed from the left in FIG. 1;
FIG. 3 is a view in longitudinal section, taken along the line 3--3 of FIG. 2 and looking in the direction of the arrows;
FIG. 4 illustrates in perspective view one form of flow modifying baffle array according to the invention;
FIGS. 5 and 6 are side views illustrating other forms of flow-modifying baffle arrays according to the invention; and
FIG. 7 is a perspective view illustrating still another form of baffle array according to the invention.
As shown in FIGS. 1, 2 and 3, a respresentative laminar separation apparatus according to the invention has a separation chamber 10 and an outlet portion 11 comprising a funnel-shaped trough 12 into which separated liquid or sediment descends and is pumped out by a conventional pump means 13 as indicated by the arrow 14. Mounted in the separation chamber 10 are a plurality of parallel, spaced apart plates which are inclined to the horizontal and form separate separation passages 16 therebetween. Separation takes place in each separation passage 16, independently of the other separation passages, in such manner that the solid particles in a suspension or the heavier liquids in an emulsion sink to the upper surface of the lower plate in each passage and thereafter slide down therealong to the trough 12. The clarified liquid ascends adjacent to the upper plate in each passage 16, as indicated by the arrows 17 in FIG. 2, and flows out through openings 18 in a horizontal plate 19 at the upper ends of the plates 15 to enter a channel 20 positioned in the upper portion of the laminar separation apparatus. The channel 20 is provided with an outlet opening 21 for discharge (arrow 22) of the clarified liquid from the laminar separation apparatus.
The influent composite liquid such as a suspension or emulsion is supplied (arrow 23) to the laminar separation apparatus via an inlet 24 to a distributor 25 which extends between two plate arrays 26 and 27. A channel 20 is positioned above each plate array and the influent flows laterally into the arrays 26 and 27 as illustrated by the arrows 28.
According to the invention, a plurality of obstacles in the form of plate baffles 29 are positioned in one or more arrays in the distributor 25. In the particular embodiment shown in FIGS. 3 and 4, the baffles are placed in two vertical arrays 30 and 31 that are spaced apart alternately in the flow direction of the influent suspension or emulsion entering through the inlet pipe 24 with the broad side of each baffle facing the flow. In this embodiment, the arrays 30 and 31 are displaced vertically so that the baffles in one array 30 face the gaps between the vertically spaced apart baffles in the other array 31, thus forming a plurality of tortuous passages through which the influent is caused to flow. In this way, the influent flow is decelerated and is divided into a plurality of flow components which change directions several times, as illustrated by the arrows 32 in FIG. 3.
In the modified baffle arrangement shown in the embodiment of FIG. 5, the spacing between the arrays 30 and 31 of flow modifying baffles according to the invention is successively increased in the direction of flow of the influent. This provides more tortuous passages at the inlet end of the distributor 25, assuring greater uniformity of distribution of the influent between the flow passages 16 for certain applications.
If so desired, the baffles 22 can be suitably shaped or oriented to guide selected flow components of the influent in desired directions. As illustrated in the modified baffle arrangement of FIG. 6, the baffles 33 of one array may be in the form of single irons disposed with the apices facing towards the flow, while other arrays may comprise flat baffles 34 and 35 inclined in either direction with respect to the flow.
Alternatively, as shown in FIG. 7, the arrangement of obstacles may comprise an array of plates 36 spaced apart in the influent flow direction and provided with openings 37. To provide the necessary tortuous path for the influent, the openings 37 in successive plates are laterally displaced with respect to the openings 37 in the preceding plate. Also, guide means may be provided for deflecting the flow.
This invention is not limited to the several embodiments described above but is intended to encompass all modifications in form and detail falling within the scope of the following claims. | Arrays of baffles are disposed in apparatus for distributing a composite liquid to the separation passages of a multi-plate laminar separation apparatus to decelerate the influent composite liquid and repeatedly deflect its direction of flow such that it is uniformly distributed to the separation passages in the apparatus. | 1 |
BACKGROUND OF THE INVENTION
This invention relates to electrostatic precipitators.
In conventional precipitators, a half-wave or full-wave transformer provides voltage to the discharge electrodes. This provides both corona charging fields and particle collecting fields. These fields are not independent and are limited to the spark breakdown voltage seen by the precipitators. For high resistivity dust collection, breakdown in the dust layer at the collecting electrodes can happen at very low voltage levels and seriously impede particle charging and collection.
The invention also relates particularly to electrostatic precipitators in which a pulse voltage is applied to the corona discharge electrodes superimposed on top of the DC base voltage.
The invention also relates to multistage precipitators in which a preceding stage may be pulsed to produce the ionization to charge the particles and a succeeding stage may be used to collect the charged particles.
SUMMARY OF THE INVENTION
The present invention is directed toward optimizing a multi-section precipitator so as to overcome the problems of handling difficult dusts and their inherently deficient particle charging and collecting fields.
It has been discovered that very high particle charging can be obtained by superposing very short pulses at very high voltage levels onto the base DC voltage without causing electrical breakdown within the precipitator. Depending on the shortness of pulsation, very high instantaneous ion densities, and possibly high electron densities, are emitted from the discharge electrodes which expand to the collecting electrode as a result of the applied underlying base voltage. By suitable adjustment of such parameters as base voltage, pulse voltage, pulse rise time, pulse width, and pulse repetition rate, very efficient particle charging at adequate particle collecting fields can be obtained.
By adjusting the pulse characteristics in combination with discharge electrode diameters and interelectrode spacing, a very high degree of freedom is obtained with respect to optimizing the charging and collecting fields.
An important feature of the present invention is the ability to vary the charging and collecting fields independently of each other. By superimposing pulse voltages over a base voltage of the same polarity, the pulse characteristics may be varied along with the base voltage, independently of each other, so that each may be adjusted to a level that results in optimum precipitator performance.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic of the multi-section precipitator used in making the laboratory tests.
FIG. 2 is a schematic of the pulser circuit used in the test runs.
FIG. 3 is a schematic illustration of a folded transmission line which may be employed as one of the sections of the multi-section precipitator.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In FIG. 1, dust or other particulate material in a waste gas stream is fed through a perforated plate 13 prior to the inlet section of a multi-section, single duct precipitator. In FIG. 1, there are only three sections shown but preferably there are at least four sections.
In FIG. 1, each section includes a pair of opposing collecting plates 20, spaced about 9" apart. The collecting plates may be of various dimensions. Suspended between a pair of high tension bars 31, and centered between the collecting plates 20 in each section, is a set of nine discharge wire electrodes 30, each as long as the plates. These discharge electrodes are of uniform size and spacing in any one installation but may vary in different installations. In one embodiment of FIG. 1, each discharge wire electrode has a diameter of 0.109 inches and the electrodes are spaced 51/4 inches apart. In another embodiment, each discharge wire electrodes has a diameter of 0.25 inches and the electrodes spaced 31/2 inches apart. The spacing from each electrode to a collecting plate is 4.5 inches.
After passing through the three or more sections of the precipitator illustrated in FIG. 1, the gas exits through the outlet duct 50. Hoppers 40 are provided in each section below the collecting plates 20 for collection of the particles collected on the plates 20.
In some modes of operation, the discharge electrodes 30 in each of the sections are pulsed. In other modes of operation, only the discharge electrodes of the inlet section are pulsed. Where only the inlet section is pulsed, the discharge electrodes of the other sections have DC base voltage applied and these sections function as collecting sections.
In most installations, the configuration of the discharge electrodes will be such that DC and pulse voltages are applied in parallel to the individual electrodes of each section. In some cases, however, it may be advantageous to employ a folded transmission line as the discharge electrode. Such a folded transmission line is illustrated in FIG. 3 of the drawing and will be described later.
The essential feature of the pulser circuit shown in FIG. 2 is the pulsing switch 61 which is a physical gap between the high voltage electrode 62 and the ground electrode 63. For a pulse to be generated, the gap has to break down temporarily, dumping the energy from capacitor 64 into a water load resistance 70, resulting in a pulse voltage. The rate of rise of pulse and its decay are determined by R-C components 66-69. The charging resistor 66 as shown in the circuit determines the frequency of pulses. Separation of the gap determines the voltage at which the gap breaks down and, hence, the pulse voltage. Pulse width is determined by the water load resistance 70, storage capacitance 64, and the capacitance of precipitator load. The coupling capacitor 71 couples the base voltage from DC power supply with the pulse voltage produced by the above means.
To establish optimum operating conditions for the precipitator of FIG. 1, the following variable parameters were studied:
______________________________________Variables Range______________________________________(1) Pulse width: 250-1500 nanoseconds(2) Pulse voltage: 30-80 KVp(3) Pulse frequency: 80-1000 pps(4) Discharge electrode diameters a. 0.109" at 51/4"with interelectrode spacing b. 0.156" at 51/4" c. 0.25" at 31/2" d. 0.50" at 1.75"(5) Gas temperature: 160-320° F.(6) Particle size and concentration: 5 μm mass median diameter, 3-4 grains/scfd(7) Gas Velocity: 4-6 ft/sec(8) Base voltage; 10 KV-50 KV(9) Particle Resistivity: 10.sup.11 -10.sup.13 ohm-cm______________________________________
The observations made included the following:
(1) Pulse Width--Increasing the pulse width from 300 to 1000 nanoseconds was beneficial to precipitator performance. (Only the decay time was subject to variation. The rise time remained substantially steady at about 100 nanoseconds.)
(2) Pulse Voltage--Optimum performance was obtained with the pulser operating at the highest voltage possible for both the 0.25" and 0.109" discharge electrodes. Pulse voltages up to 80 KVp were used. The pulse voltage and width were monitored, as shown in FIG. 2.
(3) Pulse frequency--Increasing the pulse frequency from 100 pps to 200 pps did not have an appreciable effect on precipitator performance when both the pulse voltage and pulse width were kept constant. Increasing the pulse frequency to 1000 pps had a detrimental effect. The base voltage had to be reduced to low levels (about 10 kv) and current densities were difficult to control.
(4) Discharge Electrode Diameters and Interelectrode Spacing--The discharge electrodes were 0.109" diameter at 51/4" spacing and 0.25" diameter at 31/2" spacing. Plate-to-plate spacing was 9".
(5) Gas Temperature--The dust was kept hot prior to injection into the air stream so as to prevent any agglomeration due to moisture. The high resistivity dust tests were at gas temperatures between 280 and 320 F.
(6) Base Voltage--The base voltage during pulse energization does not have to be at its highest presparking level. There is an optimum base voltage depending on resistivity of flyash after which further increase results in deteriorating precipitator performance. For effective pulser operation, the base voltages should be below normal DC breakdown. In cases of very high resistivity, the base voltage may preferably be below the DC corona starting voltage.
(7) Current Densities--For optimum operating conditions, precipitator current densities varied between 5 and 10 milliamperes per thousand square feet of collecting surface. By using high pulse voltages and adjusting the pulse frequency and the base voltage, precipitator currents can be adjusted to operate below back-corona situations.
The Laboratory Tests
FIG. 1 shows the arrangement of the precipitator system used in the laboratory test program. Dust was fed to the system by a weigh feeder in order to accurately control dust loading. The dust was well dispersed in the inlet air stream by means of an ejector-distributor arrangement in the duct. Electric heaters were used to heat the inlet air to its desired operating temperature prior to entraining the dust. Downstream of the dust feed, a low-efficiency mechanical collector was used to remove larger particles and, therefore, present the precipitator with a relatively fine particle size.
In all of the runs, hydrated alumina was used as the high-resistivity dust. Its particle size distribution at the precipitator inlet was characterized by a mean diameter of 4.5 microns and a geometric standard deviation of 2.76. Particulate loading at the precipitator inlet was 3 grains/scfd. Resistivity of the dust was controlled by varying the operating temperature. For the tests reported in this paper the temperature levels were chosen to provide operation at very high resistivity with back-corona limitation, and moderately high resistivity with sparking limitation: at 300° F. the resistivity of the dust was 5×10 12 ohm-cm and at 200° F. the resistivity was 2.5×10 11 ohm-cm.
The precipitator itself was a single-duct precipitator consisting of three energized sections with total collecting plate area of 54 square feet. Each section was 4.5 feet long with an effective flow height of 2 feet. Collecting plate spacing was 9 inches, and discharge electrodes were 0.109 inch shrouded wires spaced 51/4 inches apart. The air velocity in the precipitator was 5 feet/sec for all runs. Thus the specific collection area (SCA) was 120 square feet/1000 acfm.
The precipitator was operated as a two stage precipitator, the inlet section being energized separately from the downstream two sections. During the pulse-energized runs, only the inlet section was pulsed, the downstream sections conventionally energized, serving as the collecting section. Base electrical energization of both sections was provided by 70 kVp full-wave rectified power supplies. Pulses were superimposed on the base voltage in the inlet section from the pulser system.
Prior to the test program outlet particulate concentrations from the precipitator were measured over a range of precipitation efficiencies under the operating conditions described above. These loadings were correlated with optical density as measured at the precipitator outlet using a Lear-Siegler RM4 optical transmissometer. During the test program transmissometer readings were taken and the correlation curve was used to determine the outlet loading during each run for precipitation efficiency calculation.
Table I presents the individual test results achieved during the test program. Results are grouped according to resistivity level and mode of operation (pulsed or conventional), not chronologically. Each of the runs was made at its optimum condition of energization; i.e. for the conventional runs, voltage was set at a value yielding maximum efficiency, and for the pulsed runs, the combination of base voltage, pulse voltage, pulse width, and frequency was set to yield best performance. Thus, the numbers reported in Table I are optimums so that comparison among modes can be made on the basis of best performance. All of the runs are shown to provide an indication of the reproducibility of results.
Table I.__________________________________________________________________________Laboratory data for pulsed vs.conventional energizationMode of Temp. Resistivity Precipitation W w.sub.kOperation (Degrees K) (ohm-cm) Efficiency (%) (m/sec) (m/sec)__________________________________________________________________________Conventional 367 2.5 × 10.sup.11 96.3 .140 .286 98.0 .166 .375 96.3 .140 .286 96.3 .140 .286 95.7 .133 .265 95.3 .129 .253 97.5 .156 .342 97.0 .148 .315Pulsed 367 2.5 × 10.sup.11 98.0 .166 .375 98.0 .166 .375 98.3 .172 .401 97.3 .153 .330 99.7 .246 .707 98.3 .172 .401 98.0 .166 .375 98.0 .166 .375Conventional 422 5 × 10.sup.12 82.7 .0743 .104 82.7 .0743 .104 80.3 .0688 .0920 82.3 .0733 .102 80.0 .0681 .0906 82.7 .0743 .104Pulsed 422 5 × 10.sup.12 95.3 .129 .253 96.0 .136 .275 95.3 .129 .253 94.3 .121 .228__________________________________________________________________________ All runs were conducted with inlet loading = 3 grain/scf and gas velocity = 5 feet/sec. Precipitator electrode geometries were conventional as described. Each test was run at optimum electrical energization.
For each of the cases, Table I shows collection efficiency, Deutsch migration velocity, w, and the modified migration velocity, w k . The modified migration velocity is preferred for use in comparative evaluations of pulsed vs. unpulsed performance because its value in a given case is independent of the efficiency level. The modified efficiency equation is:
1-n=exp [-(w.sub.k A/V).sup.m ] (1)
where
n--collection efficiency, fractional
A=collecting area, m 2
V=volumetric flow rate, m 3 /sec
w k =modified migration velocity, m/sec
m=exponent depending on inlet particle size distribution For the laboratory dust m--0.635.
Examination of Table I shows the expected trends in the data. Precipitator efficiencies for 5×10 12 ohm-cm resistivity level are lower than for the 2.5×10 11 level for both pulsed and conventional operation. However, at each resistivity level the pulsed operation is more efficient than conventional. In order to quantify the improvement in performance attributable to pulsed energization, a single value of w k was calculated for each mode of operation based on the average penetration (1-n) for that mode. A very good quantitative measure of improvement due to pulsing is then the ratio of these w k values at each resistivity level. This is because w k is a direct indicator of the level of precipitator energization. 3 Since the w k ratio represents an enhancement of precipitator energization it is termed the "enhancement factor", H.
Table II shows the effective w k for each operating mode and the enhancement factors at each resistivity level.
__________________________________________________________________________Mode of Temp Resistivity Precipitation w.sub.k EnhancementOperation Degrees K (ohm-cm) Efficiency (%) m/sec Factor__________________________________________________________________________Conventional 96.55 .295 367 2.5 × 10.sup.11 1.33Pulsed 98.20 .392Conventional 81.80 .0993 422 5. 10.sup.12 2.53Pulsed 95.22 .251__________________________________________________________________________
Because of the large number of individual runs involved in Table I and their good reproducibility in each mode of operation, it is felt that the values of the enhancement factor and their difference at the two resistivity levels have very significant meaning. The fact that the level of enhancement of w k increases as resistivity increases supports the previously described concept of the effect of pulsed energization. The poorer the conventional energization, the greater degree of improvement possible by pulsing. It should be noted, however, that although the enhancement factor increases with resistivity, the value of w k for both conventional and pulsed energization decreases. This shows that pulse-energized precipitation as well as conventional is subject to resistivity-caused limitations although the limitation to the pulsed performance is much less severe. This is reasonable based on theory, because, no matter how precipitator energization is achieved, dielectric breakdown of the dust layer will preclude further useful energization. With pulsed energization, however, greater and more uniform ion densities and higher effective field strengths exist when this limit is reached.
It was mentioned previously that only the inlet section of the laboratory precipitator was pulsed. This is consistent with the expectation that pulsed energization acts primarily to enhance particle charge. Thus, the laboratory setup represents a two-stage precipitator in which enhanced charging is accomplished in the inlet section and the downstream sections act primarily as collecting sections. Indeed it was found in a series of laboratory tests that pulsing more than the inlet section results in no significant performance improvement over pulsing only the inlet section. This, however, was not borne out in the full scale tests. See below.
Full Scale Results
Full-scale investigation of pulsed energization was conducted on a Research-Cottrell precipitator following a mechanical collector serving a pulverized coal fired boiler. Each of its two fields was equipped with separate pulsers. Each pulsed field contained a collecting plate area of 8200 ft 2 . Plate spacing was 9 inches and discharge electrodes were 0.109 inch diameter wires spaced 51/2 inches apart. The downstream unpulsed precipitator consisted of two fields each with collecting area of 10800 ft 2 . The total collecting area of the precipitators was therefore 38,000 ft 2 .
In order to characterize pulsed and conventional operation of the precipitator, a full test program was run at the site. During the test program, low-sulfur Eastern Bituminous coal was burned and the boiler was operated steadily at full load. The coal burned during the test program averaged about 1.1% sulfur with 18% ash content. Gas volume flow through the precipitator varied about 110,000 acfm. Data taken during the test program included in-situ resistivity measurements, particle size distributions, velocity traverses, stack opacity readings using a Lear Siegler transmissometer, precipitator outlet loadings, mechanical collector inlet loadings, and all electrical and boiler operating data. Coal and ash samples were collected during each run. Due to unacceptable flow patterns between the mechanical collector outlet and precipitator inlet it was not possible to measure directly the precipitator inlet loading and size distribution. However, by applying the mechanical collector performance curves to the measured mechanical collector inlet data it was possible to calculate the loading and particle size distribution to the precipitator for purposes of isolating precipitator performance. The size distribution of the ash to the inlet of the precipitator was found to be characterized by a mean diameter of 2.2 microns with a geometric standard deviation of 2.2.
Operation of the precipitator during the test program was typical of the moderately-high resistivity limitation characterized by heavy sparking at very low current levels resulting in poor energization. The in-situ resistivity measurements were compatible with this type of operation. They ranged from 1×10 11 to 9×10 11 ohm-cm, averaging about 5×10 11 ohm-cm.
All of the runs made during the test program were at optimum levels of operation for the mode being tested, i.e. both pulsed and unpulsed operations were set to yield maximum collection efficiency. Pulser variables in all runs were set at levels previously determined to be optimum.
Because it was possible to pulse each of the two inlet fields independently, four modes of operation were tested;
(1) All fields energized conventionally.
(2) Inlet field (A) pulsed, others conventional.
(3) Second field (B) pulsed, others conventional.
(4) Both inlet fields (A+B) pulsed, others conventional.
Table III presents data for runs made during the test program. The data are grouped by the mode of operation as described above, not chronologically. As with the laboratory data, precipitator efficiency, w, and w k are reported for each run. In addition, the average stack opacity and specific collection area for each run are reported; variations in SCA were due to fluctuations in gas volume. Finally the enhancement factor, H, is reported for each pulsed run. It is based on the average value of w k of 0.0805 for the unpulsed runs.
Table III.__________________________________________________________________________Full-scale precipitator data for pulsed vs.conventional energization.Fields SCA Precipitator Stack w w.sub.kPulsed (ft.sup.2 /1000 acfm) Efficiency (%) Opacity (%) (m/sec) (m/sec) H__________________________________________________________________________None 341 93.84 25.9 .0415 .0768 --None 369 95.70 25.6 .0433 .0861 --None 351 94.58 26.7 .0422 .0802 --A 340 95.29 23.7 .0457 .0893 1.11A 329 98.28 15.6 .0627 .145 1.80A 339 96.05 21.5 .0484 .0978 1.21B 349 95.35 22.8 .0447 .0876 1.09B 371 95.56 20.8 .0426 .0842 1.05A + B 337 16.3 .0578 .129 1.60A+ B 355 97.99 17.0 .0559 .127 1.58A + B 371 98.24 16.3 .0553 .128 1.59A + B 371 97.17 16.7 .0488 .105 1.30__________________________________________________________________________
For the particle size distribution determined at the inlet to the precipitator, the exponent, m, in the modified Deutsch efficiency equation is essentially the same as found for the laboratory dust, i.e. 0.625. The actual levels of w and w k are lower for the full-scale tests than for the corresponding laboratory tests. This is a normally expected difference.
Examination of the data in Table III shows consistent improvement in performance creditable to pulsed energization. The best improvement occurred in those runs in which both fields A and B were pulsed; the average enhancement factor for these four runs was 1.5. Pulsing either field A alone or B alone also improved performance in every run but not to the same extent as A and B together.
While the test program was being conducted it was very obvious, just by observing the stack, that the pulsed modes of operation were improving the precipitator performance. Plotting stack opacity vs. number of sections pulsed shows the benefits in going from zero to one to two pulsed fields in the precipitator. In fact, the plot appears to indicate that further significant benefits can be realized by pulsing additional fields.
The improvement in going from one to two pulsed fields is shown both in the enhancement factors in Table III and in the opacity reduction. This appears to contradict the laboratory results which showed essentially no additional improvement in pulsing more than one section. The explanation for this probably lies in the fact that the full scale operation is limited at a lower level of energization than the laboratory, for both pulsed and unpulsed operation. It is, therefore, reasonable to expect that a greater pulsed precipitator length is necessary in the full-scale application to accomodate the benefits of enhanced energization. In fact, it may further be expected that enhancement factors greater than those measured in the laboratory are possible in this situation because of the very low energization basis of conventional operation. This is indicated by the data in Table III.
Laboratory and full-scale tests have confirmed that the pulsed energization system significantly enhances precipitator performance for the collection of high resistivity dust. Laboratory data showed enhancement factors in the range of 1.33 to 2.53 for moderately high to very high resistivity; field data for a moderately high resistivity ash showed the ratio to be 1.5.
The improvement noted above may possibly be explained by the following hypothesis: The pulse voltage is essentially responsible for corona generation. Ions and electrons are generated during the rising portion of pulse voltage. The greater the peak voltage, greater will be the ions generated. Also, peak currents produced during the pulse will be orders of magnitude higher than the average current on the collecting plates. It is believed that extremely high ion densities are realized due to the pulse. These ions mutually repel each other during the pulseless period and expand towards the collecting plates under the field due to base voltage. It is felt that particle charging takes place during the time between pulses, in the presence of very high ion concentration and the field due to base voltage. It is also hypothized that the ionic space charge field further enhances the charging process. Also, the nature of corona during pulse energization is significantly different from that under conventional methods. Pulsed corona is very uniform and well distributed along discharge wires while the corona under conventional methods is spotty and randomly changes locations along the wire. Further, the radius of corona glow during pulsed energization is much larger than the conventional corona glow radius. Thus, pulsed corona is more likely to result in improved corona current distribution in the precipitators.
In summary, the extremely high instantaneous ion densities, high ionic space charge and the uniformity of corona current distribution will act together during pulse energization to result in particle charge magnitude superior to those found in conventional energization methods.
Conclusions
(a) Effect of Pulse Voltage
It is concluded that increased pulse voltages result in higher field strengths and lead to better particle charging during each pulse. It is likely that the ion density per pulse is also higher. Thus, pulse voltages should be increased as much as possible for a precipitator configuration so as to maximize particle charging. Increasing the pulse voltage does not increase the average current significantly.
(b) Effect of Pulse Frequency
For a given pulse voltage, the ion density per second can be increased in almost linear proportion by increasing the frequency of the pulses. This leads to higher average current. Since average current on the plates is crucial for the onset of back-corona for high resistivity dusts, pulse frequency should be carefully controlled to keep the average current always under the critical current density required to trigger back-corona.
(c) Effect of Pulse Width
The pulse width is composed of pulse rise time and pulse decay time. It is believed that pulse rise time is responsible for ion and electron generation, while pulse decay time can provide high field strength conditions for particle charging. The shorter the pulse rise time, the higher can be the precipitator sparking voltage and hence higher particle charging. Increase in pulse decay time can also increase particle charging, in that particles can get charged under a longer period of high field strength. However, there is a limit for increasing the pulse decay time. Longer decay time approximates DC operation and hence lower sparking voltages will result. Increasing the rise time, will also lead to the same result and will not be effective for charging.
(d) Effect of Base Voltage
The base voltage should be operated below normal breakdown voltage (possibly below corona starting voltage) for high resistivity dust collection. It is known that DC corona is a non-uniform corona discharge and, hence, for high resistivity application back-corona could be triggered by the combination of DC corona and pulses. It is believed that the base voltage will perform the particle collection function and help in rapid expansion of the pulse generated ion-cloud to the collection plate, leading to a uniform current distribution.
(e) Optimizing Precipitator Performance
On the basis of the foregoing, a precipitator may be optimized by using suitable discharge and collecting electrode configurations that will increase the DC corona starting voltage so as to operate at higher collecting fields. The precipitator should be operated with the base voltage near or below the corona starting voltage. The pulse voltage should be increased to the highest practically feasible value. Pulse width and frequency should then be adjusted for a given precipitator to operate at its optimum performance.
For particles of moderate resistivity, it will be possible to make use of the pulsed energization concept by increasing the base voltage to values higher than its corona-starting voltage since back-corona will not be a problem. The pulse voltage could then be adjusted, along with the pulse frequency and pulse width, to optimize the precipitator performance.
It was previously mentioned that in most installations where precipitator has multiple ducts, the discharge electrodes will be connected in parallel, but that in some cases a folded transmission line may be used as the discharge electrodes. Such a folded transmission line is illustrated in FIGS. 3.
In FIG. 3, four collecting plates 21-24 are seen forming a lane for gas flow between each pair of collecting plates. The four plates 21-24 seen in FIG. 3 are merely illustrative of a larger number of plates and a larger number of lanes which might be employed. Suspended in each lane between the collecting plates 21-24 are discharge wire electrodes 32-35. The gas flow is in the direction indicated by the arrow in FIG. 3. Thus, the gas flow is parallel to the sidewalls of the collecting plates and transverse to the discharge electrodes 32-35. Each of the corresponding discharge wire electrodes in each lane are tied together, either at the bottom or at the top, to form a continuous folded transmission line, as illustrated in FIG. 3. A pulse input applied at 36 will be transmitted to all the discharge electrodes as in a folded transmission line. The advantage of the use of a transmission line for the transfer of pulse voltage is that the pulse voltage may be less affected by precipitator capacitance and hence less affected by the size of the precipitator. Thus, it may be easier to control the wave shape of the pulse. | Parameters for optimum operation of a pulsed multisection electrostatic precipitator are disclosed: It has been discovered that superior particulate collection can be achieved by a combination of pulse and conventional DC voltages. The pulse rise time and decay time are made short enough so that adverse sparking conditions do not develop. The base voltage (conventional DC voltage) is adjusted in coordination with the superposed pulse characteristics (pulse voltage, pulse frequency and pulse shape) to maintain an average current through the collected dust layer just below or at that value which would cause electrical breakdown of the dust layer. Base voltage may actually be below normal corona starting voltage in some cases. The pulse produces instanteously very high ion densities and electric field strengths. In one design of precipitator, alternate sections are pulsed, with the other alternate sections functioning as collecting sections and merely having DC base voltage applied thereto. In other designs, all sections including the collecting sections, may be pulsed to provide sufficient current to hold the collected particles on the collecting surfaces and to prevent reentrainment. In some designs, at least one of the sections may be a transmission line which is pulsed. | 1 |
[0001] This application claims the benefit of Chinese Patent Application No. 200710164139.x, titled “Motor torque management method for hybrid vehicle”, filed with the China Patent Office on Sep. 30, 2007, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of hybrid vehicle control, and in particular, to a motor torque management method for hybrid vehicles.
BACKGROUND OF THE INVENTION
[0003] Energy crisis and environmental pollution have become great bottlenecks to global economy development. Energy-saving and environment friendly vehicles provide a good way to release energy pressure and reduce environmental pollution. Hybrid vehicles have the advantages of both internal-combustion engine vehicles and pure electric vehicles, such as low gasoline consumption, less emissions and long mileage, and therefore would be a feasible solution to energy crisis and environmental pollution.
[0004] Parallel hybrid vehicles have two power sources, an engine and a motor. A Hybrid Control Unit (HCU) determines a working mode based on a current operation state of the vehicle, and sends a power request and a mode request to the engine and the motor, respectively. Control units of the engine and the motor control respective power sources according to an instruction of the HCU, to meet requirements of the whole vehicle.
[0005] When the hybrid vehicle sends a torque request for auxiliary driving, electricity generating or regenerative braking, the HCU limits the torque request according to the status of the motor, battery and engine. If more than two of the torque requests above are present, the HCU is to arbitrate the torque requests, then send a torque request to the motor. Therefore, how to limit the torque requests and whether torque arbitration mechanism is suitable will affect performance of the hybrid vehicle.
SUMMARY OF THE INVENTION
[0006] The present invention proposes a priority based motor torque management method, especially suitable for coaxial parallel moderate hybrid vehicles, thereby realizing the management of a plurality of torque request sources.
[0007] The invention includes: electric mode torque synthesis and limitation, electricity generating mode torque synthesis and limitation, torque arbitration management, etc.
[0008] 1. An electric mode torque request is a toque request for the motor to work in an electric mode, and in the present invention, this type of torque requests include auxiliary driving torque requests and battery warming-up torque (Bw_MotTq) requests. Auxiliary driving torque requests include driving torque requests aiming for fulfilling vehicle power performance (Mp) and driving torque requests aiming for improving vehicle efficiency (Me). Both the battery warming-up torque request and the driving torque request aiming for efficiency are to improve vehicle efficiency, and therefore the larger one of these two is selected to be an efficiency electric torque request (Me_Merge).
[0009] If one or more of the torque requests above are present, in order to prevent the motor from being damaged by a requested torque that is too large or too small, the HCU limits the electric toque requests within a proper range according to conditions such as peak torque allowed by the motor and maximum allowed torque in continuous operation, thereby getting an efficiency electric torque limit (Me_Limit) and a performance electric torque limit (Mp_Limit).
[0010] 2. An electricity generating mode torque request is a torque request for the motor to work in an electricity generating mode, and in this invention, this type of torque requests include electricity generating requests in the event that the State of Charge (SOC) of the battery is low, regenerative braking torque requests (Regen), battery warming-up torque requests (Bw_GenTq) and engine warming-up torque requests (Ew_GenTq).
[0011] When the battery or the engine needs to be warmed up, or the battery requires charging, the engine may have to provide all or part of the electricity generating torque, therefore the smallest one of Gen, Bw_GenTq and Ew_GenTq is selected to be a synthesized electricity generating torque Gen_Syn.
[0012] When the torque requests above are present, the motor have to work in an electricity generating state, and the requested torque has a negative value. In order to limit the motor electricity generating torque in a proper range, the HCU limits the electricity generating torque according to the minimum continuous torque allowed by the motor, thereby getting a regenerative braking toque limit (Regen_Limit) and an electricity generating torque limit (Gen_Limit).
[0013] 3. Torque arbitration management: when a plurality of torque requests are present, the HCU arbitrates according to priorities of the torque requests, and makes a torque having the highest priority a current torque request. Torques in the order of their priorities from highest to lowest are: Mp_Limit, Regen_Limit, Gen_Limit and Me_Limit. As can be seen from the priorities, auxiliary driving aiming for fulfilling vehicle power performance has the highest priority, the regenerative braking torque request is lower, then goes the electricity generating torque request, and finally auxiliary driving aiming for efficiency.
[0014] If a plurality of torque request sources are present, the HCU determines according to the priorities above, responds to the torque request with the highest priority, and then sends a torque request to the engine and motor control modules, respectively.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a mechanical connection diagram of the invention;
[0016] FIG. 2 is a structural diagram of the control principle of the invention;
[0017] FIG. 3A is a flow chart A for electric mode torque synthesis and limitation;
[0018] FIG. 3B is a flow chart B for electric mode torque synthesis and limitation;
[0019] FIG. 4 is a flow chart for electricity generating mode torque synthesis and limitation; and
[0020] FIG. 5 is a flow chart for torque arbitration.
DETAILED DESCRIPTION OF THE INVENTION
[0021] As shown in FIG. 1 , the hybrid vehicle is a uniaxial parallel hybrid vehicle, an engine 1 and a motor 2 are coaxially arranged, and the motor 2 is an ISG (Integrated Starter Generator) motor with integrated electricity generating and electric functions. The power system of the hybrid vehicle uses three control units: a Hybrid Control Unit (HCU) 3 , an Engine Management System (EMS) 4 and a Motor Control Unit (MCU) 5 . The three control units are responsible for controlling the vehicle, the engine and the motor, respectively.
[0022] The ISG may work in a torque mode, a speed mode and a zero torque mode. The torque mode is a working mode aiming for fulfilling torque requests of the HCU. In the invention, when the motor works in the torque mode, the motor has the functions of: auxiliary driving (Mp, Me), electricity generating (Gen) and regenerative braking (Regen).
[0023] FIG. 2 illustrates a structural diagram of torque management performed by the HCU according to the invention. The implementation method is described below. The HCU determines torque requests of the system based on e.g. a vehicle state, or a driver requirement, and identifies the torque requests as electric mode torque requests and electricity generating mode torque requests, then synthesizes and limits the requested torques, so as to make sure that each of the torque requests is within a proper range, next, arbitrates the torques based on set priorities, and sends a torque request with the highest priority to the motor control module after smoothing, thereby obtaining the required torque.
[0024] 1. Electric Mode Torque Synthesis and Limitation
[0025] Electric mode torque requests are toque requests for the motor to work in an electric mode, and in the present invention, this type of torque requests include auxiliary driving torque requests and battery warming-up torque (Bw_MotTq) requests. Auxiliary driving torque requests include driving torque requests aiming for fulfilling vehicle power performance (Mp) and driving torque requests aiming for improving vehicle efficiency (Me). Both the battery warming-up torque request and the driving torque request aiming for efficiency are to improve vehicle efficiency, and therefore the larger one of these two is selected to be an efficiency electric torque request (Me_Merge).
[0026] If one or more of the torque requests above are present, in order to prevent the motor from being damaged by a requested torque that is too large or too small, the HCU limits the electric toque requests within a proper range according to conditions such as peak torque allowed by the motor and maximum allowed torque in continuous operation, thereby getting an efficiency electric torque limit (Me_Limit) and a performance electric torque limit (Mp_Limit).
[0027] The torque synthesis and limitation process in the electric mode is shown in FIGS. 3A and 3B . Step 1 to step 4 illustrate the synthesis processes for Me and Bw_MotTq torques. If there is an Me request or the battery needs to be warmed up, the efficiency electric torque flag (me_flag) is set to be 1, and the larger one of the two torques is selected to be a synthesized efficiency electric torque me_merge. Step 5 -step 7 illustrate the process for determining whether there is an Mp request affecting synthesized torques mp_syn and me_syn. Step 8 -step 16 illustrate the process for limiting mp_syn and obtaining a performance torque limit mp_limit. The limitation process is described below. First, determine whether an initial value of the performance toque limit mp_init_limit is smaller than the maximum continuous torque (cont_max) that the motor can provide currently (S 10 ); and if it is not smaller than the maximum continuous torque of the motor, go to step 12 . In step 12 , determine whether mp_syn is smaller than the peak toque of the motor (peak_torque); and if so, set mp_limit to be mp_init_limit (step 15 ); if not, i.e., mp_syn is larger than the maximum torque that the motor can provide, then set the requested torque to be the peak torque of the motor (step 16 ). If it is true in step 10 , further determine whether mp_syn is larger than the maximum continuous torque of the motor (step 11 ); and if it is not larger than the maximum continuous torque of the motor, set mp_limit to be mp_syn (step 14 ); and if it is larger than the maximum continuous torque of the motor, limit mp_limit to be the maximum continuous torque of the motor (step 13 ). By the process above, the synthesized performance electric torque is limited within the range between the continuous torque and the peak torque of the motor.
[0028] Step 16 and step 17 illustrates the processes for limiting the torque Me, by which the requested value of Me is limited between a set minimum value and the maximum continuous operating torque of the motor.
[0029] 2. Electricity Generating Mode Torque Synthesis and Limitation
[0030] Electricity generating mode torque requests are torque requests for the motor to work in an electricity generating mode, and in this invention, this type of torque requests include electricity generating requests in the event that the State of Charge (SOC) of the battery is low, regenerative braking torque requests (Regen), battery warming-up torque requests (Bw_GenTq) and engine warming-up torque requests (Ew_GenTq).
[0031] When the battery or the engine needs to be warmed up, or the battery requires charging, the engine may have to provide all or part of the electricity generating torque, therefore the smallest one of Gen, Bw_GenTq and Ew_GenTq is selected to be a synthesized electricity generating torque Gen_Syn.
[0032] When the torque requests above are present, the motor have to work in an electricity generating state, and the requested torque has a negative value. In order to limit the motor electricity generating torque in a proper range, the HCU limits the electricity generating torque according to the minimum continuous torque allowed by the motor, thereby getting a regenerative braking toque limit (Regen_Limit) and an electricity generating torque limit (Gen_Limit).
[0033] FIG. 4 shows the torque synthesis and limitation process in the electricity generating mode. Step 18 -step 21 illustrate the processing of a regenerative braking torque, and when there is a regenerative braking torque request, a corresponding flag (regen_flag) is set to be 1 (true), and the requested braking torque can not be smaller than the minimum continuous operating torque of the motor (step 21 ).
[0034] Step 22 -step 35 illustrates the processing of the electricity generating torque. The process is described below. When one of the conditions for battery warming-up electricity generating requests, engine warming-up requests and battery charging requests is met, set the synthesized electricity generating request flag to be 1 (step 26 ), and select the smallest one the three toques to be the electricity generating torque request (step 27 ). Step 29 shows that the electricity generating torque can not be smaller than the minimum continuous operating torque of the motor. In step 30 , an acceptable electricity generating torque for the engine is obtained by looking up a rotation speed table of the current motor. Step 31 shows that the electricity generating torque can not exceed the acceptable range for the engine under the current rotation speed. The electricity generating request is that, the torque that the engine has to provide equals the total electricity generating requested torque minus the torque that regenerative brake provides. Step 33 -step 35 show that if the electricity generating requested torque is larger than a set minimum value (note that electricity generating torques have a negative value), the electricity generating torque is set to be zero.
[0035] 3. Torque Arbitration Management
[0036] When a plurality of torque requests are present, the HCU arbitrates according to priorities of the torque requests, and makes a torque with the highest priority a current torque request. Torques in the order of their priorities from highest to lowest are: Mp_Limit, Regen_Limit, Gen_Limit and Me_Limit. As can be seen from the priorities, auxiliary driving aiming for fulfilling vehicle power performance has the highest priority, the regenerative braking torque request is lower, then goes the electricity generating torque request, and finally auxiliary driving aiming for efficiency.
[0037] If a plurality of torque request sources are present, the HCU determines according to the priorities above, responds to the torque request with the highest priority, and then sends a torque request to the engine and motor control modules, respectively.
[0038] FIG. 5 illustrates the arbitration process of the torques after synthesis and limitation. First, determine the request Mp having the highest priority; and if Mp_flag is 1 (true), set the torque request value of the motor (ISG_reqTqSyn) to be mp_limit (step 41 ); if there is no Mp request, determine whether there is a regenerative braking torque request (regen_flag), and if there is and the requested torque is smaller than the electricity generating requested torque, set the torque request sent to the motor to be regen_limit (step 42 ); if there is no regenerative braking torque request, determine whether there is a electricity generating request (gen_flag), and if so, set ISG_reqTqSyn to be gen_limit (step 43 ); if there is no electricity generating torque request, determine whether there is an Me request, and if so, set ISG_reqTqSyn to be me_limit (step 44 ); if there is no Me request, set ISG_reqTqSyn to be zero. After the torque request to be sent to the ISG is calculated, smoothing of the torque is performed (S 45 ).
[0039] The torque request after torque arbitration and smoothing is sent to the ISG in the end, to fulfill torque requirements of the HCU, and thereby realizing various torque working modes of the hybrid vehicle in the invention. | A motor torque management method of hybrid vehicles. The method includes torque synthesis and limitation in electric driving mode, torque synthesis and limitation in electricity generating mode, and torque arbitrating management. Wherein, the torque arbitrating management arbitrates torque according to its priority, and sends the torque request with the highest priority to a motor controller ( 5 ). | 1 |
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the priority of German Patent Application, Serial No. 102 13 977.6, filed Mar. 28, 2002, pursuant to 35 U.S.C. 119(a)-(d), the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a method of making formed bodies containing active ingredients. Examples of such formed bodies include tablets or pills in the pharmaceutical and cosmetic fields, so-called “carbonation tablets” for making beverages or also pellets in the chemical or detergent industries for producing cleaning solutions.
[0003] The manufacture of tablets typically involves the production of a plate or a band of tablet material and subsequently punching out cylindrical tablets therefrom. Residue material, so-called pressed screen, has to be reshaped subsequently, which poses a problem, especially when sensitive active ingredients are involved, or the residue material has to be properly disposed of. Thus, conventional processes involve a two step process, namely the manufacture of a semi-finished product (band, plate) and the formation of the end product.
[0004] It would therefore be desirable and advantageous to provide an improved method of making formed bodies containing active ingredients, which obviates prior art shortcomings.
SUMMARY OF THE INVENTION
[0005] According to one aspect of the present invention, a method of making formed bodies with active ingredients, in particular for the pharmaceutical and chemical fields, includes the steps of mixing and advancing active ingredients and optional additives, in a screw and cylinder unit; injecting resultant material into a closed mold cavity of a molding tool; and forming the material in the molding tool.
[0006] The present invention resolves prior art problems by employing an injection molding process to make formed bodies which contain active ingredients. The injection molding process is generally known from plastics processing. Hereby, a plastic material is plasticized by a screw and advanced for subsequent injection under pressure into a mold cavity of a mold. These steps may be realized in separate units, i.e. an extruder and an injection unit or in a single aggregate in which the screw combines plasticizing and injection functions.
[0007] According to another aspect of the present invention, an injection mold assembly for making formed bodies with active ingredients, includes a screw and cylinder unit having a feed unit for supply of active ingredients and optional additives, with the screw and cylinder unit mixing the active ingredients and optional additives to form a resultant material and advancing the resultant material, and a molding tool having at least one mold cavity, in which the material is injected for subsequent injection molding of a formed body.
[0008] According to another feature of the present invention, the screw and cylinder unit is constructed to include an extruder, e.g., a twin-screw extruder, which gently mixes and advances even sensitive materials. Of course, it is also possible to add sensitive active ingredients in controlled doses at a more downstream location into the extruder. The retention time of the active ingredients while under thermal stress and intense shearing stress is hereby significantly decreased. When two injection units are employed, such an extruder is able to operate continuously in a cost-efficient manner to produce formed bodies with constant quality. A high throughput may be implemented, when providing a molding tool with several mold cavities for simultaneously injection-molding a number of formed bodies.
BRIEF DESCRIPTION OF THE DRAWING
[0009] Other features and advantages of the present invention will be more readily apparent upon reading the following description of currently preferred exemplified embodiments of the invention with reference to the accompanying drawing, in which:
[0010] [0010]FIG. 1 shows a schematic illustration of one embodiment of an injection molding machine for making formed bodies with active ingredient in accordance with the present invention;
[0011] [0011]FIG. 2 is a cutaway view of the injection molding machine of FIG. 1; and
[0012] [0012]FIG. 3 shows a schematic illustration of a single-screw extruder for use in an injection molding machine for making formed bodies with active ingredient in accordance with the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0013] Throughout all the Figures, same or corresponding elements are generally indicated by same reference numerals. These depicted embodiments are to be understood as illustrative of the invention and not as limiting in any way.
[0014] Turning now to the drawing, and in particular to FIG. 1, there is shown a schematic illustration of an injection molding machine for making formed bodies with active ingredient in accordance with the present invention, including a screw and cylinder unit in the form of a twin-screw extruder having a cylinder 10 and two screws 12 , 14 accommodated in the cylinder 10 and operated by a motor M. The screws 12 , 14 rotate in a same direction. Active ingredients and optional additives, fillers and binding agents are continuously introduced into the cylinder 10 via a feed unit 15 (FIG. 2) and mixed in the extruder, as the screws 12 , 14 rotate, and at the same time advanced by the rotation of the screws 12 , 14 into the direction of an outlet channel 16 . If desired, it is also possible to add more sensitive active ingredients in controlled doses at a more downstream zone into the cylinder 10 of the extruder, as indicated by reference numeral 15 a and shown in FIG. 2.
[0015] The outlet channel 16 connects to a three-way valve 40 by which the material flow is either routed via a passageway 46 to a first injection unit 20 for accumulation of material in an interior space 24 of the injection cylinder of the injection unit 20 , or via a passageway 48 to a second injection unit 30 for accumulation of material in an interior space 34 of the injection cylinder of the injection unit 30 . After either one of the injection units 20 , 30 is filled, in the operating stage shown in FIG. 1, the injection cylinder of the injection unit 30 , a ram 36 is activated to move forward to thereby force the material in the interior space 34 via injection ducts 44 to an injection nozzle 46 and subsequently into the molding tool. Likewise, when the injection cylinder of the injection unit 20 is filled, a ram 26 is activated to move forward to thereby feed the material in the interior space 24 via injection ducts 42 to the injection nozzle 46 for subsequent injection into the molding tool.
[0016] The molding tool has a first half-mold 54 , mounted on a fixed platen 50 , and a second half-mold 55 , mounted on a moving platen 50 , whereby each of the half-molds 54 , 55 is provided with a plurality of mold cavities 56 for formation of formed bodies. During injection, the half-mold 54 , 55 are clamped together to close the mold cavities 56 , and material is routed from the injection nozzle 46 via a manifold 58 , provided in the fixed platen 50 , to the mold cavities 56 . After conclusion of the injection molding process, the half-molds 54 , 55 are moved apart to open for removal or expulsion of finished formed bodies 60 from the molding tool.
[0017] The injection units 20 , 30 are operated alternately, i.e. while the injection cylinder of one injection unit 20 , 30 is filled with material, the other injection unit 20 , 30 executes an injection process. As a consequence, a continuous operation of the twin-screw extruder can be realized with high material throughput.
[0018] Of course, instead of a twin-screw extruder, as shown in FIG. 1, it is also possible to use a single-screw extruder, shown in more detail in FIG. 3 and generally designated by reference numeral 11 . Parts corresponding with those in FIG. 1 are denoted by identical reference numerals and not explained again. The single-screw extruder 11 includes a single screw 13 which not only assumes the functions of mixing and advancing the active ingredient but assumes also the injection function of material into the molding tool.
[0019] While the invention has been illustrated and described in connection with currently preferred embodiments shown and described in detail, 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. The embodiments were chosen and described in order to best explain the principles of the invention and practical application to thereby enable a person skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. | In a method of making formed bodies with active ingredients, in particular for the pharmaceutical and chemical fields, active ingredients and optional additives are mixed and advanced in a screw and cylinder unit. The resultant material is then injected into a closed mold cavity of a molding tool and injection-molded in the molding tool to finished formed bodies. | 1 |
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